Irritable bowel syndrome pathophysiology: Difference between revisions

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'''Lymphocytes''' — Patients with IBS have increased B lymphocyte activation in the blood<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>. However, activation of humoral immunity in IBS is specific for the gastrointestinal tract<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> as increased numbers 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>. In addition to this, IBS patients with diarrhea<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> have enhanced mucosal humoral activity, associated with activation and proliferation of B cells and immunoglobulin production, identified by microarray profiling. IBS patients with severe disease have an increase in lymphocyte infiltration in the myentric plexus<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>, in studies where full-thickness jejunal biopsies were obtained.  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. Examination of stool in patients with diarrhea prominent IBS were found to have high levels of serine protease activity<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 these fecal extracts were intra colonically infused into mice, there was increased visceral pain and colonic cellular permeability. Moreover, serine protease inhibitors prevented these effects. Studies have shown that mononuclear cell supernatants in the peripheral blood from healthy controls have greater inhibitory effects on colorectal sensory afferent nerve endings than in IBS patients.  
'''Lymphocytes''' — Patients with IBS have increased B lymphocyte activation in the blood<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>. However, activation of humoral immunity in IBS is specific for the gastrointestinal tract<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> as increased numbers 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>. In addition to this, IBS patients with diarrhea<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> have enhanced mucosal humoral activity, associated with activation and proliferation of B cells and immunoglobulin production, identified by microarray profiling. IBS patients with severe disease have an increase in lymphocyte infiltration in the myentric plexus<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>, in studies where full-thickness jejunal biopsies were obtained.  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. Examination of stool in patients with diarrhea prominent IBS were found to have high levels of serine protease activity<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 these fecal extracts were intra colonically infused into mice, there was increased visceral pain and colonic cellular permeability. Moreover, serine protease inhibitors prevented these effects. Studies have shown that mononuclear cell supernatants in the peripheral blood from healthy controls have greater inhibitory effects on colorectal sensory afferent nerve endings than in IBS patients.  


'''Mast cells''' — 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>. 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> '''Proinflammatory cytokines''' —  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>. Cytokines are proteinaceous mediators of the immune response. Higher amounts of 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>  In studies conducted using supernatants from cultured peripheral blood mononuclear cells in IBS patients,the TNF antagonist infliximab blocked 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>. Other cytokines such as interleukin 1β, interleukin 6, interleukin 10 and TNFα were found in increased amounts on analysis of the supernatants from IBS patients with diarrhea, as compared to healthy controls.Increased concentration of these cytokines was 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="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>
'''Mast cells''' — 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>. 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> '''Proinflammatory cytokines''' —  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>. Cytokines are proteinaceous mediators of the immune response. Higher amounts of 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>  In studies conducted using supernatants from cultured peripheral blood mononuclear cells in IBS patients,the TNF antagonist infliximab blocked 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>. Other cytokines such as interleukin 1β, interleukin 6, interleukin 10 and TNFα were found in increased amounts on analysis of the supernatants from IBS patients with diarrhea, as compared to healthy controls.Increased concentration of these cytokines was directly proportional to the severity and frequency of pain<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="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="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>
****Altered gut microbiota
****Altered gut microbiota
****Gastrointestinal infections-  leads to post inflammatory neuroplastic changes and visceral hypersensitivity
****Gastrointestinal infections-  leads to post inflammatory neuroplastic changes and visceral hypersensitivity

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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 [disease name] is not fully understood.

OR

It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].

OR

[Pathogen name] is usually transmitted via the [transmission route] route to the human host.

OR

Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.

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[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].

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The progression to [disease name] usually involves the [molecular pathway].

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The pathophysiology of [disease/malignancy] depends on the histological subtype.

Pathophysiology

Pathogenesis

  • The exact pathogenesis of Irritable Bowel Syndrome (IBS) is uncertain.
  • It is thought that IBS is caused by the interaction of various factors:
  • Gastrointestinal motor abnormalities- IBS is referred to as ‘spastic colon’ due to changes in colonic motor function. Manometry recordings in studies from the transverse, descending and sigmoid colon showed that spastic colon led to changed patterns of colonic and small intestinal motor function such as increased frequency and irregularity of luminal contractions[1][2][3]. Peak amplitude of high-amplitude propagating contractions (HAPCs)[4] in diarrhea-prone IBS patients[5] were found to be higher, compared to healthy subjects. This led to increased responses to ingestion, CRH(Corticotropin releasing hormone)[6][7], CCK(cholecystokinin)[8] and were associated with abdominal discomfort and accelerated transit through the colon. On the other hand, constipation prone IBS patients[5] showed fewer HAPCs, delayed transit through the colon and decreased motility. One study showed that >90% of HAPCs[8] were associated with abdominal pain.
  • CNS dysregulation- The conceptualization of IBS being a brain gut disorder is reinforced by the following-

1) Epidemiological studies that suggest that IBS occurs in individuals who have experienced childhood trauma with symptom exacerbation occurring in patients with emotional disturbances or stress[9]. Traumatic experiences before the age of 18 can directly shape adult connectivity in the executive control network. The effects on structures such as the insula, anterior cingulate cortex and the thalamus have been implicated in the pathophysiology of central pain amplification.[10]  IBS has been found to have a high association with pre-existing psychiatric and psychological conditions like anxiety and depression[11]. However, studies have shown that even when patients are not anxious or depressed, the dorsolateral prefrontal cortex activity was reduced, suggesting CNS dysfunction and increased susceptibility to stressors[12].

