Irritable bowel syndrome pathophysiology

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

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.

Pathophysiology

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:

  • Gastrointestinal motor abnormalities
    • IBS is referred to as ‘spastic colon’ due to changes in colonic motor function. Gastrointestinal motor abnormalities contribute significantly to the pathophysiology of IBS. Manometry recordings from the transverse, descending and sigmoid colon have shown that IBS leads to changed patterns of colonic and small intestinal motor function, such as increased frequency and irregularity of luminal contractions.[1][2][3]
    • Diarrhea-prone IBS patients have increased responses to ingestion, CRH (corticotropin releasing hormone), CCK (cholecystokinin), and present with abdominal discomfort with accelerated transit through the 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.[4][5][6][7][8]
    • Constipation-prone IBS patients show fewer high-amplitude propagating contractions (HAPCs) as compared to diarrhea prone IBS patients, delayed transit through the colon and decreased motility. These facts show that the changes in the motor function of the colon are responsible for producing the gastrointestinal symptoms of IBS such as altered bowel habits and abdominal pain.[7]
  • 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 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.[9][10]
      •  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.[10]
      • IBS patients have modulation of the mid-cingulate cortex engaged in attention pathways and responses. Modulation of the mid-cingulate cortex is associated with alterations in the subjective sensations of pain.[11][12]
      • 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 modulation of gastrointestinal function.[13][14]
      • Advanced brain imaging techniques that analyze differences in brain activity have shown irregularities in the mid- cingulate cortex and prefrontal cortex on 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. [15]
      • 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 probiotics in modifying signal processing in the brain also proves that IBS is a brain gut disorder.[16]
      • It has also been shown that rectal balloon distension in patients causes increased engagement of regions of the brain associated with attentional and behavioral responses.[11][17][18]
  • Visceral hypersensitivity
    • 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).[7][19][20]
    • Studies in IBS patients have shown that 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[21][22][23][24].
    • Many factors contribute to visceral hyperalgesia (i.e increased sensitivity of the intestines to normal sensations) such as:
      • Spinal hyperexcitability
      • Activation of specific gastrointestinal mediators such as kinins and serotonin that lead to afferent nerve fiber sensitization.
      • Central (brainstem and cortical) modulation with increased activation of anterior cingulate cortex, thalamus and 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.[19][25]
      • Recruitment of peripheral silent nociceptors cause increased end organ sensitivity due to hormonal or immune activation[19].
  • 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.[26][27][28][29][30][31][28]
    • 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.[26]
    • 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.[28][32][33][34][35]
    • 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.[27][29][36][37]
      • IBS patients with diarrhea have enhanced mucosal humoral activity, associated with activation and proliferation of B cells and immunoglobulin production, identified by microarray profiling.[37]
      • IBS patients with severe disease have an increase in lymphocyte infiltration in the myentric plexus, in studies where full-thickness jejunal biopsies were obtained.[29]
      • 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.[27]
      • Examination of stool in patients with diarrhea prominent IBS demonstrates high levels of serine protease activity, which is produced by lymphocytes.[38][39]When fecal extracts from IBS patients are intra colonically infused into mice, there is increased visceral pain and colonic cellular permeability. [38]
      • 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.[39][38]
    • Mast cells:
      •  Studies have shown an increased number of mast cells in IBS patients in the jejunum, terminal ileum and colon.[31]
      • Higher numbers of activated mast cells are found in proximity to colonic nerve fibres in the mucosa of the gastrointestinal tract of IBS patients. [31][30]
    • Proinflammatory cytokines:
      • Cytokines are proteinaceous mediators of the immune response.  Increased levels of cytokines have been found in IBS patients.[35][34]
      • Higher amounts of tumor necrosis factor are produced by the peripheral blood mononuclear cells of IBS patients.[40][28]
      • 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. [41]
      • 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.[28][41][40]
  • Altered gut microbiota
    •  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.[32][42] [43][44][45][46][47][48]
    • 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. [49]
    • 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. [50][51][52]
    • 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.[53][54][55][56]
  • 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.[57][58][59][60][61][62][63]
    • 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.[64]
    • 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.[65][66]

Genetics

  • 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.[67][68][69][70][71]
  • Investigations show higher concordance of IBS in monozygotic as compared to dizygotic twins, thereby proving the role of genetic factors in IBS.[68][67][72][73]
  • Individuals with a biologic relative with IBS have two times a higher risk of developing IBS.
  • 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.[74][75]
  • 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.[76][77]
  • 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.[78][79][80][81]
  • It is postulated that changed patterns of interleukin production may be associated with IBS.[75]
  • 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.[82][83][82]
  • Studies have been conducted to establish associations between neuropeptide S receptor gene (NPSR1) involved in nociception, inflammation and anxiety with abdominal pain.[84]
  • TNF polymorphisms are also associated with post infectious IBS such as rs4263839 in TNFSF15 and IBS, particularly IBS-C.[83][82]
  • Genes involved in the regulation of hepatic bile acid synthesis such as a functional Klothoβ gene variant have a proven association with the disease.[85][86]
  • 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.[87]

