Irritable bowel syndrome pathophysiology: Difference between revisions

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{{Irritable bowel syndrome}}
{{Irritable bowel syndrome}}


{{CMG}}; {{AE}}  
{{CMG}}; {{AE}} {{Cherry}}
==Overview==
==Overview==
The exact pathogenesis of Irritable bowel syndrome (IBS) is not fully understood.


It is believed to be caused by the complex interaction of various factors such as gastrointestinal motor abnormalities, CNS dysregulation, visceral hypersensitivity, immune activation, mucosal inflammation of the GI tract, altered gut microflora and abnormal serotonin pathways.
[[Irritable bowel syndrome|Irritable Bowel Syndrome]] is caused by a complex interaction of various factors such as intrinsic [[Gastrointestinal tract|gastrointestinal]] factors, [[CNS]] dysregulation and [[psychosocial]] factors, genetic, and environmental factors. Intrinsic gastrointestinal factors include [[Motor skill|motor]] abnormalities, [[Viscus|visceral]] [[hypersensitivity]], [[Immunity (medical)|immune]] activation, [[Mucous membrane|mucosal]] inflammation, altered [[Gut flora|gut microbiota]], and abnormal [[serotonin]] pathways. [[Viscus|Visceral]] [[hypersensitivity]] refers to a decreased threshold for the perception of [[Viscus|visceral]] stimuli that affects [[Spinal cord|spinal]] excitability, [[brain stem]] and [[Cortical area|cortical]] modulation, activation of specific [[Gastrointestinal tract|gastrointestinal]] mediators, and recruitment of peripheral silent [[Nociceptor|nociceptors]]. [[Immunity (medical)|Immune]] activation and [[Mucous membrane|mucosal]] inflammation involves an interaction of [[Lymphocyte|lymphocytes]], [[Mast cell|mast cells]], and [[Cytokines|proinflammatory cytokines]]. Environmental factors encompass dietary changes and [[Infection|infections]]. [[Psychosocial]] factors such as [[Stress (medicine)|stress]], [[anxiety]], and [[depression]] directly shape adult connectivity in the executive control network consisting of structures such as the [[Insular cortex|insula]], anterior [[cingulate cortex]], and the [[thalamus]]. Semipermanent or permanent changes in complex [[Nervous system|neural]] circuits lead to central pain amplification contributing to [[abdominal pain]] in [[Irritable bowel syndrome|IBS]] patients. The dorsolateral [[prefrontal cortex]] activity (responsible for vigilance and alertness of the human brain) and the mid-[[Cingulate cortex|cingulate corte]]<nowiki/>x (engaged in attention pathways and responses) is reduced in [[Irritable bowel syndrome|IBS]] patients. This reduction may lead to alterations in the subjective sensations of pain. Genetic factors also play a role in [[Irritable bowel syndrome|IBS]]. IBS has a high twin [[Concordance (genetics)|concordance]] and familial aggregation. IBS is associated with [[single nucleotide polymorphisms]] ([[Single nucleotide polymorphism|SNPs]]) in genes involved in [[Immunity (medical)|immune]] activation, [[neuropeptide]] hormone function, [[oxidative stress]], [[Pain and nociception|nociception]], [[permeability]] of the GI tract, host-[[Microbiome|microbiota]] interaction, inflammation, and [[Tumor necrosis factors|TNF]] activity.  


==Pathophysiology==
==Pathophysiology==


===Pathogenesis===
===Pathogenesis===
The exact pathogenesis of irritable bowel syndrome (IBS) is uncertain. It is understood that IBS is caused by the complex interaction of various factors:
IBS occurs as a result of an interplay between four main factors:
*'''Gastrointestinal motor abnormalities'''
{{Family tree/start}}
**IBS is referred to as ‘[[spastic colon]]’ due to changes in [[Colon (anatomy)|colonic]] motor function. Gastrointestinal motor abnormalities contribute significantly to the pathophysiology of IBS. Manometry recordings from the [[Transverse colon|transverse]], [[Descending colon|descending]] and [[sigmoid colon]] have shown that IBS leads to changed patterns of [[Colon (anatomy)|colonic]] and [[Small intestine|small intestinal]] motor function, such as increased frequency and irregularity of luminal contractions.<ref name="pmid8789897">{{cite journal |vauthors=Schmidt T, Hackelsberger N, Widmer R, Meisel C, Pfeiffer A, Kaess H |title=Ambulatory 24-hour jejunal motility in diarrhea-predominant irritable bowel syndrome |journal=Scand. J. Gastroenterol. |volume=31 |issue=6 |pages=581–9 |year=1996 |pmid=8789897 |doi= |url=}}</ref><ref name="pmid2865504">{{cite journal |vauthors=Kumar D, Wingate DL |title=The irritable bowel syndrome: a paroxysmal motor disorder |journal=Lancet |volume=2 |issue=8462 |pages=973–7 |year=1985 |pmid=2865504 |doi= |url=}}</ref><ref name="pmid11215731">{{cite journal |vauthors=Simrén M, Castedal M, Svedlund J, Abrahamsson H, Björnsson E |title=Abnormal propagation pattern of duodenal pressure waves in the irritable bowel syndrome (IBS) [correction of (IBD)] |journal=Dig. Dis. Sci. |volume=45 |issue=11 |pages=2151–61 |year=2000 |pmid=11215731 |doi= |url=}}</ref>
**[[Diarrhea]]-prone IBS patients have increased responses to ingestion, [[Corticotropin-releasing hormone|CRH]] (corticotropin releasing hormone), CCK (cholecystokinin), and present with abdominal discomfort with accelerated transit through the [[Colon (anatomy)|colon]]. It has been observed that the peak amplitude of high-amplitude propagating contractions (HAPCs) in [[diarrhea]]-prone IBS patients is higher, compared to healthy subjects. Moreover, more than 90% of HAPCs are associated with IBS related abdominal pain.<ref name="pmid11374689">{{cite journal |vauthors=Chey WY, Jin HO, Lee MH, Sun SW, Lee KY |title=Colonic motility abnormality in patients with irritable bowel syndrome exhibiting abdominal pain and diarrhea |journal=Am. J. Gastroenterol. |volume=96 |issue=5 |pages=1499–506 |year=2001 |pmid=11374689 |doi=10.1111/j.1572-0241.2001.03804.x |url=}}</ref><ref name="pmid7379673">{{cite journal |vauthors=Whitehead WE, Engel BT, Schuster MM |title=Irritable bowel syndrome: physiological and psychological differences between diarrhea-predominant and constipation-predominant patients |journal=Dig. Dis. Sci. |volume=25 |issue=6 |pages=404–13 |year=1980 |pmid=7379673 |doi= |url=}}</ref><ref name="pmid9691924">{{cite journal |vauthors=Fukudo S, Nomura T, Hongo M |title=Impact of corticotropin-releasing hormone on gastrointestinal motility and adrenocorticotropic hormone in normal controls and patients with irritable bowel syndrome |journal=Gut |volume=42 |issue=6 |pages=845–9 |year=1998 |pmid=9691924 |pmc=1727153 |doi= |url=}}</ref><ref name="pmid18456567">{{cite journal |vauthors=Camilleri M, McKinzie S, Busciglio I, Low PA, Sweetser S, Burton D, Baxter K, Ryks M, Zinsmeister AR |title=Prospective study of motor, sensory, psychologic, and autonomic functions in patients with irritable bowel syndrome |journal=Clin. Gastroenterol. Hepatol. |volume=6 |issue=7 |pages=772–81 |year=2008 |pmid=18456567 |pmc=2495078 |doi=10.1016/j.cgh.2008.02.060 |url=}}</ref><ref name="pmid3569764">{{cite journal |vauthors=Kellow JE, Phillips SF |title=Altered small bowel motility in irritable bowel syndrome is correlated with symptoms |journal=Gastroenterology |volume=92 |issue=6 |pages=1885–93 |year=1987 |pmid=3569764 |doi= |url=}}</ref>
**[[Constipation]]-prone IBS patients show fewer high-amplitude propagating contractions (HAPCs) as compared to [[diarrhea]] prone IBS patients, delayed transit through the [[Colon (anatomy)|colon]] and decreased motility. These facts show that the changes in the motor function of the [[Colon (anatomy)|colon]] are responsible for producing the gastrointestinal symptoms of IBS such as altered bowel habits and abdominal pain.<ref name="pmid18456567">{{cite journal |vauthors=Camilleri M, McKinzie S, Busciglio I, Low PA, Sweetser S, Burton D, Baxter K, Ryks M, Zinsmeister AR |title=Prospective study of motor, sensory, psychologic, and autonomic functions in patients with irritable bowel syndrome |journal=Clin. Gastroenterol. Hepatol. |volume=6 |issue=7 |pages=772–81 |year=2008 |pmid=18456567 |pmc=2495078 |doi=10.1016/j.cgh.2008.02.060 |url=}}</ref>


*'''CNS dysregulation'''
** The conceptualization of IBS being a brain gut disorder is reinforced by the following:
*** It has been found that IBS occurs in individuals who have experienced childhood trauma, with symptom exacerbation especially occurring in patients with emotional disturbances or stress. This is because traumatic experiences before the age of 18 can directly shape adult connectivity in the executive control network consisting of structures such as the [[Insular cortex|insula]], anterior [[cingulate cortex]] and the [[thalamus]]. The resulting semipermanent/permanent changes in complex neural circuits have been implicated in the pathophysiology of central pain amplification, contributing to abdominal pain in IBS patients.<ref name="pmid27061107">{{cite journal |vauthors=Park SH, Videlock EJ, Shih W, Presson AP, Mayer EA, Chang L |title=Adverse childhood experiences are associated with irritable bowel syndrome and gastrointestinal symptom severity |journal=Neurogastroenterol. Motil. |volume=28 |issue=8 |pages=1252–60 |year=2016 |pmid=27061107 |pmc=4956522 |doi=10.1111/nmo.12826 |url=}}</ref><ref name="pmid25003944">{{cite journal |vauthors=Gupta A, Kilpatrick L, Labus J, Tillisch K, Braun A, Hong JY, Ashe-McNalley C, Naliboff B, Mayer EA |title=Early adverse life events and resting state neural networks in patients with chronic abdominal pain: evidence for sex differences |journal=Psychosom Med |volume=76 |issue=6 |pages=404–12 |year=2014 |pmid=25003944 |pmc=4113723 |doi=10.1097/PSY.0000000000000089 |url=}}</ref>
***  IBS has been found to have a high association with pre-existing psychiatric and psychological conditions like anxiety and depression. However, it has been shown that even in the absence of any psychiatric condition, the dorsolateral [[prefrontal cortex]] activity (responsible for vigilance and alertness of the human brain) is reduced in IBS patients, pointing directly towards [[CNS]] dysfunction and increased susceptibility to stressors.<ref name="pmid25003944" />
*** IBS patients have modulation of the mid-[[Cingulate cortex|cingulate corte]]<nowiki/>x engaged in attention pathways and responses. Modulation of the mid-[[cingulate cortex]] is associated with alterations in the subjective sensations of pain.<ref name="pmid22108191">{{cite journal |vauthors=Larsson MB, Tillisch K, Craig AD, Engström M, Labus J, Naliboff B, Lundberg P, Ström M, Mayer EA, Walter SA |title=Brain responses to visceral stimuli reflect visceral sensitivity thresholds in patients with irritable bowel syndrome |journal=Gastroenterology |volume=142 |issue=3 |pages=463–472.e3 |year=2012 |pmid=22108191 |pmc=3288538 |doi=10.1053/j.gastro.2011.11.022 |url=}}</ref><ref name="pmid27144627">{{cite journal |vauthors=Mearin F, Lacy BE, Chang L, Chey WD, Lembo AJ, Simren M, Spiller R |title=Bowel Disorders |journal=Gastroenterology |volume= |issue= |pages= |year=2016 |pmid=27144627 |doi=10.1053/j.gastro.2016.02.031 |url=}}</ref>
*** IBS patients also have [[prefrontal cortex]] modulation which may lead to increased perception of visceral pain. Therefore, patients with IBS have aberrant processing of central information, with decreased feedback on the emotional arousal network that controls the [[Autonomic nervous system|autonomic]] modulation of gastrointestinal function.<ref name="pmid23721972">{{cite journal |vauthors=Ellingson BM, Mayer E, Harris RJ, Ashe-McNally C, Naliboff BD, Labus JS, Tillisch K |title=Diffusion tensor imaging detects microstructural reorganization in the brain associated with chronic irritable bowel syndrome |journal=Pain |volume=154 |issue=9 |pages=1528–41 |year=2013 |pmid=23721972 |pmc=3758125 |doi=10.1016/j.pain.2013.04.010 |url=}}</ref><ref name="pmid20003075">{{cite journal |vauthors=Hall GB, Kamath MV, Collins S, Ganguli S, Spaziani R, Miranda KL, Bayati A, Bienenstock J |title=Heightened central affective response to visceral sensations of pain and discomfort in IBS |journal=Neurogastroenterol. Motil. |volume=22 |issue=3 |pages=276–e80 |year=2010 |pmid=20003075 |doi=10.1111/j.1365-2982.2009.01436.x |url=}}</ref>
*** Advanced brain imaging techniques that analyze differences in brain activity have shown irregularities in the mid- [[cingulate cortex]] and [[prefrontal cortex]] on [[Diffusion MRI|diffusion tensor imaging]] in the [[white matter]] of the brain.These imaging techniques have helped outline the primary areas involved in the pathophysiology of central pain amplification in IBS. <ref name="pmid23864686">{{cite journal |vauthors=Hong JY, Kilpatrick LA, Labus J, Gupta A, Jiang Z, Ashe-McNalley C, Stains J, Heendeniya N, Ebrat B, Smith S, Tillisch K, Naliboff B, Mayer EA |title=Patients with chronic visceral pain show sex-related alterations in intrinsic oscillations of the resting brain |journal=J. Neurosci. |volume=33 |issue=29 |pages=11994–2002 |year=2013 |pmid=23864686 |pmc=3713732 |doi=10.1523/JNEUROSCI.5733-12.2013 |url=}}</ref>
*** The important role of psychological therapies that act on cerebral cortical sites and [[antidepressants]] as mainstays of therapy in IBS patients, further throws light on the involvement of the CNS in its pathophysiology. In addition to this, the role of [[Probiotic|probiotics]] in modifying signal processing in the brain also proves that IBS is a brain gut disorder.<ref name="pmid23474283">{{cite journal |vauthors=Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat B, Guyonnet D, Legrain-Raspaud S, Trotin B, Naliboff B, Mayer EA |title=Consumption of fermented milk product with probiotic modulates brain activity |journal=Gastroenterology |volume=144 |issue=7 |pages=1394–401, 1401.e1–4 |year=2013 |pmid=23474283 |pmc=3839572 |doi=10.1053/j.gastro.2013.02.043 |url=}}</ref>
*** It has also been shown that [[Rectum|rectal]] balloon distension in patients causes increased engagement of regions of the brain associated with attentional and behavioral responses.<ref name="pmid22108191">{{cite journal |vauthors=Larsson MB, Tillisch K, Craig AD, Engström M, Labus J, Naliboff B, Lundberg P, Ström M, Mayer EA, Walter SA |title=Brain responses to visceral stimuli reflect visceral sensitivity thresholds in patients with irritable bowel syndrome |journal=Gastroenterology |volume=142 |issue=3 |pages=463–472.e3 |year=2012 |pmid=22108191 |pmc=3288538 |doi=10.1053/j.gastro.2011.11.022 |url=}}</ref><ref name="pmid20600024">{{cite journal |vauthors=Elsenbruch S, Rosenberger C, Bingel U, Forsting M, Schedlowski M, Gizewski ER |title=Patients with irritable bowel syndrome have altered emotional modulation of neural responses to visceral stimuli |journal=Gastroenterology |volume=139 |issue=4 |pages=1310–9 |year=2010 |pmid=20600024 |doi=10.1053/j.gastro.2010.06.054 |url=}}</ref><ref name="pmid19651629">{{cite journal |vauthors=Elsenbruch S, Rosenberger C, Enck P, Forsting M, Schedlowski M, Gizewski ER |title=Affective disturbances modulate the neural processing of visceral pain stimuli in irritable bowel syndrome: an fMRI study |journal=Gut |volume=59 |issue=4 |pages=489–95 |year=2010 |pmid=19651629 |doi=10.1136/gut.2008.175000 |url=}}</ref>


