Irritable bowel syndrome pathophysiology: Difference between revisions

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==Overview==
==Overview==


IBS is caused by the 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 and [[Mucous membrane|mucosal]] inflammation, altered [[Gut flora|gut microbiota]] and abnormal [[serotonin]] pathways. [[Viscus|Visceral]] [[hypersensitivity]] is 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/permanent changes in complex [[Nervous system|neural]] circuits lead to central pain amplification and contribute 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,  which may lead to alterations in the subjective sensations of pain. Genetic factors also play a role in [[Irritable bowel syndrome|IBS]]. It has high twin [[Concordance (genetics)|concordance]] and familial aggregation. It is associated with [[Nucleotide|Single nucleotide polymorphisms (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.  
[[Irritable bowel syndrome|Irritable Bowel Syndrome]] is caused by the 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 and [[Mucous membrane|mucosal]] inflammation, altered [[Gut flora|gut microbiota]] and abnormal [[serotonin]] pathways. [[Viscus|Visceral]] [[hypersensitivity]] is 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/permanent changes in complex [[Nervous system|neural]] circuits lead to central pain amplification and contribute 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,  which may lead to alterations in the subjective sensations of pain. Genetic factors also play a role in [[Irritable bowel syndrome|IBS]]. It has high twin [[Concordance (genetics)|concordance]] and familial aggregation. It is associated with [[Nucleotide|Single nucleotide polymorphisms (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==
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** 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>
** 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>
* '''Altered gut microbiota'''
* '''Altered gut microbiota'''
** [[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>
** [[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>
** 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>
** 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>
** 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>
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*'''TNF polymorphisms:'''
*'''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>  
**[[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="pmid21636646" /><ref name="pmid22684480" />
**[[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" />


==Associated conditions==
==Associated conditions==
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==Microscopic Pathology==
==Microscopic Pathology==
[[Microscopic]] changes that may be found in [[Irritable bowel syndrome|IBS]] patients are as follows:<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="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="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="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="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><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>
[[Microscopic]] changes that may be found in [[Irritable bowel syndrome|IBS]] patients are as follows:<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="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="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="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="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>


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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 the 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 and mucosal inflammation, altered gut microbiota and abnormal serotonin pathways. Visceral hypersensitivity is 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/permanent changes in complex neural circuits lead to central pain amplification and contribute 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, which may lead to alterations in the subjective sensations of pain. Genetic factors also play a role in IBS. It has high twin concordance and familial aggregation. It 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 is 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
 
 
 

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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