Associated Conditions

Gross Pathology

  • On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

  • On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

References

  1. ↑ Schmidt T, Hackelsberger N, Widmer R, Meisel C, Pfeiffer A, Kaess H (1996). "Ambulatory 24-hour jejunal motility in diarrhea-predominant irritable bowel syndrome". Scand. J. Gastroenterol. 31 (6): 581–9. PMID 8789897.
  2. ↑ Kumar D, Wingate DL (1985). "The irritable bowel syndrome: a paroxysmal motor disorder". Lancet. 2 (8462): 973–7. PMID 2865504.
  3. ↑ Simrén M, Castedal M, Svedlund J, Abrahamsson H, Björnsson E (2000). "Abnormal propagation pattern of duodenal pressure waves in the irritable bowel syndrome (IBS) [correction of (IBD)]". Dig. Dis. Sci. 45 (11): 2151–61. PMID 11215731.
  4. ↑ Chey WY, Jin HO, Lee MH, Sun SW, Lee KY (2001). "Colonic motility abnormality in patients with irritable bowel syndrome exhibiting abdominal pain and diarrhea". Am. J. Gastroenterol. 96 (5): 1499–506. doi:10.1111/j.1572-0241.2001.03804.x. PMID 11374689.
  5. ↑ Whitehead WE, Engel BT, Schuster MM (1980). "Irritable bowel syndrome: physiological and psychological differences between diarrhea-predominant and constipation-predominant patients". Dig. Dis. Sci. 25 (6): 404–13. PMID 7379673.
  6. ↑ Fukudo S, Nomura T, Hongo M (1998). "Impact of corticotropin-releasing hormone on gastrointestinal motility and adrenocorticotropic hormone in normal controls and patients with irritable bowel syndrome". Gut. 42 (6): 845–9. PMC 1727153. PMID 9691924.
  7. ↑ 7.0 7.1 7.2 Camilleri M, McKinzie S, Busciglio I, Low PA, Sweetser S, Burton D, Baxter K, Ryks M, Zinsmeister AR (2008). "Prospective study of motor, sensory, psychologic, and autonomic functions in patients with irritable bowel syndrome". Clin. Gastroenterol. Hepatol. 6 (7): 772–81. doi:10.1016/j.cgh.2008.02.060. PMC 2495078. PMID 18456567.
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  9. ↑ Park SH, Videlock EJ, Shih W, Presson AP, Mayer EA, Chang L (2016). "Adverse childhood experiences are associated with irritable bowel syndrome and gastrointestinal symptom severity". Neurogastroenterol. Motil. 28 (8): 1252–60. doi:10.1111/nmo.12826. PMC 4956522. PMID 27061107.
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  11. ↑ 11.0 11.1 Larsson MB, Tillisch K, Craig AD, Engström M, Labus J, Naliboff B, Lundberg P, Ström M, Mayer EA, Walter SA (2012). "Brain responses to visceral stimuli reflect visceral sensitivity thresholds in patients with irritable bowel syndrome". Gastroenterology. 142 (3): 463–472.e3. doi:10.1053/j.gastro.2011.11.022. PMC 3288538. PMID 22108191.
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  15. ↑ 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 (2013). "Patients with chronic visceral pain show sex-related alterations in intrinsic oscillations of the resting brain". J. Neurosci. 33 (29): 11994–2002. doi:10.1523/JNEUROSCI.5733-12.2013. PMC 3713732. PMID 23864686.
  16. ↑ Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat B, Guyonnet D, Legrain-Raspaud S, Trotin B, Naliboff B, Mayer EA (2013). "Consumption of fermented milk product with probiotic modulates brain activity". Gastroenterology. 144 (7): 1394–401, 1401.e1–4. doi:10.1053/j.gastro.2013.02.043. PMC 3839572. PMID 23474283.
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  19. ↑ 19.0 19.1 19.2 Barbara G, Cremon C, De Giorgio R, Dothel G, Zecchi L, Bellacosa L, Carini G, Stanghellini V, Corinaldesi R (2011). "Mechanisms underlying visceral hypersensitivity in irritable bowel syndrome". Curr Gastroenterol Rep. 13 (4): 308–15. doi:10.1007/s11894-011-0195-7. PMID 21537962.
  20. ↑ Whitehead WE, Holtkotter B, Enck P, Hoelzl R, Holmes KD, Anthony J, Shabsin HS, Schuster MM (1990). "Tolerance for rectosigmoid distention in irritable bowel syndrome". Gastroenterology. 98 (5 Pt 1): 1187–92. PMID 2323511.
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  26. ↑ 26.0 26.1 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 (2010). "Increased proteasome-mediated degradation of occludin in irritable bowel syndrome". Am. J. Gastroenterol. 105 (5): 1181–8. doi:10.1038/ajg.2009.700. PMID 19997094.