* '''Visceral hypersensitivity'''
{{Family tree | | | | | | B01 | | | |B01='''[[CNS]] dysregulation and [[psychosocial factors]]''' }}
** [[Visceral hypersensitivity]] is an important factor in the pathogenesis of pain perception in IBS patients. IBS is associated with a decreased threshold for perception of visceral stimuli (i.e. visceral hypersensitivity).<ref name="pmid18456567">{{cite journal |vauthors=Camilleri M, McKinzie S, Busciglio I, Low PA, Sweetser S, Burton D, Baxter K, Ryks M, Zinsmeister AR |title=Prospective study of motor, sensory, psychologic, and autonomic functions in patients with irritable bowel syndrome |journal=Clin. Gastroenterol. Hepatol. |volume=6 |issue=7 |pages=772–81 |year=2008 |pmid=18456567 |pmc=2495078 |doi=10.1016/j.cgh.2008.02.060 |url=}}</ref><ref name="pmid21537962">{{cite journal |vauthors=Barbara G, Cremon C, De Giorgio R, Dothel G, Zecchi L, Bellacosa L, Carini G, Stanghellini V, Corinaldesi R |title=Mechanisms underlying visceral hypersensitivity in irritable bowel syndrome |journal=Curr Gastroenterol Rep |volume=13 |issue=4 |pages=308–15 |year=2011 |pmid=21537962 |doi=10.1007/s11894-011-0195-7 |url=}}</ref><ref name="pmid2323511">{{cite journal |vauthors=Whitehead WE, Holtkotter B, Enck P, Hoelzl R, Holmes KD, Anthony J, Shabsin HS, Schuster MM |title=Tolerance for rectosigmoid distention in irritable bowel syndrome |journal=Gastroenterology |volume=98 |issue=5 Pt 1 |pages=1187–92 |year=1990 |pmid=2323511 |doi= |url=}}</ref> 
{{Family tree | | | | | | |!| | | | | }}
** Studies in IBS patients have shown that [[Rectum|rectal]] balloon inflation produces painful and non-painful sensations at lower volumes as compared to healthy controls, suggesting the presence of afferent pathway disturbances in visceral innervation<ref name="pmid7797041">{{cite journal |vauthors=Mertz H, Naliboff B, Munakata J, Niazi N, Mayer EA |title=Altered rectal perception is a biological marker of patients with irritable bowel syndrome |journal=Gastroenterology |volume=109 |issue=1 |pages=40–52 |year=1995 |pmid=7797041 |doi= |url=}}</ref><ref name="pmid2338274">{{cite journal |vauthors=Prior A, Maxton DG, Whorwell PJ |title=Anorectal manometry in irritable bowel syndrome: differences between diarrhoea and constipation predominant subjects |journal=Gut |volume=31 |issue=4 |pages=458–62 |year=1990 |pmid=2338274 |pmc=1378424 |doi= |url=}}</ref><ref name="pmid17919487">{{cite journal |vauthors=Posserud I, Syrous A, Lindström L, Tack J, Abrahamsson H, Simrén M |title=Altered rectal perception in irritable bowel syndrome is associated with symptom severity |journal=Gastroenterology |volume=133 |issue=4 |pages=1113–23 |year=2007 |pmid=17919487 |doi=10.1053/j.gastro.2007.07.024 |url=}}</ref><ref name="pmid12055583">{{cite journal |vauthors=Bouin M, Plourde V, Boivin M, Riberdy M, Lupien F, Laganière M, Verrier P, Poitras P |title=Rectal distention testing in patients with irritable bowel syndrome: sensitivity, specificity, and predictive values of pain sensory thresholds |journal=Gastroenterology |volume=122 |issue=7 |pages=1771–7 |year=2002 |pmid=12055583 |doi= |url=}}</ref>.
{{Family tree | | | | | | |!| | | | | }}
** Many factors contribute to visceral hyperalgesia (i.e increased sensitivity of the intestines to normal sensations) such as:
{{familytree |boxstyle=text-align: left; | A01 |-|-| A02 |-|-|-| A03 | |A01= '''Intrinsic [[gastrointestinal]] factors''': <br> • [[Motor]] abnormalities <br>• [[Visceral]] [[hypersensitivity]] <br>• [[Immune]] activation and [[mucosal]] inflammation <br>• Altered [[gut]] [[microbiota]] <br>• Abnormal [[serotonin]] pathways | A02= '''IRRITABLE BOWEL SYNDROME'''| A03='''Genetic factors''': <br>• Twin concordance <br>• Familial aggregation <br>• [[SNPs|Single nucleotide polymorphisms(SNPs)]] <br>• TNF polymorphism}}
*** '''[[Spinal cord|Spinal]] hyperexcitability'''  
**** Secondary to activation of an [[NMDA receptor|N-methyl D aspartate (NMDA) receptor]], [[nitric oxide]] and possibly other neurotransmitters. 
*** '''Activation of specific gastrointestinal mediators''' such as [[kinins]] and [[serotonin]] that lead to afferent nerve fiber sensitization.
*** '''Central ([[Brain stem|brainstem]] and [[Cerebral cortex|cortical]]) modulation''' with increased activation of anterior cingulate cortex, [[thalamus]] and [[Insular cortex|insula]]. These structures are involved in processing of pain and their modulation translates into long term hypersensitivity due to neuroplasticity. Semipermanent changes in the neural response to visceral stimulation contribute to visceral hypersensitivity. These findings have been derived from brain imaging studies such as functional magnetic resonance imaging and positron emission tomography.''<ref name="pmid21537962">{{cite journal |vauthors=Barbara G, Cremon C, De Giorgio R, Dothel G, Zecchi L, Bellacosa L, Carini G, Stanghellini V, Corinaldesi R |title=Mechanisms underlying visceral hypersensitivity in irritable bowel syndrome |journal=Curr Gastroenterol Rep |volume=13 |issue=4 |pages=308–15 |year=2011 |pmid=21537962 |doi=10.1007/s11894-011-0195-7 |url=}}</ref><ref name="pmid10784583">{{cite journal |vauthors=Mertz H, Morgan V, Tanner G, Pickens D, Price R, Shyr Y, Kessler R |title=Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention |journal=Gastroenterology |volume=118 |issue=5 |pages=842–8 |year=2000 |pmid=10784583 |doi= |url=}}</ref>  ''  
*** '''Recruitment of peripheral silent nociceptors''' cause increased end organ sensitivity due to hormonal or immune activation<ref name="pmid21537962">{{cite journal |vauthors=Barbara G, Cremon C, De Giorgio R, Dothel G, Zecchi L, Bellacosa L, Carini G, Stanghellini V, Corinaldesi R |title=Mechanisms underlying visceral hypersensitivity in irritable bowel syndrome |journal=Curr Gastroenterol Rep |volume=13 |issue=4 |pages=308–15 |year=2011 |pmid=21537962 |doi=10.1007/s11894-011-0195-7 |url=}}</ref>.


* '''Immune activation and mucosal inflammation'''
 
** The high prevalence of IBS in patients with history of inflammatory bowel disease, celiac disease or microscopic colitis points towards the fact that immune activation and mucosal inflammation play an important role in the pathogenesis of IBS.<ref name="pmid19997094">{{cite journal |vauthors=Coëffier M, Gloro R, Boukhettala N, Aziz M, Lecleire S, Vandaele N, Antonietti M, Savoye G, Bôle-Feysot C, Déchelotte P, Reimund JM, Ducrotté P |title=Increased proteasome-mediated degradation of occludin in irritable bowel syndrome |journal=Am. J. Gastroenterol. |volume=105 |issue=5 |pages=1181–8 |year=2010 |pmid=19997094 |doi=10.1038/ajg.2009.700 |url=}}</ref><ref name="pmid12055584">{{cite journal |vauthors=Chadwick VS, Chen W, Shu D, Paulus B, Bethwaite P, Tie A, Wilson I |title=Activation of the mucosal immune system in irritable bowel syndrome |journal=Gastroenterology |volume=122 |issue=7 |pages=1778–83 |year=2002 |pmid=12055584 |doi= |url=}}</ref><ref name="pmid17383420">{{cite journal |vauthors=Liebregts T, Adam B, Bredack C, Röth A, Heinzel S, Lester S, Downie-Doyle S, Smith E, Drew P, Talley NJ, Holtmann G |title=Immune activation in patients with irritable bowel syndrome |journal=Gastroenterology |volume=132 |issue=3 |pages=913–20 |year=2007 |pmid=17383420 |doi=10.1053/j.gastro.2007.01.046 |url=}}</ref><ref name="pmid12454854">{{cite journal |vauthors=Törnblom H, Lindberg G, Nyberg B, Veress B |title=Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome |journal=Gastroenterology |volume=123 |issue=6 |pages=1972–9 |year=2002 |pmid=12454854 |doi=10.1053/gast.2002.37059 |url=}}</ref><ref name="pmid17005763">{{cite journal |vauthors=Guilarte M, Santos J, de Torres I, Alonso C, Vicario M, Ramos L, Martínez C, Casellas F, Saperas E, Malagelada JR |title=Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum |journal=Gut |volume=56 |issue=2 |pages=203–9 |year=2007 |pmid=17005763 |pmc=1856785 |doi=10.1136/gut.2006.100594 |url=}}</ref><ref name="pmid14988823">{{cite journal |vauthors=Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, Pasquinelli G, Morselli-Labate AM, Grady EF, Bunnett NW, Collins SM, Corinaldesi R |title=Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome |journal=Gastroenterology |volume=126 |issue=3 |pages=693–702 |year=2004 |pmid=14988823 |doi= |url=}}</ref><ref name="pmid17383420">{{cite journal |vauthors=Liebregts T, Adam B, Bredack C, Röth A, Heinzel S, Lester S, Downie-Doyle S, Smith E, Drew P, Talley NJ, Holtmann G |title=Immune activation in patients with irritable bowel syndrome |journal=Gastroenterology |volume=132 |issue=3 |pages=913–20 |year=2007 |pmid=17383420 |doi=10.1053/j.gastro.2007.01.046 |url=}}</ref>
{{Family tree | | | | | | |!| | | | | }}
** Psychological stress can significantly impact the release of proinflammatory cytokines, thereby affecting intestinal permeability and reinforcing a functional link existing between immune activation, psychological symptoms and symptoms in patients with IBS.<ref name="pmid19997094">{{cite journal |vauthors=Coëffier M, Gloro R, Boukhettala N, Aziz M, Lecleire S, Vandaele N, Antonietti M, Savoye G, Bôle-Feysot C, Déchelotte P, Reimund JM, Ducrotté P |title=Increased proteasome-mediated degradation of occludin in irritable bowel syndrome |journal=Am. J. Gastroenterol. |volume=105 |issue=5 |pages=1181–8 |year=2010 |pmid=19997094 |doi=10.1038/ajg.2009.700 |url=}}</ref>
{{Family tree | | | | | | |!| | | | | }}
** Patients are found to have higher mucosal counts of lymphocytes (T cells, B cells), mast cells and immune mediators such as prostanoids, proteases, cytokines and histamines.<ref name="pmid17383420">{{cite journal |vauthors=Liebregts T, Adam B, Bredack C, Röth A, Heinzel S, Lester S, Downie-Doyle S, Smith E, Drew P, Talley NJ, Holtmann G |title=Immune activation in patients with irritable bowel syndrome |journal=Gastroenterology |volume=132 |issue=3 |pages=913–20 |year=2007 |pmid=17383420 |doi=10.1053/j.gastro.2007.01.046 |url=}}</ref><ref name="pmid20427395">{{cite journal |vauthors=Marshall JK, Thabane M, Garg AX, Clark WF, Moayyedi P, Collins SM |title=Eight year prognosis of postinfectious irritable bowel syndrome following waterborne bacterial dysentery |journal=Gut |volume=59 |issue=5 |pages=605–11 |year=2010 |pmid=20427395 |doi=10.1136/gut.2009.202234 |url=}}</ref><ref name="pmid21911849">{{cite journal |vauthors=Wensaas KA, Langeland N, Hanevik K, Mørch K, Eide GE, Rortveit G |title=Irritable bowel syndrome and chronic fatigue 3 years after acute giardiasis: historic cohort study |journal=Gut |volume=61 |issue=2 |pages=214–9 |year=2012 |pmid=21911849 |doi=10.1136/gutjnl-2011-300220 |url=}}</ref><ref name="pmid19711225">{{cite journal |vauthors=Mearin F, Perelló A, Balboa A, Perona M, Sans M, Salas A, Angulo S, Lloreta J, Benasayag R, García-Gonzalez MA, Pérez-Oliveras M, Coderch J |title=Pathogenic mechanisms of postinfectious functional gastrointestinal disorders: results 3 years after gastroenteritis |journal=Scand. J. Gastroenterol. |volume=44 |issue=10 |pages=1173–85 |year=2009 |pmid=19711225 |doi=10.1080/00365520903171276 |url=}}</ref><ref name="pmid12631663">{{cite journal |vauthors=Gwee KA, Collins SM, Read NW, Rajnakova A, Deng Y, Graham JC, McKendrick MW, Moochhala SM |title=Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome |journal=Gut |volume=52 |issue=4 |pages=523–6 |year=2003 |pmid=12631663 |pmc=1773606 |doi= |url=}}</ref>
{{familytree |boxstyle=text-align: left; | | | | | | B01 | | | |B01= '''Environmental factors''': <br>•Diet <br>•[[Infections]]}}
{{Family tree/end}}
 
==='''Environmental factors'''===
*[[Diet (nutrition)|Diet]]
**Fermentable [[Oligosaccharide|oligosaccharides]], [[Monosaccharide|monosaccharides]],  [[Disaccharide|disaccharides]], and [[Polyol|polyols]] (FODMAPs) are present in stone fruits, artificial sweeteners, lactose-containing foods, and [[Legume|legumes]]. Changes in diet such as increased amounts  (FODMAPs) can alter [[Gut flora|gut microflora]].<ref name="pmid23935555">{{cite journal |vauthors=Muir JG, Gibson PR |title=The Low FODMAP Diet for Treatment of Irritable Bowel Syndrome and Other Gastrointestinal Disorders |journal=Gastroenterol Hepatol (N Y) |volume=9 |issue=7 |pages=450–2 |year=2013 |pmid=23935555 |pmc=3736783 |doi= |url=}}</ref>
***[[Fermentation (biochemistry)|Fermentation]] and [[Osmosis|osmotic]] effects of FODMAPs produce [[Abdominal pain|abdominal discomfort]] and [[diarrhea]] in IBS.
***FODMAPs yield carbon dioxide, methane, and hydrogen that are responsible for bloating.
**[[Osmosis|Osmotically]] active carbohydrate by products lead to [[diarrhea]] by enhancing [[Intestine|intestinal]] contractions and precipitating fluid secretion.<ref name="pmid23644955">{{cite journal |vauthors=Böhn L, Störsrud S, Törnblom H, Bengtsson U, Simrén M |title=Self-reported food-related gastrointestinal symptoms in IBS are common and associated with more severe symptoms and reduced quality of life |journal=Am. J. Gastroenterol. |volume=108 |issue=5 |pages=634–41 |year=2013 |pmid=23644955 |doi=10.1038/ajg.2013.105 |url=}}</ref><ref name="pmid7910231">{{cite journal |vauthors=Young E, Stoneham MD, Petruckevitch A, Barton J, Rona R |title=A population study of food intolerance |journal=Lancet |volume=343 |issue=8906 |pages=1127–30 |year=1994 |pmid=7910231 |doi= |url=}}</ref><ref name="pmid24336217">{{cite journal |vauthors=David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA, Biddinger SB, Dutton RJ, Turnbaugh PJ |title=Diet rapidly and reproducibly alters the human gut microbiome |journal=Nature |volume=505 |issue=7484 |pages=559–63 |year=2014 |pmid=24336217 |pmc=3957428 |doi=10.1038/nature12820 |url=}}</ref><ref name="pmid26867199">{{cite journal |vauthors=Elli L, Tomba C, Branchi F, Roncoroni L, Lombardo V, Bardella MT, Ferretti F, Conte D, Valiante F, Fini L, Forti E, Cannizzaro R, Maiero S, Londoni C, Lauri A, Fornaciari G, Lenoci N, Spagnuolo R, Basilisco G, Somalvico F, Borgatta B, Leandro G, Segato S, Barisani D, Morreale G, Buscarini E |title=Evidence for the Presence of Non-Celiac Gluten Sensitivity in Patients with Functional Gastrointestinal Symptoms: Results from a Multicenter Randomized Double-Blind Placebo-Controlled Gluten Challenge |journal=Nutrients |volume=8 |issue=2 |pages=84 |year=2016 |pmid=26867199 |pmc=4772047 |doi=10.3390/nu8020084 |url=}}</ref><ref name="pmid26522233">{{cite journal |vauthors=Coletta M, Gates FK, Marciani L, Shiwani H, Major G, Hoad CL, Chaddock G, Gowland PA, Spiller RC |title=Effect of bread gluten content on gastrointestinal function: a crossover MRI study on healthy humans |journal=Br. J. Nutr. |volume=115 |issue=1 |pages=55–61 |year=2016 |pmid=26522233 |doi=10.1017/S0007114515004183 |url=}}</ref><ref name="pmid24308871">{{cite journal |vauthors=Yang J, Fox M, Cong Y, Chu H, Zheng X, Long Y, Fried M, Dai N |title=Lactose intolerance in irritable bowel syndrome patients with diarrhoea: the roles of anxiety, activation of the innate mucosal immune system and visceral sensitivity |journal=Aliment. Pharmacol. Ther. |volume=39 |issue=3 |pages=302–11 |year=2014 |pmid=24308871 |doi=10.1111/apt.12582 |url=}}</ref><ref name="pmid24445613">{{cite journal |vauthors=Staudacher HM, Irving PM, Lomer MC, Whelan K |title=Mechanisms and efficacy of dietary FODMAP restriction in IBS |journal=Nat Rev Gastroenterol Hepatol |volume=11 |issue=4 |pages=256–66 |year=2014 |pmid=24445613 |doi=10.1038/nrgastro.2013.259 |url=}}</ref>
*&nbsp;[[Infection]]
**[[Infection|Infectious]] [[gastroenteritis]] triggers micro [[inflammation]] and up to one third of [[irritable bowel syndrome]] cases follow [[Gastroenteritis|acute gastroenteritis.]]
**Micro [[inflammation]] of the [[Gastrointestinal tract|gut]] causes activation of the [[Lymphocyte|lymphocytes]], [[Mast cell|mast cells]] and pro inflammatory [[Cytokine|cytokines]] that stimulate the [[enteric nervous system]] and lead to abnormal [[Viscus|visceral]] and [[Motor skill|motor]] responses within the [[Gastrointestinal tract|gastrointestinal]] tract.
**[[Immunity (medical)|Immune]] activation due to GI [[infection]] also increases [[Enteroendocrine cells|enteroendocrine]] cells, calprotectin-positive [[Macrophage|macrophages]], [[Intraepithelial lymphocyte|intraepithelial]] [[Lymphocyte|lymphocytes]], and l[[Lamina propria|amina propria]] [[T cell|T cells]] which contribute directly to [[abdominal pain]] perception.&nbsp;<ref name="pmid20101257">{{cite journal |vauthors=Ohman L, Simrén M |title=Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions |journal=Nat Rev Gastroenterol Hepatol |volume=7 |issue=3 |pages=163–73 |year=2010 |pmid=20101257 |doi=10.1038/nrgastro.2010.4 |url=}}</ref><ref name="pmid22730468">{{cite journal |vauthors=Simrén M, Barbara G, Flint HJ, Spiegel BM, Spiller RC, Vanner S, Verdu EF, Whorwell PJ, Zoetendal EG |title=Intestinal microbiota in functional bowel disorders: a Rome foundation report |journal=Gut |volume=62 |issue=1 |pages=159–76 |year=2013 |pmid=22730468 |pmc=3551212 |doi=10.1136/gutjnl-2012-302167 |url=}}</ref><ref name="pmid23580243">{{cite journal |vauthors=Ohman L, Simrén M |title=Intestinal microbiota and its role in irritable bowel syndrome (IBS) |journal=Curr Gastroenterol Rep |volume=15 |issue=5 |pages=323 |year=2013 |pmid=23580243 |doi=10.1007/s11894-013-0323-7 |url=}}</ref><ref name="pmid17148502">{{cite journal |vauthors=Posserud I, Stotzer PO, Björnsson ES, Abrahamsson H, Simrén M |title=Small intestinal bacterial overgrowth in patients with irritable bowel syndrome |journal=Gut |volume=56 |issue=6 |pages=802–8 |year=2007 |pmid=17148502 |pmc=1954873 |doi=10.1136/gut.2006.108712 |url=}}</ref><ref name="pmid22180058">{{cite journal |vauthors=Jeffery IB, O'Toole PW, Öhman L, Claesson MJ, Deane J, Quigley EM, Simrén M |title=An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota |journal=Gut |volume=61 |issue=7 |pages=997–1006 |year=2012 |pmid=22180058 |doi=10.1136/gutjnl-2011-301501 |url=}}</ref><ref name="pmid19457422">{{cite journal |vauthors=Spiller R, Garsed K |title=Postinfectious irritable bowel syndrome |journal=Gastroenterology |volume=136 |issue=6 |pages=1979–88 |year=2009 |pmid=19457422 |doi=10.1053/j.gastro.2009.02.074 |url=}}</ref><ref name="pmid25611066">{{cite journal |vauthors=Joo YE |title=Alteration of fecal microbiota in patients with postinfectious irritable bowel syndrome |journal=J Neurogastroenterol Motil |volume=21 |issue=1 |pages=135–7 |year=2015 |pmid=25611066 |pmc=4288086 |doi=10.5056/jnm14133 |url=}}</ref><ref name="pmid10026328">{{cite journal |vauthors=Gwee KA, Leong YL, Graham C, McKendrick MW, Collins SM, Walters SJ, Underwood JE, Read NW |title=The role of psychological and biological factors in postinfective gut dysfunction |journal=Gut |volume=44 |issue=3 |pages=400–6 |year=1999 |pmid=10026328 |pmc=1727402 |doi= |url=}}</ref><ref name="pmid24646319">{{cite journal |vauthors=Nielsen HL, Engberg J, Ejlertsen T, Nielsen H |title=Psychometric scores and persistence of irritable bowel after Campylobacter concisus infection |journal=Scand. J. Gastroenterol. |volume=49 |issue=5 |pages=545–51 |year=2014 |pmid=24646319 |doi=10.3109/00365521.2014.886718 |url=}}</ref>
** The role of [[small intestinal bacterial overgrowth syndrome]] is strongest when testing with glucose breath tests (relative risk = 4.2) or jejunal aspirates (relative risk = 3.0) are compared among patients with IBS and controls<ref name="pmid31750966">{{cite journal| author=Ghoshal UC, Nehra A, Mathur A, Rai S| title=A meta-analysis on small intestinal bacterial overgrowth in patients with different subtypes of irritable bowel syndrome. | journal=J Gastroenterol Hepatol | year= 2020 | volume= 35 | issue= 6 | pages= 922-931 | pmid=31750966 | doi=10.1111/jgh.14938 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31750966  }} </ref>.
 
==='''Intrinsic gastrointestinal factors'''===
*'''Motor abnormalities:'''
**IBS is referred to as ‘[[spastic colon]]’ due to changes in [[Colon (anatomy)|colonic]] [[Motor coordination|motor]] function.
**Manometry recordings from the [[Transverse colon|transverse]], [[Descending colon|descending]] and [[sigmoid colon]] have shown that IBS leads to altered [[Colon (anatomy)|colonic]] and [[Small intestine|small intestinal]] [[Motor coordination|motor]] function, such as increased frequency and irregularity of [[Lumen|luminal]] contractions.
**[[Muscle|Motor]] changes lead to symptoms of [[diarrhea]] and [[constipation]].<ref name="pmid8789897">{{cite journal |vauthors=Schmidt T, Hackelsberger N, Widmer R, Meisel C, Pfeiffer A, Kaess H |title=Ambulatory 24-hour jejunal motility in diarrhea-predominant irritable bowel syndrome |journal=Scand. J. Gastroenterol. |volume=31 |issue=6 |pages=581–9 |year=1996 |pmid=8789897 |doi= |url=}}</ref><ref name="pmid2865504">{{cite journal |vauthors=Kumar D, Wingate DL |title=The irritable bowel syndrome: a paroxysmal motor disorder |journal=Lancet |volume=2 |issue=8462 |pages=973–7 |year=1985 |pmid=2865504 |doi= |url=}}</ref><ref name="pmid11215731">{{cite journal |vauthors=Simrén M, Castedal M, Svedlund J, Abrahamsson H, Björnsson E |title=Abnormal propagation pattern of duodenal pressure waves in the irritable bowel syndrome (IBS) [correction of (IBD)] |journal=Dig. Dis. Sci. |volume=45 |issue=11 |pages=2151–61 |year=2000 |pmid=11215731 |doi= |url=}}</ref>
***[[Diarrhea]]-prone IBS patients have increased responses to [[ingestion]], [[Corticotropin-releasing hormone|CRH]] ([[Corticotropin-releasing hormone|corticotropin releasing hormone]]), [[Cholecystokinin|CCK]] ([[cholecystokinin]]), which increase the peak amplitude of high-amplitude propagating [[Contraction|contractions]] (HAPCs)  and lead to [[Abdominal pain|abdominal discomfort]] with accelerated transit through the [[Colon (anatomy)|colon]]. <ref name="pmid11374689">{{cite journal |vauthors=Chey WY, Jin HO, Lee MH, Sun SW, Lee KY |title=Colonic motility abnormality in patients with irritable bowel syndrome exhibiting abdominal pain and diarrhea |journal=Am. J. Gastroenterol. |volume=96 |issue=5 |pages=1499–506 |year=2001 |pmid=11374689 |doi=10.1111/j.1572-0241.2001.03804.x |url=}}</ref><ref name="pmid7379673">{{cite journal |vauthors=Whitehead WE, Engel BT, Schuster MM |title=Irritable bowel syndrome: physiological and psychological differences between diarrhea-predominant and constipation-predominant patients |journal=Dig. Dis. Sci. |volume=25 |issue=6 |pages=404–13 |year=1980 |pmid=7379673 |doi= |url=}}</ref><ref name="pmid9691924">{{cite journal |vauthors=Fukudo S, Nomura T, Hongo M |title=Impact of corticotropin-releasing hormone on gastrointestinal motility and adrenocorticotropic hormone in normal controls and patients with irritable bowel syndrome |journal=Gut |volume=42 |issue=6 |pages=845–9 |year=1998 |pmid=9691924 |pmc=1727153 |doi= |url=}}</ref><ref name="pmid18456567">{{cite journal |vauthors=Camilleri M, McKinzie S, Busciglio I, Low PA, Sweetser S, Burton D, Baxter K, Ryks M, Zinsmeister AR |title=Prospective study of motor, sensory, psychologic, and autonomic functions in patients with irritable bowel syndrome |journal=Clin. Gastroenterol. Hepatol. |volume=6 |issue=7 |pages=772–81 |year=2008 |pmid=18456567 |pmc=2495078 |doi=10.1016/j.cgh.2008.02.060 |url=}}</ref><ref name="pmid3569764">{{cite journal |vauthors=Kellow JE, Phillips SF |title=Altered small bowel motility in irritable bowel syndrome is correlated with symptoms |journal=Gastroenterology |volume=92 |issue=6 |pages=1885–93 |year=1987 |pmid=3569764 |doi= |url=}}</ref>
***[[Constipation]]-prone [[Irritable bowel syndrome|IBS]] patients show fewer high-amplitude propagating [[Contraction|contractions]] (HAPCs) as compared to [[diarrhea]] prone [[Irritable bowel syndrome|IBS]] patients, delayed transit through the [[Colon (anatomy)|colon]] and decreased [[motility]].
****Changes in the [[Muscle|motor]] function of the [[Colon (anatomy)|colon]] are responsible for producing the [[Gastrointestinal tract|gastrointestinal]] symptoms of [[Irritable bowel syndrome|IBS]] such as altered [[Intestine|bowel]] habits and [[abdominal pain]].<ref name="pmid18456567" />
**'''Visceral hypersensitivity:'''
***IBS is associated with a decreased threshold for perception of [[Viscus|visceral]] stimuli (i.e. [[Viscus|visceral]] [[hypersensitivity]])<ref name="pmid18456567" /><ref name="pmid21537962">{{cite journal |vauthors=Barbara G, Cremon C, De Giorgio R, Dothel G, Zecchi L, Bellacosa L, Carini G, Stanghellini V, Corinaldesi R |title=Mechanisms underlying visceral hypersensitivity in irritable bowel syndrome |journal=Curr Gastroenterol Rep |volume=13 |issue=4 |pages=308–15 |year=2011 |pmid=21537962 |doi=10.1007/s11894-011-0195-7 |url=}}</ref><ref name="pmid2323511">{{cite journal |vauthors=Whitehead WE, Holtkotter B, Enck P, Hoelzl R, Holmes KD, Anthony J, Shabsin HS, Schuster MM |title=Tolerance for rectosigmoid distention in irritable bowel syndrome |journal=Gastroenterology |volume=98 |issue=5 Pt 1 |pages=1187–92 |year=1990 |pmid=2323511 |doi= |url=}}</ref>
***[[Rectum|Rectal]] [[distension]] produces painful and non-painful sensations at lower volumes in [[Irritable bowel syndrome|IBS]] patients as compared to healthy controls, suggesting the presence of [[afferent]] pathway disturbances in [[Viscus|visceral]] [[Nerve|innervation]]<ref name="pmid7797041">{{cite journal |vauthors=Mertz H, Naliboff B, Munakata J, Niazi N, Mayer EA |title=Altered rectal perception is a biological marker of patients with irritable bowel syndrome |journal=Gastroenterology |volume=109 |issue=1 |pages=40–52 |year=1995 |pmid=7797041 |doi= |url=}}</ref><ref name="pmid2338274">{{cite journal |vauthors=Prior A, Maxton DG, Whorwell PJ |title=Anorectal manometry in irritable bowel syndrome: differences between diarrhoea and constipation predominant subjects |journal=Gut |volume=31 |issue=4 |pages=458–62 |year=1990 |pmid=2338274 |pmc=1378424 |doi= |url=}}</ref><ref name="pmid17919487">{{cite journal |vauthors=Posserud I, Syrous A, Lindström L, Tack J, Abrahamsson H, Simrén M |title=Altered rectal perception in irritable bowel syndrome is associated with symptom severity |journal=Gastroenterology |volume=133 |issue=4 |pages=1113–23 |year=2007 |pmid=17919487 |doi=10.1053/j.gastro.2007.07.024 |url=}}</ref><ref name="pmid12055583">{{cite journal |vauthors=Bouin M, Plourde V, Boivin M, Riberdy M, Lupien F, Laganière M, Verrier P, Poitras P |title=Rectal distention testing in patients with irritable bowel syndrome: sensitivity, specificity, and predictive values of pain sensory thresholds |journal=Gastroenterology |volume=122 |issue=7 |pages=1771–7 |year=2002 |pmid=12055583 |doi= |url=}}</ref>.
***[[Viscus|Visceral]] [[hypersensitivity]] contributes to [[Irritable bowel syndrome|IBS]] by involving the following:
****'''[[Spinal cord|Spinal]] hyperexcitability'''
*****Secondary to activation of  [[Neurotransmitter|neurotransmitters]] such as:
*****[[NMDA receptor|N-methyl D aspartate (NMDA) receptor]]
*****[[Nitric oxide]] 
****'''Activation of specific [[Gastrointestinal tract|gastrointestinal]] mediators''' that lead to [[Afferent nerve|afferent]] [[nerve]] fiber sensitization:
*****[[Kinins]] 
*****[[Serotonin]] 
****'''Central ([[Brain stem|brainstem]] and [[Cerebral cortex|cortical]]) modulation''' with increased activation of anterior [[cingulate cortex]], [[thalamus]] and [[Insular cortex|insula]].
*****These structures are involved in processing of pain. 
*****[[Cortical area|Cortical]] and [[brain stem]] modulation translate into long term hypersensitivity due to [[neuroplasticity]].
*****Semi permanent changes(seen on functional [[magnetic resonance imaging]] and [[positron emission tomography]])  in the [[Nervous system|neural]] response to [[Viscus|visceral]] stimulation contribute to [[Viscus|visceral]] [[hypersensitivity]].''<ref name="pmid21537962" /><ref name="pmid10784583">{{cite journal |vauthors=Mertz H, Morgan V, Tanner G, Pickens D, Price R, Shyr Y, Kessler R |title=Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention |journal=Gastroenterology |volume=118 |issue=5 |pages=842–8 |year=2000 |pmid=10784583 |doi= |url=}}</ref>  ''
****'''Recruitment of peripheral silent [[Nociceptor|nociceptors]]''' cause increased end [[Organ (anatomy)|organ]] sensitivity due to
*****[[Hormone|Hormonal]] activation ( increased [[serotonin]] affects [[Gastrointestinal tract|gastrointestinal]] [[motility]] and [[Viscus|visceral]] [[pain]] perception)
*****[[Immunity (medical)|Immune]] activation(recruitment of [[Inflammation|inflammatory]] mediators)<ref name="pmid21537962" />
{{familytree/start |summary=PE diagnosis Algorithm.}}
{{familytree | | | | | | | | | |,|-| A01 |-| A02 | | | |A01=[[Spinal cord|Spinal]] hyperexcitability |A02= Activation of <br>• [[NMDA receptor|N-methyl D aspartate (NMDA) receptor]] <br>• [[nitric oxide]] }}
{{familytree | | | | | | | | | |!| | | | | | | | | | | | | | | | | | }}
{{familytree | | | | | | | | | |)|-| B01 |-| B02 | | | |B01=Central ([[Brain stem|brainstem]] and [[Cerebral cortex|cortical]]) modulation |B02=Increased activation of: <br>• Anterior [[cingulate cortex]] <br>• [[Thalamus]] <br>• [[Insular cortex|insula]] <br> }}
{{familytree | | | | | | C01 |-|(| | | | | | | | | | | | | | | | | |C01='''[[Visceral]] [[hypersensitivity]]''' }}
{{familytree | | | | | | | | | |)|-| C02 |-| C03 | | | |C02=Activation of specific [[gastrointestinal]] [[mediators]] |C03=[[Kinins]] and [[serotonin]] activation lead to [[afferent nerve]] fiber sensitization  }}
{{familytree | | | | | | | | | |!| | | | | | | | | | | | | | | | | | }}
{{familytree | | | | | | | | | |`|-| D01 |-| D02 | | | |D01=Recruitment of [[peripheral]] silent [[nociceptors]] |D02=Increased [[end]] [[organ]] sensitivity due to [[hormonal]] or [[immune]] activation }}
 
 
{{familytree/end}}
<br><br><br>
*'''[[Immune]] activation and [[mucosal]] [[inflammation]]'''{{Family tree/start}}
{{Family tree | A01 |-|-| A02 |-|-|-| A03 | |A01= '''[[Mast cells]]'''| A02= '''[[IMMUNE]] ACTIVATION AND [[MUCOSAL]] [[INFLAMMATION]]'''| A03='''[[Lymphocytes]]'''}}
 