  27. ↑ 27.0 27.1 27.2 Chadwick VS, Chen W, Shu D, Paulus B, Bethwaite P, Tie A, Wilson I (2002). "Activation of the mucosal immune system in irritable bowel syndrome". Gastroenterology. 122 (7): 1778–83. PMID 12055584.
  28. ↑ 28.0 28.1 28.2 28.3 28.4 Liebregts T, Adam B, Bredack C, Röth A, Heinzel S, Lester S, Downie-Doyle S, Smith E, Drew P, Talley NJ, Holtmann G (2007). "Immune activation in patients with irritable bowel syndrome". Gastroenterology. 132 (3): 913–20. doi:10.1053/j.gastro.2007.01.046. PMID 17383420.
  29. ↑ 29.0 29.1 29.2 Törnblom H, Lindberg G, Nyberg B, Veress B (2002). "Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome". Gastroenterology. 123 (6): 1972–9. doi:10.1053/gast.2002.37059. PMID 12454854.
  30. ↑ 30.0 30.1 Guilarte M, Santos J, de Torres I, Alonso C, Vicario M, Ramos L, Martínez C, Casellas F, Saperas E, Malagelada JR (2007). "Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum". Gut. 56 (2): 203–9. doi:10.1136/gut.2006.100594. PMC 1856785. PMID 17005763.
  31. ↑ 31.0 31.1 31.2 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 (2004). "Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome". Gastroenterology. 126 (3): 693–702. PMID 14988823.
  32. ↑ 32.0 32.1 Marshall JK, Thabane M, Garg AX, Clark WF, Moayyedi P, Collins SM (2010). "Eight year prognosis of postinfectious irritable bowel syndrome following waterborne bacterial dysentery". Gut. 59 (5): 605–11. doi:10.1136/gut.2009.202234. PMID 20427395.
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  34. ↑ 34.0 34.1 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 (2009). "Pathogenic mechanisms of postinfectious functional gastrointestinal disorders: results 3 years after gastroenteritis". Scand. J. Gastroenterol. 44 (10): 1173–85. doi:10.1080/00365520903171276. PMID 19711225.
  35. ↑ 35.0 35.1 Gwee KA, Collins SM, Read NW, Rajnakova A, Deng Y, Graham JC, McKendrick MW, Moochhala SM (2003). "Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome". Gut. 52 (4): 523–6. PMC 1773606. PMID 12631663.
  36. ↑ Ohman L, Lindmark AC, Isaksson S, Posserud I, Strid H, Sjövall H, Simrén M (2009). "B-cell activation in patients with irritable bowel syndrome (IBS)". Neurogastroenterol. Motil. 21 (6): 644–50, e27. doi:10.1111/j.1365-2982.2009.01272.x. PMID 19222763.
  37. ↑ 37.0 37.1 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 (2015). "Increased humoral immunity in the jejunum of diarrhoea-predominant irritable bowel syndrome associated with clinical manifestations". Gut. 64 (9): 1379–88. doi:10.1136/gutjnl-2013-306236. PMID 25209656.
  38. ↑ 38.0 38.1 38.2 Bueno L (2008). "Protease activated receptor 2: a new target for IBS treatment". Eur Rev Med Pharmacol Sci. 12 Suppl 1: 95–102. PMID 18924448.
  39. ↑ 39.0 39.1 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 (2008). "Increased faecal serine protease activity in diarrhoeic IBS patients: a colonic lumenal factor impairing colonic permeability and sensitivity". Gut. 57 (5): 591–9. doi:10.1136/gut.2007.140210. PMID 18194983.
  40. ↑ 40.0 40.1 Dinan TG, Quigley EM, Ahmed SM, Scully P, O'Brien S, O'Mahony L, O'Mahony S, Shanahan F, Keeling PW (2006). "Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker?". Gastroenterology. 130 (2): 304–11. doi:10.1053/j.gastro.2005.11.033. PMID 16472586.
  41. ↑ 41.0 41.1 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 (2014). "Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients". Brain Behav. Immun. 42: 191–203. doi:10.1016/j.bbi.2014.07.001. PMID 25063707.
  42. ↑ Walker MM, Talley NJ, Inganäs L, Engstrand L, Jones MP, Nyhlin H, Agréus L, Kjellstrom L, Öst Å, Andreasson A (2015). "Colonic spirochetosis is associated with colonic eosinophilia and irritable bowel syndrome in a general population in Sweden". Hum. Pathol. 46 (2): 277–83. doi:10.1016/j.humpath.2014.10.026. PMID 25540866.
  43. ↑ Kassinen A, Krogius-Kurikka L, Mäkivuokko H, Rinttilä T, Paulin L, Corander J, Malinen E, Apajalahti J, Palva A (2007). "The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects". Gastroenterology. 133 (1): 24–33. doi:10.1053/j.gastro.2007.04.005. PMID 17631127.
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