 
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | | | | | B01 | | | |B01= '''[[Proinflammatory]] [[cytokines]]'''}}
{{Family tree/end}}
*IBS in patients with history of [[inflammatory bowel disease]], [[celiac disease]] or [[microscopic colitis]] points towards the fact that [[Immunity (medical)|immune]] activation and local [[Gastrointestinal tract|GI]] [[Mucous membrane|mucosal]] [[inflammation]] play an important role in its [[pathogenesis]].<ref name="pmid19997094">{{cite journal |vauthors=Coëffier M, Gloro R, Boukhettala N, Aziz M, Lecleire S, Vandaele N, Antonietti M, Savoye G, Bôle-Feysot C, Déchelotte P, Reimund JM, Ducrotté P |title=Increased proteasome-mediated degradation of occludin in irritable bowel syndrome |journal=Am. J. Gastroenterol. |volume=105 |issue=5 |pages=1181–8 |year=2010 |pmid=19997094 |doi=10.1038/ajg.2009.700 |url=}}</ref><ref name="pmid12055584">{{cite journal |vauthors=Chadwick VS, Chen W, Shu D, Paulus B, Bethwaite P, Tie A, Wilson I |title=Activation of the mucosal immune system in irritable bowel syndrome |journal=Gastroenterology |volume=122 |issue=7 |pages=1778–83 |year=2002 |pmid=12055584 |doi= |url=}}</ref><ref name="pmid17383420">{{cite journal |vauthors=Liebregts T, Adam B, Bredack C, Röth A, Heinzel S, Lester S, Downie-Doyle S, Smith E, Drew P, Talley NJ, Holtmann G |title=Immune activation in patients with irritable bowel syndrome |journal=Gastroenterology |volume=132 |issue=3 |pages=913–20 |year=2007 |pmid=17383420 |doi=10.1053/j.gastro.2007.01.046 |url=}}</ref><ref name="pmid12454854">{{cite journal |vauthors=Törnblom H, Lindberg G, Nyberg B, Veress B |title=Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome |journal=Gastroenterology |volume=123 |issue=6 |pages=1972–9 |year=2002 |pmid=12454854 |doi=10.1053/gast.2002.37059 |url=}}</ref><ref name="pmid17005763">{{cite journal |vauthors=Guilarte M, Santos J, de Torres I, Alonso C, Vicario M, Ramos L, Martínez C, Casellas F, Saperas E, Malagelada JR |title=Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum |journal=Gut |volume=56 |issue=2 |pages=203–9 |year=2007 |pmid=17005763 |pmc=1856785 |doi=10.1136/gut.2006.100594 |url=}}</ref><ref name="pmid14988823">{{cite journal |vauthors=Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, Pasquinelli G, Morselli-Labate AM, Grady EF, Bunnett NW, Collins SM, Corinaldesi R |title=Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome |journal=Gastroenterology |volume=126 |issue=3 |pages=693–702 |year=2004 |pmid=14988823 |doi= |url=}}</ref><ref name="pmid17383420" />
* IBS patients have higher [[Mucous membrane|mucosal]] counts of ''[[Lymphocyte|lymphocytes]]'' (T cells, B cells), ''[[Mast cell|mast]] cells'' and immune ''mediators'' such as prostanoids, [[Protease|proteases]], [[Cytokine|cytokines]] and [[Histamine|histamines]].<ref name="pmid17383420" /><ref name="pmid20427395">{{cite journal |vauthors=Marshall JK, Thabane M, Garg AX, Clark WF, Moayyedi P, Collins SM |title=Eight year prognosis of postinfectious irritable bowel syndrome following waterborne bacterial dysentery |journal=Gut |volume=59 |issue=5 |pages=605–11 |year=2010 |pmid=20427395 |doi=10.1136/gut.2009.202234 |url=}}</ref><ref name="pmid21911849">{{cite journal |vauthors=Wensaas KA, Langeland N, Hanevik K, Mørch K, Eide GE, Rortveit G |title=Irritable bowel syndrome and chronic fatigue 3 years after acute giardiasis: historic cohort study |journal=Gut |volume=61 |issue=2 |pages=214–9 |year=2012 |pmid=21911849 |doi=10.1136/gutjnl-2011-300220 |url=}}</ref><ref name="pmid19711225">{{cite journal |vauthors=Mearin F, Perelló A, Balboa A, Perona M, Sans M, Salas A, Angulo S, Lloreta J, Benasayag R, García-Gonzalez MA, Pérez-Oliveras M, Coderch J |title=Pathogenic mechanisms of postinfectious functional gastrointestinal disorders: results 3 years after gastroenteritis |journal=Scand. J. Gastroenterol. |volume=44 |issue=10 |pages=1173–85 |year=2009 |pmid=19711225 |doi=10.1080/00365520903171276 |url=}}</ref><ref name="pmid12631663">{{cite journal |vauthors=Gwee KA, Collins SM, Read NW, Rajnakova A, Deng Y, Graham JC, McKendrick MW, Moochhala SM |title=Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome |journal=Gut |volume=52 |issue=4 |pages=523–6 |year=2003 |pmid=12631663 |pmc=1773606 |doi= |url=}}</ref>
** '''Lymphocytes:'''
** '''Lymphocytes:'''
***  Patients with IBS have increased B lymphocyte activation in the blood. However, activation of humoral immunity in IBS is specific for the gastrointestinal tract as increased number of lymphocytes have been found in the small intestine and colon of IBS patients.<ref name="pmid12055584">{{cite journal |vauthors=Chadwick VS, Chen W, Shu D, Paulus B, Bethwaite P, Tie A, Wilson I |title=Activation of the mucosal immune system in irritable bowel syndrome |journal=Gastroenterology |volume=122 |issue=7 |pages=1778–83 |year=2002 |pmid=12055584 |doi= |url=}}</ref><ref name="pmid12454854">{{cite journal |vauthors=Törnblom H, Lindberg G, Nyberg B, Veress B |title=Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome |journal=Gastroenterology |volume=123 |issue=6 |pages=1972–9 |year=2002 |pmid=12454854 |doi=10.1053/gast.2002.37059 |url=}}</ref><ref name="pmid19222763">{{cite journal |vauthors=Ohman L, Lindmark AC, Isaksson S, Posserud I, Strid H, Sjövall H, Simrén M |title=B-cell activation in patients with irritable bowel syndrome (IBS) |journal=Neurogastroenterol. Motil. |volume=21 |issue=6 |pages=644–50, e27 |year=2009 |pmid=19222763 |doi=10.1111/j.1365-2982.2009.01272.x |url=}}</ref><ref name="pmid25209656">{{cite journal |vauthors=Vicario M, González-Castro AM, Martínez C, Lobo B, Pigrau M, Guilarte M, de Torres I, Mosquera JL, Fortea M, Sevillano-Aguilera C, Salvo-Romero E, Alonso C, Rodiño-Janeiro BK, Söderholm JD, Azpiroz F, Santos J |title=Increased humoral immunity in the jejunum of diarrhoea-predominant irritable bowel syndrome associated with clinical manifestations |journal=Gut |volume=64 |issue=9 |pages=1379–88 |year=2015 |pmid=25209656 |doi=10.1136/gutjnl-2013-306236 |url=}}</ref>
***Activation of [[humoral immunity]] in [[Irritable bowel syndrome|IBS]] is specific for the [[gastrointestinal tract]]. Increased number of [[Lymphocyte|lymphocytes]] have been found in the [[small intestine]] and [[Colon (anatomy)|colon]] of [[Irritable bowel syndrome|IBS]] patients.<ref name="pmid12055584" /><ref name="pmid12454854" /><ref name="pmid19222763">{{cite journal |vauthors=Ohman L, Lindmark AC, Isaksson S, Posserud I, Strid H, Sjövall H, Simrén M |title=B-cell activation in patients with irritable bowel syndrome (IBS) |journal=Neurogastroenterol. Motil. |volume=21 |issue=6 |pages=644–50, e27 |year=2009 |pmid=19222763 |doi=10.1111/j.1365-2982.2009.01272.x |url=}}</ref><ref name="pmid25209656">{{cite journal |vauthors=Vicario M, González-Castro AM, Martínez C, Lobo B, Pigrau M, Guilarte M, de Torres I, Mosquera JL, Fortea M, Sevillano-Aguilera C, Salvo-Romero E, Alonso C, Rodiño-Janeiro BK, Söderholm JD, Azpiroz F, Santos J |title=Increased humoral immunity in the jejunum of diarrhoea-predominant irritable bowel syndrome associated with clinical manifestations |journal=Gut |volume=64 |issue=9 |pages=1379–88 |year=2015 |pmid=25209656 |doi=10.1136/gutjnl-2013-306236 |url=}}</ref>  
*** IBS patients with diarrhea have enhanced mucosal humoral activity, associated with activation and proliferation of B cells and immunoglobulin production, identified by microarray profiling.<ref name="pmid25209656">{{cite journal |vauthors=Vicario M, González-Castro AM, Martínez C, Lobo B, Pigrau M, Guilarte M, de Torres I, Mosquera JL, Fortea M, Sevillano-Aguilera C, Salvo-Romero E, Alonso C, Rodiño-Janeiro BK, Söderholm JD, Azpiroz F, Santos J |title=Increased humoral immunity in the jejunum of diarrhoea-predominant irritable bowel syndrome associated with clinical manifestations |journal=Gut |volume=64 |issue=9 |pages=1379–88 |year=2015 |pmid=25209656 |doi=10.1136/gutjnl-2013-306236 |url=}}</ref>
***[[Irritable bowel syndrome|IBS]] patients with [[diarrhea]] have enhanced [[Mucous membrane|mucosal]] [[Humoral immunity|humoral]] activity, associated with activation and [[Cell growth|proliferation]] of [[B cell|B cells]] and [[Antibody|immunoglobulin]] production, identified by microarray profiling.<ref name="pmid25209656" />
*** IBS patients with severe disease have an increase in lymphocyte infiltration in the myentric plexus, in studies where full-thickness jejunal biopsies were obtained.<ref name="pmid12454854">{{cite journal |vauthors=Törnblom H, Lindberg G, Nyberg B, Veress B |title=Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome |journal=Gastroenterology |volume=123 |issue=6 |pages=1972–9 |year=2002 |pmid=12454854 |doi=10.1053/gast.2002.37059 |url=}}</ref>
***[[Irritable bowel syndrome|IBS]] patients with severe disease have an increase in [[lymphocyte]] [[Infiltration (medical)|infiltration]] in the myentric plexus.<ref name="pmid12454854" />
*** Mediators released by lymphocytes include histamine, proteases and nitric oxide. The stimulation of the enteric nervous system by these mediators leads to abnormal visceral and motor responses within the gastrointestinal tract.<ref name="pmid12055584" />
***Mediators released by [[Lymphocyte|lymphocytes]] include [[histamine]], [[Protease|proteases]] and [[nitric oxide]]. The stimulation of the [[enteric nervous system]] by these mediators leads to abnormal [[Viscus|visceral]] and [[Muscle|motor]] responses within the [[gastrointestinal tract]].<ref name="pmid12055584" />  
*** Examination of stool in patients with diarrhea prominent IBS demonstrates high levels of serine protease activity, which is produced by lymphocytes.<ref name="pmid18924448">{{cite journal |vauthors=Bueno L |title=Protease activated receptor 2: a new target for IBS treatment |journal=Eur Rev Med Pharmacol Sci |volume=12 Suppl 1 |issue= |pages=95–102 |year=2008 |pmid=18924448 |doi= |url=}}</ref><ref name="pmid18194983">{{cite journal |vauthors=Gecse K, Róka R, Ferrier L, Leveque M, Eutamene H, Cartier C, Ait-Belgnaoui A, Rosztóczy A, Izbéki F, Fioramonti J, Wittmann T, Bueno L |title=Increased faecal serine protease activity in diarrhoeic IBS patients: a colonic lumenal factor impairing colonic permeability and sensitivity |journal=Gut |volume=57 |issue=5 |pages=591–9 |year=2008 |pmid=18194983 |doi=10.1136/gut.2007.140210 |url=}}</ref>When fecal extracts from IBS patients are intra colonically infused into mice, there is increased visceral pain and colonic cellular permeability. <ref name="pmid18924448" />
***Stool in patients with [[diarrhea]] prominent [[Irritable bowel syndrome|IBS]] demonstrates high levels of [[serine]] [[protease]] activity, which is produced by [[Lymphocyte|lymphocytes]].<ref name="pmid18924448">{{cite journal |vauthors=Bueno L |title=Protease activated receptor 2: a new target for IBS treatment |journal=Eur Rev Med Pharmacol Sci |volume=12 Suppl 1 |issue= |pages=95–102 |year=2008 |pmid=18924448 |doi= |url=}}</ref><ref name="pmid18194983">{{cite journal |vauthors=Gecse K, Róka R, Ferrier L, Leveque M, Eutamene H, Cartier C, Ait-Belgnaoui A, Rosztóczy A, Izbéki F, Fioramonti J, Wittmann T, Bueno L |title=Increased faecal serine protease activity in diarrhoeic IBS patients: a colonic lumenal factor impairing colonic permeability and sensitivity |journal=Gut |volume=57 |issue=5 |pages=591–9 |year=2008 |pmid=18194983 |doi=10.1136/gut.2007.140210 |url=}}</ref>  
*** Serine protease inhibitors prevent effects mediated by high levels of serine protease in IBS patients. Mononuclear cell supernatants in the peripheral blood from healthy controls have greater inhibitory effects on colorectal sensory afferent nerve endings than in IBS patients.<ref name="pmid18194983" /><ref name="pmid18924448" />
***In response to high levels of [[serine protease]], there is increased [[Viscus|visceral]] pain and [[Colon (anatomy)|colonic]] cellular permeability. <ref name="pmid18924448" />  
** '''Mast cells:'''
***[[Serine protease]] inhibitors prevent effects mediated by high levels of [[serine protease]] in [[Irritable bowel syndrome|IBS]] patients.<ref name="pmid18194983" /><ref name="pmid18924448" />
***  Studies have shown an increased number of mast cells in IBS patients in the jejunum, terminal ileum and colon.<ref name="pmid14988823">{{cite journal |vauthors=Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, Pasquinelli G, Morselli-Labate AM, Grady EF, Bunnett NW, Collins SM, Corinaldesi R |title=Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome |journal=Gastroenterology |volume=126 |issue=3 |pages=693–702 |year=2004 |pmid=14988823 |doi= |url=}}</ref>
**'''Mast cells:'''
*** Higher numbers of activated mast cells are found in proximity to colonic nerve fibres in the mucosa of the gastrointestinal tract of IBS patients. <ref name="pmid14988823">{{cite journal |vauthors=Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, Pasquinelli G, Morselli-Labate AM, Grady EF, Bunnett NW, Collins SM, Corinaldesi R |title=Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome |journal=Gastroenterology |volume=126 |issue=3 |pages=693–702 |year=2004 |pmid=14988823 |doi= |url=}}</ref><ref name="pmid17005763">{{cite journal |vauthors=Guilarte M, Santos J, de Torres I, Alonso C, Vicario M, Ramos L, Martínez C, Casellas F, Saperas E, Malagelada JR |title=Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum |journal=Gut |volume=56 |issue=2 |pages=203–9 |year=2007 |pmid=17005763 |pmc=1856785 |doi=10.1136/gut.2006.100594 |url=}}</ref>  
***  [[Irritable bowel syndrome|IBS]] leads to an increased number of [[Mast cell|mast cells]] in [[Irritable bowel syndrome|IBS]] patients in the [[jejunum]], [[terminal ileum]] and [[Colon (anatomy)|colon]].<ref name="pmid14988823" />  
** '''Proinflammatory cytokines:'''
*** Higher numbers of activated [[Mast cell|mast cells]] are found in proximity to [[Colon (anatomy)|colonic]] nerve fibres in the mucosa of the [[Gastrointestinal tract|gastrointestinal]] [[tract]] of [[Irritable bowel syndrome|IBS]] patients. <ref name="pmid14988823" /><ref name="pmid17005763" />
*** Cytokines are proteinaceous mediators of the immune response.  Increased levels of cytokines have been found in IBS patients.<ref name="pmid12631663">{{cite journal |vauthors=Gwee KA, Collins SM, Read NW, Rajnakova A, Deng Y, Graham JC, McKendrick MW, Moochhala SM |title=Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome |journal=Gut |volume=52 |issue=4 |pages=523–6 |year=2003 |pmid=12631663 |pmc=1773606 |doi= |url=}}</ref><ref name="pmid19711225">{{cite journal |vauthors=Mearin F, Perelló A, Balboa A, Perona M, Sans M, Salas A, Angulo S, Lloreta J, Benasayag R, García-Gonzalez MA, Pérez-Oliveras M, Coderch J |title=Pathogenic mechanisms of postinfectious functional gastrointestinal disorders: results 3 years after gastroenteritis |journal=Scand. J. Gastroenterol. |volume=44 |issue=10 |pages=1173–85 |year=2009 |pmid=19711225 |doi=10.1080/00365520903171276 |url=}}</ref>  
** '''Proinflammatory cytokines:'''
*** Higher amounts of tumor necrosis factor are produced by the peripheral blood mononuclear cells of IBS patients.<ref name="pmid16472586">{{cite journal |vauthors=Dinan TG, Quigley EM, Ahmed SM, Scully P, O'Brien S, O'Mahony L, O'Mahony S, Shanahan F, Keeling PW |title=Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker? |journal=Gastroenterology |volume=130 |issue=2 |pages=304–11 |year=2006 |pmid=16472586 |doi=10.1053/j.gastro.2005.11.033 |url=}}</ref><ref name="pmid17383420">{{cite journal |vauthors=Liebregts T, Adam B, Bredack C, Röth A, Heinzel S, Lester S, Downie-Doyle S, Smith E, Drew P, Talley NJ, Holtmann G |title=Immune activation in patients with irritable bowel syndrome |journal=Gastroenterology |volume=132 |issue=3 |pages=913–20 |year=2007 |pmid=17383420 |doi=10.1053/j.gastro.2007.01.046 |url=}}</ref>
*** [[Cytokine|Cytokines]] are protein mediators of the [[Immunity (medical)|immune]] response. Increased levels of [[Cytokine|cytokines]] have been found in [[Irritable bowel syndrome|IBS]] patients.<ref name="pmid19711225" /><ref name="pmid12631663" />  
*** In supernatants from cultured peripheral blood mononuclear cells in IBS patients,the TNF antagonist infliximab has been found to block the mechanical hypersensitivity of the mouse colonic afferent nerve endings. <ref name="pmid25063707">{{cite journal |vauthors=Hughes PA, Moretta M, Lim A, Grasby DJ, Bird D, Brierley SM, Liebregts T, Adam B, Blackshaw LA, Holtmann G, Bampton P, Hoffmann P, Andrews JM, Zola H, Krumbiegel D |title=Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients |journal=Brain Behav. Immun. |volume=42 |issue= |pages=191–203 |year=2014 |pmid=25063707 |doi=10.1016/j.bbi.2014.07.001 |url=}}</ref>
*** Higher amounts of [[Tumour necrosis factor|tumor necrosis factor]] are produced by the peripheral blood [[Monocyte|mononuclear]] cells of [[Irritable bowel syndrome|IBS]] patients.<ref name="pmid17383420" /><ref name="pmid16472586">{{cite journal |vauthors=Dinan TG, Quigley EM, Ahmed SM, Scully P, O'Brien S, O'Mahony L, O'Mahony S, Shanahan F, Keeling PW |title=Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker? |journal=Gastroenterology |volume=130 |issue=2 |pages=304–11 |year=2006 |pmid=16472586 |doi=10.1053/j.gastro.2005.11.033 |url=}}</ref>
*** Other cytokines such as interleukin 1β, interleukin 6, interleukin 10, and TNFα have been found in increased amounts on analysis of the supernatants from IBS patients with diarrhea, as compared to healthy controls. Increased concentration of these cytokines is directly proportional to the severity and frequency of pain.<ref name="pmid17383420">{{cite journal |vauthors=Liebregts T, Adam B, Bredack C, Röth A, Heinzel S, Lester S, Downie-Doyle S, Smith E, Drew P, Talley NJ, Holtmann G |title=Immune activation in patients with irritable bowel syndrome |journal=Gastroenterology |volume=132 |issue=3 |pages=913–20 |year=2007 |pmid=17383420 |doi=10.1053/j.gastro.2007.01.046 |url=}}</ref><ref name="pmid25063707">{{cite journal |vauthors=Hughes PA, Moretta M, Lim A, Grasby DJ, Bird D, Brierley SM, Liebregts T, Adam B, Blackshaw LA, Holtmann G, Bampton P, Hoffmann P, Andrews JM, Zola H, Krumbiegel D |title=Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients |journal=Brain Behav. Immun. |volume=42 |issue= |pages=191–203 |year=2014 |pmid=25063707 |doi=10.1016/j.bbi.2014.07.001 |url=}}</ref><ref name="pmid16472586">{{cite journal |vauthors=Dinan TG, Quigley EM, Ahmed SM, Scully P, O'Brien S, O'Mahony L, O'Mahony S, Shanahan F, Keeling PW |title=Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker? |journal=Gastroenterology |volume=130 |issue=2 |pages=304–11 |year=2006 |pmid=16472586 |doi=10.1053/j.gastro.2005.11.033 |url=}}</ref>
*** Other [[Cytokine|cytokines]] such as [[Interleukin|interleukin 1β]], [[interleukin]] 6,  [[Interleukin 10|interleukin10]], and [[Tumor necrosis factor-alpha|TNFα]] are raised in [[Irritable bowel syndrome|IBS]] patients.
* '''Altered gut microbiota'''
*** Increased concentration of [[Cytokine|cytokines]] is directly proportional to the severity and frequency of pain.<ref name="pmid17383420" /><ref name="pmid16472586" /><ref name="pmid25063707" />  
**  It is postulated that altered fecal microflora may be associated with IBS. There are numerous studies that suggest that altered fecal microflora in IBS patients differ from healthy controls. Some IBS patients who have undergone colonoscopy, with biopsies taken from the colon and terminal ileum have been found to have colonic spirochaetosis, showing the presence of altered gut microflora. In addition to this, the samples have been found to have a unique pathology of increased lymphoid follicles and eosinophils as compared to healthy controls.<ref name="pmid20427395">{{cite journal |vauthors=Marshall JK, Thabane M, Garg AX, Clark WF, Moayyedi P, Collins SM |title=Eight year prognosis of postinfectious irritable bowel syndrome following waterborne bacterial dysentery |journal=Gut |volume=59 |issue=5 |pages=605–11 |year=2010 |pmid=20427395 |doi=10.1136/gut.2009.202234 |url=}}</ref><ref name="pmid25540866">{{cite journal |vauthors=Walker MM, Talley NJ, Inganäs L, Engstrand L, Jones MP, Nyhlin H, Agréus L, Kjellstrom L, Öst Å, Andreasson A |title=Colonic spirochetosis is associated with colonic eosinophilia and irritable bowel syndrome in a general population in Sweden |journal=Hum. Pathol. |volume=46 |issue=2 |pages=277–83 |year=2015 |pmid=25540866 |doi=10.1016/j.humpath.2014.10.026 |url=}}</ref> <ref name="pmid17631127">{{cite journal |vauthors=Kassinen A, Krogius-Kurikka L, Mäkivuokko H, Rinttilä T, Paulin L, Corander J, Malinen E, Apajalahti J, Palva A |title=The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects |journal=Gastroenterology |volume=133 |issue=1 |pages=24–33 |year=2007 |pmid=17631127 |doi=10.1053/j.gastro.2007.04.005 |url=}}</ref><ref name="pmid15667495">{{cite journal |vauthors=Malinen E, Rinttilä T, Kajander K, Mättö J, Kassinen A, Krogius L, Saarela M, Korpela R, Palva A |title=Analysis of the fecal microbiota of irritable bowel syndrome patients and healthy controls with real-time PCR |journal=Am. J. Gastroenterol. |volume=100 |issue=2 |pages=373–82 |year=2005 |pmid=15667495 |doi=10.1111/j.1572-0241.2005.40312.x |url=}}</ref><ref name="pmid21820992">{{cite journal |vauthors=Rajilić-Stojanović M, Biagi E, Heilig HG, Kajander K, Kekkonen RA, Tims S, de Vos WM |title=Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome |journal=Gastroenterology |volume=141 |issue=5 |pages=1792–801 |year=2011 |pmid=21820992 |doi=10.1053/j.gastro.2011.07.043 |url=}}</ref><ref name="pmid21741921">{{cite journal |vauthors=Saulnier DM, Riehle K, Mistretta TA, Diaz MA, Mandal D, Raza S, Weidler EM, Qin X, Coarfa C, Milosavljevic A, Petrosino JF, Highlander S, Gibbs R, Lynch SV, Shulman RJ, Versalovic J |title=Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome |journal=Gastroenterology |volume=141 |issue=5 |pages=1782–91 |year=2011 |pmid=21741921 |pmc=3417828 |doi=10.1053/j.gastro.2011.06.072 |url=}}</ref><ref name="pmid22180058">{{cite journal |vauthors=Jeffery IB, O'Toole PW, Öhman L, Claesson MJ, Deane J, Quigley EM, Simrén M |title=An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota |journal=Gut |volume=61 |issue=7 |pages=997–1006 |year=2012 |pmid=22180058 |doi=10.1136/gutjnl-2011-301501 |url=}}</ref><ref name="pmid20117111">{{cite journal |vauthors=Ford AC, Thabane M, Collins SM, Moayyedi P, Garg AX, Clark WF, Marshall JK |title=Prevalence of uninvestigated dyspepsia 8 years after a large waterborne outbreak of bacterial dysentery: a cohort study |journal=Gastroenterology |volume=138 |issue=5 |pages=1727–36; quiz e12 |year=2010 |pmid=20117111 |doi=10.1053/j.gastro.2010.01.043 |url=}}</ref>
*** The [[Tumor necrosis factors|TNF]] [[antagonist]] [[infliximab]] counteracts pain in [[Irritable bowel syndrome|IBS]] patients, proving [[Tumor necrosis factors|TNF]] involvement in mechanical [[hypersensitivity]] of the [[Colon (anatomy)|colonic]] [[afferent nerve]] endings.<ref name="pmid25063707">{{cite journal |vauthors=Hughes PA, Moretta M, Lim A, Grasby DJ, Bird D, Brierley SM, Liebregts T, Adam B, Blackshaw LA, Holtmann G, Bampton P, Hoffmann P, Andrews JM, Zola H, Krumbiegel D |title=Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients |journal=Brain Behav. Immun. |volume=42 |issue= |pages=191–203 |year=2014 |pmid=25063707 |doi=10.1016/j.bbi.2014.07.001 |url=}}</ref>
** Inoculation of germ free animals with fecal microbiota from IBS patients has demonstrated increased colonic hypersensitivity, as compared to samples inoculated from healthy controls, showing that altered gut microbiota may be responsible for symptoms in IBS patients. <ref name="pmid23433203">{{cite journal |vauthors=Crouzet L, Gaultier E, Del'Homme C, Cartier C, Delmas E, Dapoigny M, Fioramonti J, Bernalier-Donadille A |title=The hypersensitivity to colonic distension of IBS patients can be transferred to rats through their fecal microbiota |journal=Neurogastroenterol. Motil. |volume=25 |issue=4 |pages=e272–82 |year=2013 |pmid=23433203 |doi=10.1111/nmo.12103 |url=}}</ref>
* '''Altered gut microbiota'''
** Acute GI infection that alters gut microflora switches on a T-helper-2 immune-cell response and causes increased susceptibility to the development of IBS. It is understood that the fecal microbiota in patients with post infectious IBS differs markedly from healthy controls, with decrease in the diversity of the fecal microbiome, correlating with increased numbers of CD8 and CD4RA-positive intraepithelial lymphocytes. <ref name="pmid25521822">{{cite journal |vauthors=Sundin J, Rangel I, Fuentes S, Heikamp-de Jong I, Hultgren-Hörnquist E, de Vos WM, Brummer RJ |title=Altered faecal and mucosal microbial composition in post-infectious irritable bowel syndrome patients correlates with mucosal lymphocyte phenotypes and psychological distress |journal=Aliment. Pharmacol. Ther. |volume=41 |issue=4 |pages=342–51 |year=2015 |pmid=25521822 |doi=10.1111/apt.13055 |url=}}</ref><ref name="pmid26071133">{{cite journal |vauthors=Wouters MM, Van Wanrooy S, Nguyen A, Dooley J, Aguilera-Lizarraga J, Van Brabant W, Garcia-Perez JE, Van Oudenhove L, Van Ranst M, Verhaegen J, Liston A, Boeckxstaens G |title=Psychological comorbidity increases the risk for postinfectious IBS partly by enhanced susceptibility to develop infectious gastroenteritis |journal=Gut |volume=65 |issue=8 |pages=1279–88 |year=2016 |pmid=26071133 |doi=10.1136/gutjnl-2015-309460 |url=}}</ref><ref name="pmid26729548">{{cite journal |vauthors=Riddle MS, Welsh M, Porter CK, Nieh C, Boyko EJ, Gackstetter G, Hooper TI |title=The Epidemiology of Irritable Bowel Syndrome in the US Military: Findings from the Millennium Cohort Study |journal=Am. J. Gastroenterol. |volume=111 |issue=1 |pages=93–104 |year=2016 |pmid=26729548 |pmc=4759150 |doi=10.1038/ajg.2015.386 |url=}}</ref>
** [[Gut flora|Fecal microflora]] in [[Irritable bowel syndrome|IBS]] patients differ from healthy individuals. Some IBS patients have [[Colon (anatomy)|colonic]] [[Spirochaete|spirochaetosis]], with a unique pathology of increased [[Lymphatic system|lymphoid]] follicles and [[Eosinophil granulocyte|eosinophils]] on [[histology]].<ref name="pmid20427395" /><ref name="pmid25540866">{{cite journal |vauthors=Walker MM, Talley NJ, Inganäs L, Engstrand L, Jones MP, Nyhlin H, Agréus L, Kjellstrom L, Öst Å, Andreasson A |title=Colonic spirochetosis is associated with colonic eosinophilia and irritable bowel syndrome in a general population in Sweden |journal=Hum. Pathol. |volume=46 |issue=2 |pages=277–83 |year=2015 |pmid=25540866 |doi=10.1016/j.humpath.2014.10.026 |url=}}</ref><ref name="pmid17631127">{{cite journal |vauthors=Kassinen A, Krogius-Kurikka L, Mäkivuokko H, Rinttilä T, Paulin L, Corander J, Malinen E, Apajalahti J, Palva A |title=The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects |journal=Gastroenterology |volume=133 |issue=1 |pages=24–33 |year=2007 |pmid=17631127 |doi=10.1053/j.gastro.2007.04.005 |url=}}</ref><ref name="pmid15667495">{{cite journal |vauthors=Malinen E, Rinttilä T, Kajander K, Mättö J, Kassinen A, Krogius L, Saarela M, Korpela R, Palva A |title=Analysis of the fecal microbiota of irritable bowel syndrome patients and healthy controls with real-time PCR |journal=Am. J. Gastroenterol. |volume=100 |issue=2 |pages=373–82 |year=2005 |pmid=15667495 |doi=10.1111/j.1572-0241.2005.40312.x |url=}}</ref><ref name="pmid21820992">{{cite journal |vauthors=Rajilić-Stojanović M, Biagi E, Heilig HG, Kajander K, Kekkonen RA, Tims S, de Vos WM |title=Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome |journal=Gastroenterology |volume=141 |issue=5 |pages=1792–801 |year=2011 |pmid=21820992 |doi=10.1053/j.gastro.2011.07.043 |url=}}</ref><ref name="pmid21741921">{{cite journal |vauthors=Saulnier DM, Riehle K, Mistretta TA, Diaz MA, Mandal D, Raza S, Weidler EM, Qin X, Coarfa C, Milosavljevic A, Petrosino JF, Highlander S, Gibbs R, Lynch SV, Shulman RJ, Versalovic J |title=Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome |journal=Gastroenterology |volume=141 |issue=5 |pages=1782–91 |year=2011 |pmid=21741921 |pmc=3417828 |doi=10.1053/j.gastro.2011.06.072 |url=}}</ref><ref name="pmid22180058">{{cite journal |vauthors=Jeffery IB, O'Toole PW, Öhman L, Claesson MJ, Deane J, Quigley EM, Simrén M |title=An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota |journal=Gut |volume=61 |issue=7 |pages=997–1006 |year=2012 |pmid=22180058 |doi=10.1136/gutjnl-2011-301501 |url=}}</ref><ref name="pmid20117111">{{cite journal |vauthors=Ford AC, Thabane M, Collins SM, Moayyedi P, Garg AX, Clark WF, Marshall JK |title=Prevalence of uninvestigated dyspepsia 8 years after a large waterborne outbreak of bacterial dysentery: a cohort study |journal=Gastroenterology |volume=138 |issue=5 |pages=1727–36; quiz e12 |year=2010 |pmid=20117111 |doi=10.1053/j.gastro.2010.01.043 |url=}}</ref>
** The fact that patients benefit from probiotics that serve to alter metabolism and composition of the microflora, shows that the composition of gut microflora determines an individual's predisposition to IBS.  Administration of probiotics and probiotic yogurt containing Bacteroides in patients has been found to decrease flatulence in patients relative to Lactobacillus.<ref name="pmid22713265">{{cite journal |vauthors=Maccaferri S, Candela M, Turroni S, Centanni M, Severgnini M, Consolandi C, Cavina P, Brigidi P |title=IBS-associated phylogenetic unbalances of the intestinal microbiota are not reverted by probiotic supplementation |journal=Gut Microbes |volume=3 |issue=5 |pages=406–13 |year=2012 |pmid=22713265 |doi=10.4161/gmic.21009 |url=}}</ref><ref name="pmid22315951">{{cite journal |vauthors=Chassard C, Dapoigny M, Scott KP, Crouzet L, Del'homme C, Marquet P, Martin JC, Pickering G, Ardid D, Eschalier A, Dubray C, Flint HJ, Bernalier-Donadille A |title=Functional dysbiosis within the gut microbiota of patients with constipated-irritable bowel syndrome |journal=Aliment. Pharmacol. Ther. |volume=35 |issue=7 |pages=828–38 |year=2012 |pmid=22315951 |doi=10.1111/j.1365-2036.2012.05007.x |url=}}</ref><ref name="pmid18806702">{{cite journal |vauthors=Camilleri M |title=Probiotics and irritable bowel syndrome: rationale, mechanisms, and efficacy |journal=J. Clin. Gastroenterol. |volume=42 Suppl 3 Pt 1 |issue= |pages=S123–5 |year=2008 |pmid=18806702 |doi=10.1097/MCG.0b013e3181574393 |url=}}</ref><ref name="pmid10811333">{{cite journal |vauthors=Nobaek S, Johansson ML, Molin G, Ahrné S, Jeppsson B |title=Alteration of intestinal microflora is associated with reduction in abdominal bloating and pain in patients with irritable bowel syndrome |journal=Am. J. Gastroenterol. |volume=95 |issue=5 |pages=1231–8 |year=2000 |pmid=10811333 |doi=10.1111/j.1572-0241.2000.02015.x |url=}}</ref>  
** Acute [[Gastrointestinal tract|GI]] [[infection]] alters [[Gut flora|gut microflora]] switches on a [[T helper cell|T-helper-2]] [[Immunity (medical)|immune]]-cell response with increased numbers of [[CD8]] and CD4RA-positive [[Intraepithelial lymphocyte|intraepithelial]] [[Lymphocyte|lymphocytes]], causing increased susceptibility to the development of [[Irritable bowel syndrome|IBS]].   <ref name="pmid25521822">{{cite journal |vauthors=Sundin J, Rangel I, Fuentes S, Heikamp-de Jong I, Hultgren-Hörnquist E, de Vos WM, Brummer RJ |title=Altered faecal and mucosal microbial composition in post-infectious irritable bowel syndrome patients correlates with mucosal lymphocyte phenotypes and psychological distress |journal=Aliment. Pharmacol. Ther. |volume=41 |issue=4 |pages=342–51 |year=2015 |pmid=25521822 |doi=10.1111/apt.13055 |url=}}</ref><ref name="pmid26071133">{{cite journal |vauthors=Wouters MM, Van Wanrooy S, Nguyen A, Dooley J, Aguilera-Lizarraga J, Van Brabant W, Garcia-Perez JE, Van Oudenhove L, Van Ranst M, Verhaegen J, Liston A, Boeckxstaens G |title=Psychological comorbidity increases the risk for postinfectious IBS partly by enhanced susceptibility to develop infectious gastroenteritis |journal=Gut |volume=65 |issue=8 |pages=1279–88 |year=2016 |pmid=26071133 |doi=10.1136/gutjnl-2015-309460 |url=}}</ref><ref name="pmid26729548">{{cite journal |vauthors=Riddle MS, Welsh M, Porter CK, Nieh C, Boyko EJ, Gackstetter G, Hooper TI |title=The Epidemiology of Irritable Bowel Syndrome in the US Military: Findings from the Millennium Cohort Study |journal=Am. J. Gastroenterol. |volume=111 |issue=1 |pages=93–104 |year=2016 |pmid=26729548 |pmc=4759150 |doi=10.1038/ajg.2015.386 |url=}}</ref>
** Altered [[Gut flora|gut microbiota]] causes increased [[Colon (anatomy)|colonic]] [[hypersensitivity]]. <ref name="pmid23433203">{{cite journal |vauthors=Crouzet L, Gaultier E, Del'Homme C, Cartier C, Delmas E, Dapoigny M, Fioramonti J, Bernalier-Donadille A |title=The hypersensitivity to colonic distension of IBS patients can be transferred to rats through their fecal microbiota |journal=Neurogastroenterol. Motil. |volume=25 |issue=4 |pages=e272–82 |year=2013 |pmid=23433203 |doi=10.1111/nmo.12103 |url=}}</ref>
* '''Abnormal serotonin pathways'''
* '''Abnormal serotonin pathways'''
** Serotonin(5-HT) is an important neurotransmitter produced by the enterochromaffin cells in the colon, in response to chemical and mechanical stimuli (short chain fatty acids produced by gastrointestinal microflora and food) and is increased in IBS patients with diarrhea as compared to controls.<ref name="pmid14724817">{{cite journal |vauthors=Dunlop SP, Jenkins D, Neal KR, Spiller RC |title=Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS |journal=Gastroenterology |volume=125 |issue=6 |pages=1651–9 |year=2003 |pmid=14724817 |doi= |url=}}</ref><ref name="pmid2078274">{{cite journal |vauthors=Gershon MD, Wade PR, Kirchgessner AL, Tamir H |title=5-HT receptor subtypes outside the central nervous system. Roles in the physiology of the gut |journal=Neuropsychopharmacology |volume=3 |issue=5-6 |pages=385–95 |year=1990 |pmid=2078274 |doi= |url=}}</ref><ref name="pmid19630576">{{cite journal |vauthors=Berger M, Gray JA, Roth BL |title=The expanded biology of serotonin |journal=Annu. Rev. Med. |volume=60 |issue= |pages=355–66 |year=2009 |pmid=19630576 |doi=10.1146/annurev.med.60.042307.110802 |url=}}</ref><ref name="pmid15822040">{{cite journal |vauthors=Dunlop SP, Coleman NS, Blackshaw E, Perkins AC, Singh G, Marsden CA, Spiller RC |title=Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome |journal=Clin. Gastroenterol. Hepatol. |volume=3 |issue=4 |pages=349–57 |year=2005 |pmid=15822040 |doi= |url=}}</ref><ref name="pmid16401466">{{cite journal |vauthors=Atkinson W, Lockhart S, Whorwell PJ, Keevil B, Houghton LA |title=Altered 5-hydroxytryptamine signaling in patients with constipation- and diarrhea-predominant irritable bowel syndrome |journal=Gastroenterology |volume=130 |issue=1 |pages=34–43 |year=2006 |pmid=16401466 |doi=10.1053/j.gastro.2005.09.031 |url=}}</ref><ref name="pmid23222853">{{cite journal |vauthors=Gershon MD |title=5-Hydroxytryptamine (serotonin) in the gastrointestinal tract |journal=Curr Opin Endocrinol Diabetes Obes |volume=20 |issue=1 |pages=14–21 |year=2013 |pmid=23222853 |pmc=3708472 |doi=10.1097/MED.0b013e32835bc703 |url=}}</ref><ref name="pmid23872499">{{cite journal |vauthors=Shekhar C, Monaghan PJ, Morris J, Issa B, Whorwell PJ, Keevil B, Houghton LA |title=Rome III functional constipation and irritable bowel syndrome with constipation are similar disorders within a spectrum of sensitization, regulated by serotonin |journal=Gastroenterology |volume=145 |issue=4 |pages=749–57; quiz e13–4 |year=2013 |pmid=23872499 |doi=10.1053/j.gastro.2013.07.014 |url=}}</ref>   
** [[Serotonin]](5-HT) is an important [[neurotransmitter]] produced by the [[Enterochromaffin cell|enterochromaffin cells]] in the [[Colon (anatomy)|colon]], in response to [[Chemical substance|chemical]] stimuli ([[Short chain fatty acid|short chain fatty acids]] produced by [[Gut flora|gastrointestinal microflora]] ) and mechanical [[Stimulus (physiology)|stimuli]] ( food) and is increased in [[Irritable bowel syndrome|IBS]] patients.<ref name="pmid14724817">{{cite journal |vauthors=Dunlop SP, Jenkins D, Neal KR, Spiller RC |title=Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS |journal=Gastroenterology |volume=125 |issue=6 |pages=1651–9 |year=2003 |pmid=14724817 |doi= |url=}}</ref><ref name="pmid2078274">{{cite journal |vauthors=Gershon MD, Wade PR, Kirchgessner AL, Tamir H |title=5-HT receptor subtypes outside the central nervous system. Roles in the physiology of the gut |journal=Neuropsychopharmacology |volume=3 |issue=5-6 |pages=385–95 |year=1990 |pmid=2078274 |doi= |url=}}</ref><ref name="pmid19630576">{{cite journal |vauthors=Berger M, Gray JA, Roth BL |title=The expanded biology of serotonin |journal=Annu. Rev. Med. |volume=60 |issue= |pages=355–66 |year=2009 |pmid=19630576 |doi=10.1146/annurev.med.60.042307.110802 |url=}}</ref><ref name="pmid15822040">{{cite journal |vauthors=Dunlop SP, Coleman NS, Blackshaw E, Perkins AC, Singh G, Marsden CA, Spiller RC |title=Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome |journal=Clin. Gastroenterol. Hepatol. |volume=3 |issue=4 |pages=349–57 |year=2005 |pmid=15822040 |doi= |url=}}</ref><ref name="pmid16401466">{{cite journal |vauthors=Atkinson W, Lockhart S, Whorwell PJ, Keevil B, Houghton LA |title=Altered 5-hydroxytryptamine signaling in patients with constipation- and diarrhea-predominant irritable bowel syndrome |journal=Gastroenterology |volume=130 |issue=1 |pages=34–43 |year=2006 |pmid=16401466 |doi=10.1053/j.gastro.2005.09.031 |url=}}</ref><ref name="pmid23222853">{{cite journal |vauthors=Gershon MD |title=5-Hydroxytryptamine (serotonin) in the gastrointestinal tract |journal=Curr Opin Endocrinol Diabetes Obes |volume=20 |issue=1 |pages=14–21 |year=2013 |pmid=23222853 |pmc=3708472 |doi=10.1097/MED.0b013e32835bc703 |url=}}</ref><ref name="pmid23872499">{{cite journal |vauthors=Shekhar C, Monaghan PJ, Morris J, Issa B, Whorwell PJ, Keevil B, Houghton LA |title=Rome III functional constipation and irritable bowel syndrome with constipation are similar disorders within a spectrum of sensitization, regulated by serotonin |journal=Gastroenterology |volume=145 |issue=4 |pages=749–57; quiz e13–4 |year=2013 |pmid=23872499 |doi=10.1053/j.gastro.2013.07.014 |url=}}</ref>   
** Serotonin affects gastrointestinal motility and influences CNS transmission of information. It is known that the spontaneous release of 5-HT is markedly elevated in IBS patients, regardless of bowel habit and directly correlates with abdominal pain severity.<ref name="pmid21427712">{{cite journal |vauthors=Cremon C, Carini G, Wang B, Vasina V, Cogliandro RF, De Giorgio R, Stanghellini V, Grundy D, Tonini M, De Ponti F, Corinaldesi R, Barbara G |title=Intestinal serotonin release, sensory neuron activation, and abdominal pain in irritable bowel syndrome |journal=Am. J. Gastroenterol. |volume=106 |issue=7 |pages=1290–8 |year=2011 |pmid=21427712 |doi=10.1038/ajg.2011.86 |url=}}</ref>
** [[Serotonin]] affects [[Gastrointestinal tract|gastrointestinal]] [[motility]] and [[Viscus|visceral]] pain perception. Spontaneous release of 5-[[Serotonin|HT]] correlates with [[abdominal pain]] severity.<ref name="pmid21427712">{{cite journal |vauthors=Cremon C, Carini G, Wang B, Vasina V, Cogliandro RF, De Giorgio R, Stanghellini V, Grundy D, Tonini M, De Ponti F, Corinaldesi R, Barbara G |title=Intestinal serotonin release, sensory neuron activation, and abdominal pain in irritable bowel syndrome |journal=Am. J. Gastroenterol. |volume=106 |issue=7 |pages=1290–8 |year=2011 |pmid=21427712 |doi=10.1038/ajg.2011.86 |url=}}</ref>  
** Serotonin plays a vital role in visceral perception and motility and its increased production contributes to postprandial symptoms in IBS patients, hence providing the rationale for the therapeutic efficacy of 5-HT 3 receptor antagonists and 5-HT 4 receptor agonists on symptoms in IBS patients.<ref name="pmid17241888">{{cite journal |vauthors=Gershon MD, Tack J |title=The serotonin signaling system: from basic understanding to drug development for functional GI disorders |journal=Gastroenterology |volume=132 |issue=1 |pages=397–414 |year=2007 |pmid=17241888 |doi=10.1053/j.gastro.2006.11.002 |url=}}</ref><ref name="pmid22071696">{{cite journal |vauthors=Camilleri M |title=Pharmacology of the new treatments for lower gastrointestinal motility disorders and irritable bowel syndrome |journal=Clin. Pharmacol. Ther. |volume=91 |issue=1 |pages=44–59 |year=2012 |pmid=22071696 |doi=10.1038/clpt.2011.261 |url=}}</ref>
** There is an established relationship between [[Irritable bowel syndrome|IBS]] and [[polymorphisms]] in the gene for [[serotonin]] transport causing alteration in [[Intestine|intestinal]] [[peristalsis]] due to change in the [[serotonin]] reuptake efficacy.<ref name="pmid24060757">{{cite journal |vauthors=Grasberger H, Chang L, Shih W, Presson AP, Sayuk GS, Newberry RD, Karagiannides I, Pothoulakis C, Mayer E, Merchant JL |title=Identification of a functional TPH1 polymorphism associated with irritable bowel syndrome bowel habit subtypes |journal=Am. J. Gastroenterol. |volume=108 |issue=11 |pages=1766–74 |year=2013 |pmid=24060757 |pmc=4067697 |doi=10.1038/ajg.2013.304 |url=}}</ref><ref name="pmid21073637">{{cite journal |vauthors=Jun S, Kohen R, Cain KC, Jarrett ME, Heitkemper MM |title=Associations of tryptophan hydroxylase gene polymorphisms with irritable bowel syndrome |journal=Neurogastroenterol. Motil. |volume=23 |issue=3 |pages=233–9, e116 |year=2011 |pmid=21073637 |pmc=3057463 |doi=10.1111/j.1365-2982.2010.01623.x |url=}}</ref><ref name="pmid15138209">{{cite journal |vauthors=Kim HJ, Camilleri M, Carlson PJ, Cremonini F, Ferber I, Stephens D, McKinzie S, Zinsmeister AR, Urrutia R |title=Association of distinct alpha(2) adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders |journal=Gut |volume=53 |issue=6 |pages=829–37 |year=2004 |pmid=15138209 |pmc=1774073 |doi= |url=}}</ref><ref name="pmid15361494">{{cite journal |vauthors=Yeo A, Boyd P, Lumsden S, Saunders T, Handley A, Stubbins M, Knaggs A, Asquith S, Taylor I, Bahari B, Crocker N, Rallan R, Varsani S, Montgomery D, Alpers DH, Dukes GE, Purvis I, Hicks GA |title=Association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome in women |journal=Gut |volume=53 |issue=10 |pages=1452–8 |year=2004 |pmid=15361494 |pmc=1774243 |doi=10.1136/gut.2003.035451 |url=}}</ref> 
** Increased [[serotonin]] production contributes to [[postprandial]] symptoms in [[Irritable bowel syndrome|IBS]] patients, hence providing the rationale for the therapeutic efficacy of 5-HT 3 receptor [[Receptor antagonist|antagonists]] and 5-HT 4 receptor [[Agonist|agonists]] on symptoms in [[Irritable bowel syndrome|IBS]] patients.<ref name="pmid17241888">{{cite journal |vauthors=Gershon MD, Tack J |title=The serotonin signaling system: from basic understanding to drug development for functional GI disorders |journal=Gastroenterology |volume=132 |issue=1 |pages=397–414 |year=2007 |pmid=17241888 |doi=10.1053/j.gastro.2006.11.002 |url=}}</ref><ref name="pmid22071696">{{cite journal |vauthors=Camilleri M |title=Pharmacology of the new treatments for lower gastrointestinal motility disorders and irritable bowel syndrome |journal=Clin. Pharmacol. Ther. |volume=91 |issue=1 |pages=44–59 |year=2012 |pmid=22071696 |doi=10.1038/clpt.2011.261 |url=}}</ref>
 
==='''Psychosocial factors and CNS dysregulation'''===
* [[Symptom]] exacerbation occurs in [[Irritable bowel syndrome|IBS]] patients with emotional disturbances,[[Stress (medicine)|stress]], [[anxiety]] or [[depression]]. Traumatic experiences before 18 years of age directly shape adult connectivity in the executive control network consisting of structures such as the [[Insular cortex|insula]], anterior [[cingulate cortex]] and the [[thalamus]].
* Semipermanent/permanent changes in complex [[Nervous system|neural]] circuits lead to central pain amplification and contribute to [[abdominal pain]] in IBS patients.<ref name="pmid27061107">{{cite journal |vauthors=Park SH, Videlock EJ, Shih W, Presson AP, Mayer EA, Chang L |title=Adverse childhood experiences are associated with irritable bowel syndrome and gastrointestinal symptom severity |journal=Neurogastroenterol. Motil. |volume=28 |issue=8 |pages=1252–60 |year=2016 |pmid=27061107 |pmc=4956522 |doi=10.1111/nmo.12826 |url=}}</ref><ref name="pmid25003944">{{cite journal |vauthors=Gupta A, Kilpatrick L, Labus J, Tillisch K, Braun A, Hong JY, Ashe-McNalley C, Naliboff B, Mayer EA |title=Early adverse life events and resting state neural networks in patients with chronic abdominal pain: evidence for sex differences |journal=Psychosom Med |volume=76 |issue=6 |pages=404–12 |year=2014 |pmid=25003944 |pmc=4113723 |doi=10.1097/PSY.0000000000000089 |url=}}</ref>
* The dorsolateral [[prefrontal cortex]] activity (responsible for vigilance and alertness of the human brain) and the mid-[[Cingulate cortex|cingulate corte]]<nowiki/>x (engaged in attention pathways and responses) is reduced in [[Irritable bowel syndrome|IBS]] patients, seen on advanced brain imaging techniques as irregularities in the mid- [[cingulate cortex]] and [[prefrontal cortex]] on [[Diffusion MRI|diffusion tensor imaging]]. <ref name="pmid23864686">{{cite journal |vauthors=Hong JY, Kilpatrick LA, Labus J, Gupta A, Jiang Z, Ashe-McNalley C, Stains J, Heendeniya N, Ebrat B, Smith S, Tillisch K, Naliboff B, Mayer EA |title=Patients with chronic visceral pain show sex-related alterations in intrinsic oscillations of the resting brain |journal=J. Neurosci. |volume=33 |issue=29 |pages=11994–2002 |year=2013 |pmid=23864686 |pmc=3713732 |doi=10.1523/JNEUROSCI.5733-12.2013 |url=}}</ref>
* [[prefrontal cortex]] modulation may lead to increased perception of [[Viscus|visceral]] pain.
* Modulation of the mid-[[cingulate cortex]] is associated with alterations in the subjective sensations of pain.<ref name="pmid22108191">{{cite journal |vauthors=Larsson MB, Tillisch K, Craig AD, Engström M, Labus J, Naliboff B, Lundberg P, Ström M, Mayer EA, Walter SA |title=Brain responses to visceral stimuli reflect visceral sensitivity thresholds in patients with irritable bowel syndrome |journal=Gastroenterology |volume=142 |issue=3 |pages=463–472.e3 |year=2012 |pmid=22108191 |pmc=3288538 |doi=10.1053/j.gastro.2011.11.022 |url=}}</ref><ref name="pmid27144627">{{cite journal |vauthors=Mearin F, Lacy BE, Chang L, Chey WD, Lembo AJ, Simren M, Spiller R |title=Bowel Disorders |journal=Gastroenterology |volume= |issue= |pages= |year=2016 |pmid=27144627 |doi=10.1053/j.gastro.2016.02.031 |url=}}</ref>
* Patients with IBS have aberrant processing of central information, with decreased feedback on the emotional arousal network that controls the [[Autonomic nervous system|autonomic]] activity of the [[Gastrointestinal tract|gastrointestinal]] tract and changes gut [[motility]].<ref name="pmid23721972">{{cite journal |vauthors=Ellingson BM, Mayer E, Harris RJ, Ashe-McNally C, Naliboff BD, Labus JS, Tillisch K |title=Diffusion tensor imaging detects microstructural reorganization in the brain associated with chronic irritable bowel syndrome |journal=Pain |volume=154 |issue=9 |pages=1528–41 |year=2013 |pmid=23721972 |pmc=3758125 |doi=10.1016/j.pain.2013.04.010 |url=}}</ref><ref name="pmid20003075">{{cite journal |vauthors=Hall GB, Kamath MV, Collins S, Ganguli S, Spaziani R, Miranda KL, Bayati A, Bienenstock J |title=Heightened central affective response to visceral sensations of pain and discomfort in IBS |journal=Neurogastroenterol. Motil. |volume=22 |issue=3 |pages=276–e80 |year=2010 |pmid=20003075 |doi=10.1111/j.1365-2982.2009.01436.x |url=}}</ref>
* IBS is a [[brain]] [[Gastrointestinal tract|gut]] disorder as [[Rectum|rectal]] distension in patients causes increased engagement of regions of the [[brain]] associated with attentional and [[Behavior|behavioral]] responses.<ref name="pmid22108191">{{cite journal |vauthors=Larsson MB, Tillisch K, Craig AD, Engström M, Labus J, Naliboff B, Lundberg P, Ström M, Mayer EA, Walter SA |title=Brain responses to visceral stimuli reflect visceral sensitivity thresholds in patients with irritable bowel syndrome |journal=Gastroenterology |volume=142 |issue=3 |pages=463–472.e3 |year=2012 |pmid=22108191 |pmc=3288538 |doi=10.1053/j.gastro.2011.11.022 |url=}}</ref><ref name="pmid20600024">{{cite journal |vauthors=Elsenbruch S, Rosenberger C, Bingel U, Forsting M, Schedlowski M, Gizewski ER |title=Patients with irritable bowel syndrome have altered emotional modulation of neural responses to visceral stimuli |journal=Gastroenterology |volume=139 |issue=4 |pages=1310–9 |year=2010 |pmid=20600024 |doi=10.1053/j.gastro.2010.06.054 |url=}}</ref><ref name="pmid19651629">{{cite journal |vauthors=Elsenbruch S, Rosenberger C, Enck P, Forsting M, Schedlowski M, Gizewski ER |title=Affective disturbances modulate the neural processing of visceral pain stimuli in irritable bowel syndrome: an fMRI study |journal=Gut |volume=59 |issue=4 |pages=489–95 |year=2010 |pmid=19651629 |doi=10.1136/gut.2008.175000 |url=}}</ref>
* [[Stress (medicine)|Psychological stress]] also impacts the release of gut [[Inflammation|proinflammatory]] [[Cytokine|cytokines]], contributing to pain in [[Irritable bowel syndrome|IBS]] patients.<ref name="pmid19997094" />


==Genetics==
==Genetic factors==
*IBS is a complex disease with interactions between genetic and environmental factors. The role of genetic predisposition in IBS is suggested by epidemiological studies of twins and familial aggregation.<ref name="pmid17509102">{{cite journal |vauthors=Lembo A, Zaman M, Jones M, Talley NJ |title=Influence of genetics on irritable bowel syndrome, gastro-oesophageal reflux and dyspepsia: a twin study |journal=Aliment. Pharmacol. Ther. |volume=25 |issue=11 |pages=1343–50 |year=2007 |pmid=17509102 |doi=10.1111/j.1365-2036.2007.03326.x |url=}}</ref><ref name="pmid11606493">{{cite journal |vauthors=Levy RL, Jones KR, Whitehead WE, Feld SI, Talley NJ, Corey LA |title=Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology |journal=Gastroenterology |volume=121 |issue=4 |pages=799–804 |year=2001 |pmid=11606493 |doi= |url=}}</ref><ref name="pmid16271334">{{cite journal |vauthors=Saito YA, Petersen GM, Locke GR, Talley NJ |title=The genetics of irritable bowel syndrome |journal=Clin. Gastroenterol. Hepatol. |volume=3 |issue=11 |pages=1057–65 |year=2005 |pmid=16271334 |doi= |url=}}</ref><ref name="pmid24041540">{{cite journal |vauthors=Wouters MM, Lambrechts D, Knapp M, Cleynen I, Whorwell P, Agréus L, Dlugosz A, Schmidt PT, Halfvarson J, Simrén M, Ohlsson B, Karling P, Van Wanrooy S, Mondelaers S, Vermeire S, Lindberg G, Spiller R, Dukes G, D'Amato M, Boeckxstaens G |title=Genetic variants in CDC42 and NXPH1 as susceptibility factors for constipation and diarrhoea predominant irritable bowel syndrome |journal=Gut |volume=63 |issue=7 |pages=1103–11 |year=2014 |pmid=24041540 |doi=10.1136/gutjnl-2013-304570 |url=}}</ref><ref name="pmid20234344">{{cite journal |vauthors=Saito YA, Petersen GM, Larson JJ, Atkinson EJ, Fridley BL, de Andrade M, Locke GR, Zimmerman JM, Almazar-Elder AE, Talley NJ |title=Familial aggregation of irritable bowel syndrome: a family case-control study |journal=Am. J. Gastroenterol. |volume=105 |issue=4 |pages=833–41 |year=2010 |pmid=20234344 |pmc=2875200 |doi=10.1038/ajg.2010.116 |url=}}</ref>
*IBS has high '''[[twin]] [[Concordance (genetics)|concordance]] and [[Family|familial]] [[aggregation]]''':<ref name="pmid11606493">{{cite journal |vauthors=Levy RL, Jones KR, Whitehead WE, Feld SI, Talley NJ, Corey LA |title=Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology |journal=Gastroenterology |volume=121 |issue=4 |pages=799–804 |year=2001 |pmid=11606493 |doi= |url=}}</ref><ref name="pmid9707057">{{cite journal |vauthors=Morris-Yates A, Talley NJ, Boyce PM, Nandurkar S, Andrews G |title=Evidence of a genetic contribution to functional bowel disorder |journal=Am. J. Gastroenterol. |volume=93 |issue=8 |pages=1311–7 |year=1998 |pmid=9707057 |doi=10.1111/j.1572-0241.1998.440_j.x |url=}}</ref><ref name="pmid17509102">{{cite journal |vauthors=Lembo A, Zaman M, Jones M, Talley NJ |title=Influence of genetics on irritable bowel syndrome, gastro-oesophageal reflux and dyspepsia: a twin study |journal=Aliment. Pharmacol. Ther. |volume=25 |issue=11 |pages=1343–50 |year=2007 |pmid=17509102 |doi=10.1111/j.1365-2036.2007.03326.x |url=}}</ref><ref name="pmid16271334">{{cite journal |vauthors=Saito YA, Petersen GM, Locke GR, Talley NJ |title=The genetics of irritable bowel syndrome |journal=Clin. Gastroenterol. Hepatol. |volume=3 |issue=11 |pages=1057–65 |year=2005 |pmid=16271334 |doi= |url=}}</ref><ref name="pmid24041540">{{cite journal |vauthors=Wouters MM, Lambrechts D, Knapp M, Cleynen I, Whorwell P, Agréus L, Dlugosz A, Schmidt PT, Halfvarson J, Simrén M, Ohlsson B, Karling P, Van Wanrooy S, Mondelaers S, Vermeire S, Lindberg G, Spiller R, Dukes G, D'Amato M, Boeckxstaens G |title=Genetic variants in CDC42 and NXPH1 as susceptibility factors for constipation and diarrhoea predominant irritable bowel syndrome |journal=Gut |volume=63 |issue=7 |pages=1103–11 |year=2014 |pmid=24041540 |doi=10.1136/gutjnl-2013-304570 |url=}}</ref><ref name="pmid20234344">{{cite journal |vauthors=Saito YA, Petersen GM, Larson JJ, Atkinson EJ, Fridley BL, de Andrade M, Locke GR, Zimmerman JM, Almazar-Elder AE, Talley NJ |title=Familial aggregation of irritable bowel syndrome: a family case-control study |journal=Am. J. Gastroenterol. |volume=105 |issue=4 |pages=833–41 |year=2010 |pmid=20234344 |pmc=2875200 |doi=10.1038/ajg.2010.116 |url=}}</ref>
*Investigations show higher concordance of IBS in monozygotic as compared to dizygotic twins, thereby proving the role of genetic factors in IBS.<ref name="pmid11606493">{{cite journal |vauthors=Levy RL, Jones KR, Whitehead WE, Feld SI, Talley NJ, Corey LA |title=Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology |journal=Gastroenterology |volume=121 |issue=4 |pages=799–804 |year=2001 |pmid=11606493 |doi= |url=}}</ref><ref name="pmid17509102">{{cite journal |vauthors=Lembo A, Zaman M, Jones M, Talley NJ |title=Influence of genetics on irritable bowel syndrome, gastro-oesophageal reflux and dyspepsia: a twin study |journal=Aliment. Pharmacol. Ther. |volume=25 |issue=11 |pages=1343–50 |year=2007 |pmid=17509102 |doi=10.1111/j.1365-2036.2007.03326.x |url=}}</ref><ref name="pmid17008364">{{cite journal |vauthors=Bengtson MB, Rønning T, Vatn MH, Harris JR |title=Irritable bowel syndrome in twins: genes and environment |journal=Gut |volume=55 |issue=12 |pages=1754–9 |year=2006 |pmid=17008364 |pmc=1856463 |doi=10.1136/gut.2006.097287 |url=}}</ref><ref name="pmid9707057">{{cite journal |vauthors=Morris-Yates A, Talley NJ, Boyce PM, Nandurkar S, Andrews G |title=Evidence of a genetic contribution to functional bowel disorder |journal=Am. J. Gastroenterol. |volume=93 |issue=8 |pages=1311–7 |year=1998 |pmid=9707057 |doi=10.1111/j.1572-0241.1998.440_j.x |url=}}</ref>
**IBS has higher [[Concordance (genetics)|concordance]] in [[Twin|monozygotic]] as compared to [[Twin|dizygotic]] twins.<ref name="pmid11606493" /><ref name="pmid9707057" /><ref name="pmid17509102" /><ref name="pmid17008364">{{cite journal |vauthors=Bengtson MB, Rønning T, Vatn MH, Harris JR |title=Irritable bowel syndrome in twins: genes and environment |journal=Gut |volume=55 |issue=12 |pages=1754–9 |year=2006 |pmid=17008364 |pmc=1856463 |doi=10.1136/gut.2006.097287 |url=}}</ref>
*Effects of single nucleotide polymorphisms (SNPs) in genes of IBS patients have been extensively studied. SNPs in genes play an important role in host-microbiota interaction (TLR9, IL-6 and CDH1), immune activation and epithelial barriers.<ref name="pmid20044998">{{cite journal |vauthors=Villani AC, Lemire M, Thabane M, Belisle A, Geneau G, Garg AX, Clark WF, Moayyedi P, Collins SM, Franchimont D, Marshall JK |title=Genetic risk factors for post-infectious irritable bowel syndrome following a waterborne outbreak of gastroenteritis |journal=Gastroenterology |volume=138 |issue=4 |pages=1502–13 |year=2010 |pmid=20044998 |doi=10.1053/j.gastro.2009.12.049 |url=}}</ref><ref name="pmid12477767">{{cite journal |vauthors=Gonsalkorale WM, Perrey C, Pravica V, Whorwell PJ, Hutchinson IV |title=Interleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component? |journal=Gut |volume=52 |issue=1 |pages=91–3 |year=2003 |pmid=12477767 |pmc=1773523 |doi= |url=}}</ref>  
**Individuals with a biologic relative with [[Irritable bowel syndrome|IBS]] have two times a higher risk of developing [[Irritable bowel syndrome|IBS]]. <ref name="pmid10994826">{{cite journal |vauthors=Locke GR, Zinsmeister AR, Talley NJ, Fett SL, Melton LJ |title=Familial association in adults with functional gastrointestinal disorders |journal=Mayo Clin. Proc. |volume=75 |issue=9 |pages=907–12 |year=2000 |pmid=10994826 |doi=10.4065/75.9.907 |url=}}</ref>
*The mutation of type V (alpha subunit) of ''SCN5A''-encoded voltage gated sodium channel associated with congenital prolonged QT syndrome can be correlated with symptoms of Irritable bowel syndrome. IBS patients with moderately severe pain in the abdomen have showed a missense mutation in ''SCN5A'', causing loss of function of this channel, more commonly in patients with IBS associated with constipation.<ref name="pmid16771953">{{cite journal |vauthors=Locke GR, Ackerman MJ, Zinsmeister AR, Thapa P, Farrugia G |title=Gastrointestinal symptoms in families of patients with an SCN5A-encoded cardiac channelopathy: evidence of an intestinal channelopathy |journal=Am. J. Gastroenterol. |volume=101 |issue=6 |pages=1299–304 |year=2006 |pmid=16771953 |doi=10.1111/j.1572-0241.2006.00507.x |url=}}</ref><ref name="pmid19056759">{{cite journal |vauthors=Saito YA, Strege PR, Tester DJ, Locke GR, Talley NJ, Bernard CE, Rae JL, Makielski JC, Ackerman MJ, Farrugia G |title=Sodium channel mutation in irritable bowel syndrome: evidence for an ion channelopathy |journal=Am. J. Physiol. Gastrointest. Liver Physiol. |volume=296 |issue=2 |pages=G211–8 |year=2009 |pmid=19056759 |pmc=2643921 |doi=10.1152/ajpgi.90571.2008 |url=}}</ref>  
*'''[[Single nucleotide polymorphism|Single nucleotide polymorphisms (SNPs)]] in genes:'''
*There is an established relationship between IBS and polymorphisms in the gene for serotonin transport causing alteration in intestinal peristalsis due to change in the serotonin reuptake efficacy.<ref name="pmid24060757">{{cite journal |vauthors=Grasberger H, Chang L, Shih W, Presson AP, Sayuk GS, Newberry RD, Karagiannides I, Pothoulakis C, Mayer E, Merchant JL |title=Identification of a functional TPH1 polymorphism associated with irritable bowel syndrome bowel habit subtypes |journal=Am. J. Gastroenterol. |volume=108 |issue=11 |pages=1766–74 |year=2013 |pmid=24060757 |pmc=4067697 |doi=10.1038/ajg.2013.304 |url=}}</ref><ref name="pmid21073637">{{cite journal |vauthors=Jun S, Kohen R, Cain KC, Jarrett ME, Heitkemper MM |title=Associations of tryptophan hydroxylase gene polymorphisms with irritable bowel syndrome |journal=Neurogastroenterol. Motil. |volume=23 |issue=3 |pages=233–9, e116 |year=2011 |pmid=21073637 |pmc=3057463 |doi=10.1111/j.1365-2982.2010.01623.x |url=}}</ref><ref name="pmid15138209">{{cite journal |vauthors=Kim HJ, Camilleri M, Carlson PJ, Cremonini F, Ferber I, Stephens D, McKinzie S, Zinsmeister AR, Urrutia R |title=Association of distinct alpha(2) adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders |journal=Gut |volume=53 |issue=6 |pages=829–37 |year=2004 |pmid=15138209 |pmc=1774073 |doi= |url=}}</ref><ref name="pmid15361494">{{cite journal |vauthors=Yeo A, Boyd P, Lumsden S, Saunders T, Handley A, Stubbins M, Knaggs A, Asquith S, Taylor I, Bahari B, Crocker N, Rallan R, Varsani S, Montgomery D, Alpers DH, Dukes GE, Purvis I, Hicks GA |title=Association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome in women |journal=Gut |volume=53 |issue=10 |pages=1452–8 |year=2004 |pmid=15361494 |pmc=1774243 |doi=10.1136/gut.2003.035451 |url=}}</ref>  
**IBS has [[Single nucleotide polymorphism|SNPs]] in genes playing an important role in host-[[Microbiome|microbiota]] interaction ([[Toll-like receptor|TLR9]], [[Interleukin 6|IL-6]] and [[CDH11|CDH1]]), [[Immunity (medical)|immune]] activation and [[Epithelium|epithelial]] barriers. 
*It is postulated that changed patterns of interleukin production may be associated with IBS.<ref name="pmid12477767">{{cite journal |vauthors=Gonsalkorale WM, Perrey C, Pravica V, Whorwell PJ, Hutchinson IV |title=Interleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component? |journal=Gut |volume=52 |issue=1 |pages=91–3 |year=2003 |pmid=12477767 |pmc=1773523 |doi= |url=}}</ref>
**[[Single nucleotide polymorphism|SNPs]] cause [[inflammation]] and increased [[permeability]] of the [[Gastrointestinal tract|GI tract]], leading to [[Abdominal pain|abdominal discomfort]] and increased [[motility]].<ref name="pmid20044998">{{cite journal |vauthors=Villani AC, Lemire M, Thabane M, Belisle A, Geneau G, Garg AX, Clark WF, Moayyedi P, Collins SM, Franchimont D, Marshall JK |title=Genetic risk factors for post-infectious irritable bowel syndrome following a waterborne outbreak of gastroenteritis |journal=Gastroenterology |volume=138 |issue=4 |pages=1502–13 |year=2010 |pmid=20044998 |doi=10.1053/j.gastro.2009.12.049 |url=}}</ref><ref name="pmid12477767">{{cite journal |vauthors=Gonsalkorale WM, Perrey C, Pravica V, Whorwell PJ, Hutchinson IV |title=Interleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component? |journal=Gut |volume=52 |issue=1 |pages=91–3 |year=2003 |pmid=12477767 |pmc=1773523 |doi= |url=}}</ref>  
**Mutation of type V (alpha [[Protein subunit|subunit]]) of ''SCN5A''-encoded [[Voltage-gated ion channel|voltage gated]] [[sodium channel]] causes [[Irritable bowel syndrome|IBS]].<ref name="pmid16771953">{{cite journal |vauthors=Locke GR, Ackerman MJ, Zinsmeister AR, Thapa P, Farrugia G |title=Gastrointestinal symptoms in families of patients with an SCN5A-encoded cardiac channelopathy: evidence of an intestinal channelopathy |journal=Am. J. Gastroenterol. |volume=101 |issue=6 |pages=1299–304 |year=2006 |pmid=16771953 |doi=10.1111/j.1572-0241.2006.00507.x |url=}}</ref><ref name="pmid19056759">{{cite journal |vauthors=Saito YA, Strege PR, Tester DJ, Locke GR, Talley NJ, Bernard CE, Rae JL, Makielski JC, Ackerman MJ, Farrugia G |title=Sodium channel mutation in irritable bowel syndrome: evidence for an ion channelopathy |journal=Am. J. Physiol. Gastrointest. Liver Physiol. |volume=296 |issue=2 |pages=G211–8 |year=2009 |pmid=19056759 |pmc=2643921 |doi=10.1152/ajpgi.90571.2008 |url=}}</ref>  
**[[Genome]] wide [[DNA methylation]] profiling is impaired in [[Irritable bowel syndrome|IBS]] and this involves genes linked to [[neuropeptide]] [[hormone]] function and [[Oxidative stress|oxidative]] stress.<ref name="pmid26670691">{{cite journal |vauthors=Mahurkar S, Polytarchou C, Iliopoulos D, Pothoulakis C, Mayer EA, Chang L |title=Genome-wide DNA methylation profiling of peripheral blood mononuclear cells in irritable bowel syndrome |journal=Neurogastroenterol. Motil. |volume=28 |issue=3 |pages=410–22 |year=2016 |pmid=26670691 |pmc=4760882 |doi=10.1111/nmo.12741 |url=}}</ref>  
**IBS causes [[mutation]] in the [[neuropeptide]] S [[Receptor (biochemistry)|receptor]] [[gene]] (NPSR1) involved in [[Pain and nociception|nociception]], [[inflammation]] and [[anxiety]] with [[abdominal pain]].<ref name="pmid19732772">{{cite journal |vauthors=Camilleri M, Carlson P, Zinsmeister AR, McKinzie S, Busciglio I, Burton D, Zucchelli M, D'Amato M |title=Neuropeptide S receptor induces neuropeptide expression and associates with intermediate phenotypes of functional gastrointestinal disorders |journal=Gastroenterology |volume=138 |issue=1 |pages=98–107.e4 |year=2010 |pmid=19732772 |pmc=2813358 |doi=10.1053/j.gastro.2009.08.051 |url=}}</ref>
**[[Gene|Genes]] involved in the regulation of [[Liver|hepatic]] [[bile acid]] [[Chemical synthesis|synthesis]] such as a functional ''Klothoβ'' [[gene]] are mutated in [[Irritable bowel syndrome|IBS]].<ref name="pmid22610000">{{cite journal |vauthors=Wong BS, Camilleri M, Carlson P, McKinzie S, Busciglio I, Bondar O, Dyer RB, Lamsam J, Zinsmeister AR |title=Increased bile acid biosynthesis is associated with irritable bowel syndrome with diarrhea |journal=Clin. Gastroenterol. Hepatol. |volume=10 |issue=9 |pages=1009–15.e3 |year=2012 |pmid=22610000 |pmc=3565429 |doi=10.1016/j.cgh.2012.05.006 |url=}}</ref><ref name="pmid21396369">{{cite journal |vauthors=Wong BS, Camilleri M, Carlson PJ, Guicciardi ME, Burton D, McKinzie S, Rao AS, Zinsmeister AR, Gores GJ |title=A Klothoβ variant mediates protein stability and associates with colon transit in irritable bowel syndrome with diarrhea |journal=Gastroenterology |volume=140 |issue=7 |pages=1934–42 |year=2011 |pmid=21396369 |pmc=3109206 |doi=10.1053/j.gastro.2011.02.063 |url=}}</ref>  
*'''TNF polymorphisms:'''
**[[Single nucleotide polymorphism|SNPs]] in [[Tumour necrosis factor|tumour necrosis factor alpha]] ([[Tumor necrosis factor-alpha|TNFα)]] and genes coding for superfamily member 15 (''TNFSF15'') have proven associations with [[Irritable bowel syndrome|IBS]].<ref name="pmid12477767" /><ref name="pmid22684480">{{cite journal |vauthors=Swan C, Duroudier NP, Campbell E, Zaitoun A, Hastings M, Dukes GE, Cox J, Kelly FM, Wilde J, Lennon MG, Neal KR, Whorwell PJ, Hall IP, Spiller RC |title=Identifying and testing candidate genetic polymorphisms in the irritable bowel syndrome (IBS): association with TNFSF15 and TNFα |journal=Gut |volume=62 |issue=7 |pages=985–94 |year=2013 |pmid=22684480 |doi=10.1136/gutjnl-2011-301213 |url=}}</ref><ref name="pmid21636646">{{cite journal |vauthors=Zucchelli M, Camilleri M, Andreasson AN, Bresso F, Dlugosz A, Halfvarson J, Törkvist L, Schmidt PT, Karling P, Ohlsson B, Duerr RH, Simren M, Lindberg G, Agreus L, Carlson P, Zinsmeister AR, D'Amato M |title=Association of TNFSF15 polymorphism with irritable bowel syndrome |journal=Gut |volume=60 |issue=12 |pages=1671–1677 |year=2011 |pmid=21636646 |pmc=3922294 |doi=10.1136/gut.2011.241877 |url=}}</ref>
**[[Tumor necrosis factors|TNF]] [[polymorphisms]] are also associated with post [[Infection|infectious]] [[Irritable bowel syndrome|IBS]] such as ''rs4263839'' in ''TNFSF15'' and [[Irritable bowel syndrome|IBS]], particularly IBS associated with [[constipation]].<ref name="pmid22684480" /><ref name="pmid21636646" />


*SNPs in tumour necrosis factor alpha (TNFα) and genes coding for superfamily member 15 (''TNFSF15'') that are associated with inflammatory bowel disease, have proven associations with IBS.<ref name="pmid22684480">{{cite journal |vauthors=Swan C, Duroudier NP, Campbell E, Zaitoun A, Hastings M, Dukes GE, Cox J, Kelly FM, Wilde J, Lennon MG, Neal KR, Whorwell PJ, Hall IP, Spiller RC |title=Identifying and testing candidate genetic polymorphisms in the irritable bowel syndrome (IBS): association with TNFSF15 and TNFα |journal=Gut |volume=62 |issue=7 |pages=985–94 |year=2013 |pmid=22684480 |doi=10.1136/gutjnl-2011-301213 |url=}}</ref><ref name="pmid21636646">{{cite journal |vauthors=Zucchelli M, Camilleri M, Andreasson AN, Bresso F, Dlugosz A, Halfvarson J, Törkvist L, Schmidt PT, Karling P, Ohlsson B, Duerr RH, Simren M, Lindberg G, Agreus L, Carlson P, Zinsmeister AR, D'Amato M |title=Association of TNFSF15 polymorphism with irritable bowel syndrome |journal=Gut |volume=60 |issue=12 |pages=1671–1677 |year=2011 |pmid=21636646 |pmc=3922294 |doi=10.1136/gut.2011.241877 |url=}}</ref><ref name="pmid22684480" />
==Associated conditions==
*Studies have been conducted to establish associations between neuropeptide S receptor gene (NPSR1) involved in nociception, inflammation and anxiety with abdominal pain.<ref name="pmid19732772">{{cite journal |vauthors=Camilleri M, Carlson P, Zinsmeister AR, McKinzie S, Busciglio I, Burton D, Zucchelli M, D'Amato M |title=Neuropeptide S receptor induces neuropeptide expression and associates with intermediate phenotypes of functional gastrointestinal disorders |journal=Gastroenterology |volume=138 |issue=1 |pages=98–107.e4 |year=2010 |pmid=19732772 |pmc=2813358 |doi=10.1053/j.gastro.2009.08.051 |url=}}</ref> 
Several medical [[comorbidities]] appear with greater frequency in [[Irritable bowel syndrome|IBS]] patients.
*TNF polymorphisms are also associated with post infectious IBS such as rs4263839 in TNFSF15 and IBS, particularly IBS-C.<ref name="pmid21636646">{{cite journal |vauthors=Zucchelli M, Camilleri M, Andreasson AN, Bresso F, Dlugosz A, Halfvarson J, Törkvist L, Schmidt PT, Karling P, Ohlsson B, Duerr RH, Simren M, Lindberg G, Agreus L, Carlson P, Zinsmeister AR, D'Amato M |title=Association of TNFSF15 polymorphism with irritable bowel syndrome |journal=Gut |volume=60 |issue=12 |pages=1671–1677 |year=2011 |pmid=21636646 |pmc=3922294 |doi=10.1136/gut.2011.241877 |url=}}</ref><ref name="pmid22684480">{{cite journal |vauthors=Swan C, Duroudier NP, Campbell E, Zaitoun A, Hastings M, Dukes GE, Cox J, Kelly FM, Wilde J, Lennon MG, Neal KR, Whorwell PJ, Hall IP, Spiller RC |title=Identifying and testing candidate genetic polymorphisms in the irritable bowel syndrome (IBS): association with TNFSF15 and TNFα |journal=Gut |volume=62 |issue=7 |pages=985–94 |year=2013 |pmid=22684480 |doi=10.1136/gutjnl-2011-301213 |url=}}</ref>
*Genes involved in the regulation of hepatic bile acid synthesis such as a functional Klothoβ gene variant have a proven association with the disease.<ref name="pmid22610000">{{cite journal |vauthors=Wong BS, Camilleri M, Carlson P, McKinzie S, Busciglio I, Bondar O, Dyer RB, Lamsam J, Zinsmeister AR |title=Increased bile acid biosynthesis is associated with irritable bowel syndrome with diarrhea |journal=Clin. Gastroenterol. Hepatol. |volume=10 |issue=9 |pages=1009–15.e3 |year=2012 |pmid=22610000 |pmc=3565429 |doi=10.1016/j.cgh.2012.05.006 |url=}}</ref><ref name="pmid21396369">{{cite journal |vauthors=Wong BS, Camilleri M, Carlson PJ, Guicciardi ME, Burton D, McKinzie S, Rao AS, Zinsmeister AR, Gores GJ |title=A Klothoβ variant mediates protein stability and associates with colon transit in irritable bowel syndrome with diarrhea |journal=Gastroenterology |volume=140 |issue=7 |pages=1934–42 |year=2011 |pmid=21396369 |pmc=3109206 |doi=10.1053/j.gastro.2011.02.063 |url=}}</ref>
*It is known that genome as well as genome-wide methylation of DNA plays an important role in IBS. Genome wide DNA methylation profiling is different in IBS patients as compared to healthy controls, especially involving genes linked to neuropeptide hormone function and oxidative stress.<ref name="pmid26670691">{{cite journal |vauthors=Mahurkar S, Polytarchou C, Iliopoulos D, Pothoulakis C, Mayer EA, Chang L |title=Genome-wide DNA methylation profiling of peripheral blood mononuclear cells in irritable bowel syndrome |journal=Neurogastroenterol. Motil. |volume=28 |issue=3 |pages=410–22 |year=2016 |pmid=26670691 |pmc=4760882 |doi=10.1111/nmo.12741 |url=}}</ref>


==Associated Conditions==
===Headache, Fibromyalgia, and Depression===
[[Irritable bowel syndrome|IBS]] patients may be identified with comorbidities such as [[headache]], [[fibromyalgia]] and [[depression]].<ref>{{cite journal |author=Cole JA, Rothman KJ, Cabral HJ, Zhang Y, Farraye FA |title=Migraine,[[fibromyalgia]], and depression among people with IBS:  a prevalence study |journal=BMC gastroenterology |volume=6 |issue=|pages=26 |year=2006 |pmid=17007634 |doi=10.1186/1471-230X-6-26}}</ref><ref name="pmid16614951">{{cite journal |author=Kurland JE, Coyle WJ, Winkler A, Zable E |title=Prevalence of irritable bowel syndrome and depression in [[fibromyalgia]] |journal=Dig. Dis. Sci. |volume=51 |issue=3 |pages=454-60 |year=2006|pmid=16614951 |doi=10.1007/s10620-006-3154-7}}</ref><ref name="pmid16042909">{{cite journal |author=Frissora CL, Koch KL|title=Symptom overlap and comorbidity of irritable bowel syndrome with other conditions |journal=Current gastroenterology reports|volume=7 |issue=4 |pages=264-71 |year=2005 |pmid=16042909 |doi=}}</ref>
 
===Inflammatory Bowel Disease===
* [[Irritable bowel syndrome|IBS]] and [[Inflammatory bowel disease|IBD]] are interrelated diseases, as patients with [[Inflammatory bowel disease|IBD]] experience [[Irritable bowel syndrome|IBS]]-like symptoms when their [[Inflammatory bowel disease|IBD]] is in remission.<ref name="SIMREN_2002">{{cite journal |author=Simrén M, Axelsson J, Gillberg R, Abrahamsson H, Svedlund J, Björnsson ES|title=Quality of life in inflammatory bowel disease in remission: the impact of IBS-like symptoms and associated psychological factors |journal=Am. J. Gastroenterol. |volume=97 |issue=2 |pages=389-96 |year=2002 |pmid=11866278 |doi=}}</ref><ref name="MINDERHOUD_2004">{{cite journal |author=Minderhoud IM, Oldenburg B, Wismeijer JA, van Berge Henegouwen GP, Smout AJ|title=IBS-like symptoms in patients with inflammatory bowel disease in remission; relationships with quality of life and coping behavior |journal=Dig. Dis. Sci. |volume=49 |issue=3 |pages=469-74 |year=2004 |pmid=15139501 |doi=}}</ref><ref name="QUIGLEY_2005">{{cite journal |author=Quigley EM |title=Irritable bowel syndrome and inflammatory bowel disease: interrelated diseases? |journal=Chinese journal of digestive diseases |volume=6 |issue=3 |pages=122-32 |year=2005 |pmid=16045602|doi=10.1111/j.1443-9573.2005.00202.x}}</ref>
* [[Irritable bowel syndrome|IBS]] is believed to be a type of low-grade [[inflammatory bowel disease]] as serum markers associated with [[inflammation]] have also been found in patients with [[Irritable bowel syndrome|IBS]].<ref name="BERCIK_2005">{{cite journal |author=Bercik P, Verdu EF, Collins SM |title=Is irritable bowel syndrome a low-grade inflammatory bowel disease? |journal=Gastroenterol. Clin. North Am. |volume=34 |issue=2 |pages=235-45, vi-vii |year=2005|pmid=15862932 |doi=10.1016/j.gtc.2005.02.007}}</ref>
* [[Irritable bowel syndrome|IBS]] patients are16.3 times more likely to develop [[Inflammatory bowel disease|IBD]].<ref name="GARCIA_2000">{{cite journal |author=García Rodríguez LA, Ruigómez A, Wallander MA, Johansson S, Olbe L |title=Detection of colorectal tumor and inflammatory bowel disease during follow-up of patients with initial diagnosis of irritable bowel syndrome |journal=Scand. J. Gastroenterol. |volume=35 |issue=3 |pages=306-11 |year=2000 |pmid=10766326 |doi=}}</ref> 
 
===Abdominal Surgery===
* [[Irritable bowel syndrome|IBS]] patients are 87% more likely to undergo [[Abdomen|abdominal]] and [[Pelvis|pelvic]] [[surgery]], and three times more likely to undergo [[gallbladder]] [[surgery]].<ref name="pmid16416174">{{cite journal |author=Cole JA, Yeaw JM, Cutone JA, ''et al'' |title=The incidence of abdominal and pelvic surgery among patients with irritable bowel syndrome |journal=Dig. Dis. Sci. |volume=50 |issue=12 |pages=2268–75 |year=2005 |pmid=16416174|doi=10.1007/s10620-005-3047-1}}</ref> 
* [[Irritable bowel syndrome|IBS]] patients were twice as likely to undergo [[hysterectomy]].<ref name="pmid15188159">{{cite journal |author=Longstreth GF, Yao JF|title=Irritable bowel syndrome and surgery: a multivariable analysis |journal=Gastroenterology |volume=126 |issue=7 |pages=1665–73|year=2004 |pmid=15188159 |doi=}}</ref>
 
===Endometriosis===
There is a statistically significant link between [[Migraine|migraine headaches]], [[Irritable bowel syndrome|IBS]], and [[endometriosis]].<ref name="pmid17635599">{{cite journal |author=Tietjen GE, Bushnell CD, Herial NA, Utley C, White L, Hafeez F|title=Endometriosis is associated with prevalence of comorbid conditions in migraine |journal=Headache |volume=47 |issue=7|pages=1069-78 |year=2007 |pmid=17635599 |doi=10.1111/j.1526-4610.2007.00784.x}}</ref>
 
==Medical conditions that accompany IBS==
Several medical [[comorbidities]] appear with greater frequency in [[Irritable bowel syndrome|IBS]] patients. 
 
===Headache, Fibromyalgia, and Depression===
[[Irritable bowel syndrome|IBS]] patients may be identified with comorbidities such as [[headache]], [[fibromyalgia]] and [[depression]].<ref name="pmid16614951">{{cite journal |author=Kurland JE, Coyle WJ, Winkler A, Zable E |title=Prevalence of irritable bowel syndrome and depression in [[fibromyalgia]] |journal=Dig. Dis. Sci. |volume=51 |issue=3 |pages=454-60 |year=2006|pmid=16614951 |doi=10.1007/s10620-006-3154-7}}</ref><ref name="pmid16042909">{{cite journal |author=Frissora CL, Koch KL|title=Symptom overlap and comorbidity of irritable bowel syndrome with other conditions |journal=Current gastroenterology reports|volume=7 |issue=4 |pages=264-71 |year=2005 |pmid=16042909 |doi=}}</ref><ref>{{cite journal |author=Cole JA, Rothman KJ, Cabral HJ, Zhang Y, Farraye FA |title=Migraine,[[fibromyalgia]], and depression among people with IBS:  a prevalence study |journal=BMC gastroenterology |volume=6 |issue=|pages=26 |year=2006 |pmid=17007634 |doi=10.1186/1471-230X-6-26}}</ref>
 
===Inflammatory Bowel Disease===
* [[Irritable bowel syndrome|IBS]] and [[Inflammatory bowel disease|IBD]] are interrelated diseases, as patients with [[Inflammatory bowel disease|IBD]] experience [[Irritable bowel syndrome|IBS]]-like symptoms when their [[Inflammatory bowel disease|IBD]] is in remission.<ref name="SIMREN_2002">{{cite journal |author=Simrén M, Axelsson J, Gillberg R, Abrahamsson H, Svedlund J, Björnsson ES|title=Quality of life in inflammatory bowel disease in remission: the impact of IBS-like symptoms and associated psychological factors |journal=Am. J. Gastroenterol. |volume=97 |issue=2 |pages=389-96 |year=2002 |pmid=11866278 |doi=}}</ref><ref name="MINDERHOUD_2004">{{cite journal |author=Minderhoud IM, Oldenburg B, Wismeijer JA, van Berge Henegouwen GP, Smout AJ|title=IBS-like symptoms in patients with inflammatory bowel disease in remission; relationships with quality of life and coping behavior |journal=Dig. Dis. Sci. |volume=49 |issue=3 |pages=469-74 |year=2004 |pmid=15139501 |doi=}}</ref><ref name="QUIGLEY_2005">{{cite journal |author=Quigley EM |title=Irritable bowel syndrome and inflammatory bowel disease: interrelated diseases? |journal=Chinese journal of digestive diseases |volume=6 |issue=3 |pages=122-32 |year=2005 |pmid=16045602|doi=10.1111/j.1443-9573.2005.00202.x}}</ref>
* [[Irritable bowel syndrome|IBS]] is believed to be a type of low-grade [[inflammatory bowel disease]] as serum markers associated with [[inflammation]] have also been found in patients with [[Irritable bowel syndrome|IBS]] .<ref name="BERCIK_2005">{{cite journal |author=Bercik P, Verdu EF, Collins SM |title=Is irritable bowel syndrome a low-grade inflammatory bowel disease? |journal=Gastroenterol. Clin. North Am. |volume=34 |issue=2 |pages=235-45, vi-vii |year=2005|pmid=15862932 |doi=10.1016/j.gtc.2005.02.007}}</ref>
* [[Irritable bowel syndrome|IBS]] patients are16.3 times more likely to develop [[Inflammatory bowel disease|IBD]].<ref name="GARCIA_2000">{{cite journal |author=García Rodríguez LA, Ruigómez A, Wallander MA, Johansson S, Olbe L |title=Detection of colorectal tumor and inflammatory bowel disease during follow-up of patients with initial diagnosis of irritable bowel syndrome |journal=Scand. J. Gastroenterol. |volume=35 |issue=3 |pages=306-11 |year=2000 |pmid=10766326 |doi=}}</ref> 
 
===Abdominal Surgery===
* [[Irritable bowel syndrome|IBS]] patients are 87% more likely to undergo [[Abdomen|abdominal]] and [[Pelvis|pelvic]] [[surgery]], and three times more likely to undergo [[gallbladder]] [[surgery]].<ref name="pmid16416174">{{cite journal |author=Cole JA, Yeaw JM, Cutone JA, ''et al'' |title=The incidence of abdominal and pelvic surgery among patients with irritable bowel syndrome |journal=Dig. Dis. Sci. |volume=50 |issue=12 |pages=2268–75 |year=2005 |pmid=16416174|doi=10.1007/s10620-005-3047-1}}</ref> 
* [[Irritable bowel syndrome|IBS]] patients were twice as likely to undergo [[hysterectomy]].<ref name="pmid15188159">{{cite journal |author=Longstreth GF, Yao JF|title=Irritable bowel syndrome and surgery: a multivariable analysis |journal=Gastroenterology |volume=126 |issue=7 |pages=1665–73|year=2004 |pmid=15188159 |doi=}}</ref>
 
===Endometriosis===
There is a statistically significant link between [[Migraine|migraine headaches]], [[Irritable bowel syndrome|IBS]], and [[endometriosis]].<ref name="pmid17635599">{{cite journal |author=Tietjen GE, Bushnell CD, Herial NA, Utley C, White L, Hafeez F|title=Endometriosis is associated with prevalence of comorbid conditions in migraine |journal=Headache |volume=47 |issue=7|pages=1069-78 |year=2007 |pmid=17635599 |doi=10.1111/j.1526-4610.2007.00784.x}}</ref>


==Gross Pathology==
==Gross Pathology==
*On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
*On [[Gross examination|gross]] [[pathology]], the [[Gastrointestinal tract|GI tract]] appears normal in [[Irritable bowel syndrome|IBS]].


==Microscopic Pathology==
==Microscopic Pathology==
*On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
[[Microscopic]] changes that may be found in [[Irritable bowel syndrome|IBS]] patients are as follows:<ref name="pmid12454854" /><ref name="pmid14988823" /><ref name="pmid14724817">{{cite journal |vauthors=Dunlop SP, Jenkins D, Neal KR, Spiller RC |title=Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS |journal=Gastroenterology |volume=125 |issue=6 |pages=1651–9 |year=2003 |pmid=14724817 |doi= |url=}}</ref><ref name="pmid11076879">{{cite journal |vauthors=Spiller RC, Jenkins D, Thornley JP, Hebden JM, Wright T, Skinner M, Neal KR |title=Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome |journal=Gut |volume=47 |issue=6 |pages=804–11 |year=2000 |pmid=11076879 |pmc=1728147 |doi= |url=}}</ref><ref name="pmid10026328">{{cite journal |vauthors=Gwee KA, Leong YL, Graham C, McKendrick MW, Collins SM, Walters SJ, Underwood JE, Read NW |title=The role of psychological and biological factors in postinfective gut dysfunction |journal=Gut |volume=44 |issue=3 |pages=400–6 |year=1999 |pmid=10026328 |pmc=1727402 |doi= |url=}}</ref><ref name="pmid12873581">{{cite journal |vauthors=Dunlop SP, Jenkins D, Spiller RC |title=Distinctive clinical, psychological, and histological features of postinfective irritable bowel syndrome |journal=Am. J. Gastroenterol. |volume=98 |issue=7 |pages=1578–83 |year=2003 |pmid=12873581 |doi=10.1111/j.1572-0241.2003.07542.x |url=}}</ref><ref name="pmid8359068">{{cite journal |vauthors=Weston AP, Biddle WL, Bhatia PS, Miner PB |title=Terminal ileal mucosal mast cells in irritable bowel syndrome |journal=Dig. Dis. Sci. |volume=38 |issue=9 |pages=1590–5 |year=1993 |pmid=8359068 |doi= |url=}}</ref><ref name="pmid11012945">{{cite journal |vauthors=O'Sullivan M, Clayton N, Breslin NP, Harman I, Bountra C, McLaren A, O'Morain CA |title=Increased mast cells in the irritable bowel syndrome |journal=Neurogastroenterol. Motil. |volume=12 |issue=5 |pages=449–57 |year=2000 |pmid=11012945 |doi= |url=}}</ref><ref name="pmid12692417">{{cite journal |vauthors=Park CH, Joo YE, Choi SK, Rew JS, Kim SJ, Lee MC |title=Activated mast cells infiltrate in close proximity to enteric nerves in diarrhea-predominant irritable bowel syndrome |journal=J. Korean Med. Sci. |volume=18 |issue=2 |pages=204–10 |year=2003 |pmid=12692417 |pmc=3055014 |doi=10.3346/jkms.2003.18.2.204 |url=}}</ref><ref name="pmid15247174">{{cite journal |vauthors=Wang LH, Fang XC, Pan GZ |title=Bacillary dysentery as a causative factor of irritable bowel syndrome and its pathogenesis |journal=Gut |volume=53 |issue=8 |pages=1096–101 |year=2004 |pmid=15247174 |pmc=1774156 |doi=10.1136/gut.2003.021154 |url=}}</ref><ref name="pmid2733385">{{cite journal |vauthors=Salzmann JL, Peltier-Koch F, Bloch F, Petite JP, Camilleri JP |title=Morphometric study of colonic biopsies: a new method of estimating inflammatory diseases |journal=Lab. Invest. |volume=60 |issue=6 |pages=847–51 |year=1989 |pmid=2733385 |doi= |url=}}</ref><ref name="pmid13907162">{{cite journal |vauthors=HIATT RB, KATZ L |title=Mast cells in inflammatory conditions of the gastrointestinal tract |journal=Am. J. Gastroenterol. |volume=37 |issue= |pages=541–5 |year=1962 |pmid=13907162 |doi= |url=}}</ref>
 
{| class="wikitable"
! align="center" style="background: #4479BA; color: #FFFFFF; " |LOCATION
! align="center" style="background: #4479BA; color: #FFFFFF; " ! |LAYER OF INTESTINE INVOLVED
! align="center" style="background: #4479BA; color: #FFFFFF; " ! |MAST CELLS
! align="center" style="background: #4479BA; color: #FFFFFF; " ! |T LYMPHOCYTES
! align="center" style="background: #4479BA; color: #FFFFFF; " ! |ENTEROCHROMAFFIN CELLS
|-
|[[Rectum]]
|[[Mucous membrane|Mucosa]]
| +++/-
| +/-
| +/-
|-
|[[Terminal ileum]]
|[[Mucous membrane|Mucosa]]
| -
| ++
| -
|-
|[[Cecum]]
|[[Mucous membrane|Mucosa]]
| ++
| -
| -
|-
|[[Colon (anatomy)|Colon]]
|[[Muscularis externa]]
| +/-
| -
| -
|-
|[[Jejunum]]
|[[Myentric]] [[plexus]]
| ++
| -
| -
|}


==References==
==References==

Latest revision as of 19:15, 28 August 2021

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sudarshana Datta, MD [2]

Overview

Irritable Bowel Syndrome is caused by a complex interaction of various factors such as intrinsic gastrointestinal factors, CNS dysregulation and psychosocial factors, genetic, and environmental factors. Intrinsic gastrointestinal factors include motor abnormalities, visceral hypersensitivity, immune activation, mucosal inflammation, altered gut microbiota, and abnormal serotonin pathways. Visceral hypersensitivity refers to a decreased threshold for the perception of visceral stimuli that affects spinal excitability, brain stem and cortical modulation, activation of specific gastrointestinal mediators, and recruitment of peripheral silent nociceptors. Immune activation and mucosal inflammation involves an interaction of lymphocytes, mast cells, and proinflammatory cytokines. Environmental factors encompass dietary changes and infections. Psychosocial factors such as stress, anxiety, and depression directly shape adult connectivity in the executive control network consisting of structures such as the insula, anterior cingulate cortex, and the thalamus. Semipermanent or permanent changes in complex neural circuits lead to central pain amplification contributing to abdominal pain in IBS patients. The dorsolateral prefrontal cortex activity (responsible for vigilance and alertness of the human brain) and the mid-cingulate cortex (engaged in attention pathways and responses) is reduced in IBS patients. This reduction may lead to alterations in the subjective sensations of pain. Genetic factors also play a role in IBS. IBS has a high twin concordance and familial aggregation. IBS is associated with single nucleotide polymorphisms (SNPs) in genes involved in immune activation, neuropeptide hormone function, oxidative stress, nociception, permeability of the GI tract, host-microbiota interaction, inflammation, and TNF activity.

Pathophysiology

Pathogenesis

IBS occurs as a result of an interplay between four main factors:


 
 
 
 
 
CNS dysregulation and psychosocial factors
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intrinsic gastrointestinal factors:
• Motor abnormalities
• Visceral hypersensitivity
• Immune activation and mucosal inflammation
• Altered gut microbiota
• Abnormal serotonin pathways
 
 
IRRITABLE BOWEL SYNDROME
 
 
 
Genetic factors:
• Twin concordance
• Familial aggregation
• Single nucleotide polymorphisms(SNPs)
• TNF polymorphism
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Environmental factors:
•Diet
•Infections
 
 
 

Environmental factors

Intrinsic gastrointestinal factors


 
 
 
 
 
 
 
 
 
 
 
 
Spinal hyperexcitability
 
Activation of
• N-methyl D aspartate (NMDA) receptor
• nitric oxide
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central (brainstem and cortical) modulation
 
Increased activation of:
• Anterior cingulate cortex
• Thalamus
• insula
 
 
 
 
 
 
 
 
 
 
 
Visceral hypersensitivity
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Activation of specific gastrointestinal mediators
 
Kinins and serotonin activation lead to afferent nerve fiber sensitization
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recruitment of peripheral silent nociceptors
 
Increased end organ sensitivity due to hormonal or immune activation
 
 
 
 
 
 




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