2) Psychological therapies that act on cerebral cortical sites and antidepressants have proven to be one of the mainstays of therapy for patients.  For example, the fact that probiotics can modify signal processing in the brain also supports this theory[13].

3) Studies using advanced brain imaging techniques have analyzed differences in brain activity between patients and healthy controls and have helped us appreciate that the mid-cingulate cortex- responsible for attention processes and responses and the prefrontal cortex-responsible for vigilance and alertness of the human brain could be involved in IBS. Modulation of the mid-cingulate cortex is associated with alterations in the subjective sensations of pain whereas prefrontal cortex modulation may lead to increased perception of visceral pain[10]. Patients with IBS have been found to have aberrant processing of central information[14], with decreased feedback on the emotional arousal network that controls the autonomic modulation of gastrointestinal function[15]. These have been seen as irregularities on diffusion tensor imaging[16] in the white matter of the brain. Rectal balloon distension in patients has shown the increased involvement of regions of the brain associated with attentional and behavioral responses to the arrival of such stimuli[17][18][12]

  • Visceral hypersensitivity- Visceral hypersensitivity is an important factor in the pathogenesis of pain perception in IBS patients[19]. IBS is associated with a decreased threshold for perception of visceral stimuli[5][20] (i.e. visceral hypersensitivity).  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)- 1.Spinal hyperexcitability due to activation of an N-methyl D aspartate(NMDA) receptor, Nitric oxide and possibly other neurotransmitters. 2.'Activation of specific gastrointestinal mediators like kinins and serotonin that lead to afferent nerve fibre sensitisation 3.'Central (brainstem and cortical) modulation with increased activation of anterior circulate cortex, thalamus and insula, involved in processing of pain, translating into long term hypersensitivity due to neuroplasticity, causing semipermanent changes in the neural response to all kinds of visceral stimulation. These findings have been proven by brain imaging studies. (e.g. functional magnetic resonance imaging, positron emission tomography)[20][25] 4.Recruitment of peripheral silent nociceptors causing increased end organ sensitivity due to hormonal or immune activation[20].
  • 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]

Moreover, psychological stress can significantly impact the release of proinflammatory cytokines, thereby affecting intestinal permeability 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[36]. However, activation of humoral immunity in IBS is specific for the gastrointestinal tract[37] as increased numbers of lymphocytes have been found in the small intestine and colon of IBS patients[27][29]. In addition to this, IBS patients with diarrhea[37] have enhanced mucosal humoral activity, associated with activation and proliferation of B cells and immunoglobulin production, identified by microarray profiling. IBS patients with severe disease have an increase in lymphocyte infiltration in the myentric plexus[29], in studies where full-thickness jejunal biopsies were obtained. 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. Examination of stool in patients with diarrhea prominent IBS were found to have high levels of serine protease activity[38][39]. When these fecal extracts were intra colonically infused into mice, there was increased visceral pain and colonic cellular permeability. Moreover, serine protease inhibitors prevented these effects. Studies have shown that mononuclear cell supernatants in the peripheral blood from healthy controls have greater inhibitory effects on colorectal sensory afferent nerve endings than in IBS patients.

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 — Increased levels of cytokines have been found in IBS patients[35][34]. Cytokines are proteinaceous mediators of the immune response. Higher amounts of of tumor necrosis factor are produced by the peripheral blood mononuclear cells of IBS patients.[40][28] In studies conducted using supernatants from cultured peripheral blood mononuclear cells in IBS patients,the TNF antagonist infliximab blocked the mechanical hypersensitivity of the mouse colonic afferent nerve endings[41]. Other cytokines such as interleukin 1β, interleukin 6, interleukin 10 and TNFα were found in increased amounts on analysis of the supernatants from IBS patients with diarrhea, as compared to healthy controls.Increased concentration of these cytokines was directly proportional to the severity and frequency of pain[41].[28][40]

        • Altered gut microbiota
        • Gastrointestinal infections- leads to post inflammatory neuroplastic changes and visceral hypersensitivity
        • Abnormal serotonin pathways
        • Neuroimmune factors
        • Genetic factors- Mutations in SCN5A encode alpha subunit of voltage gated sodium channel NaV1.5
        • Bile acid malabsorption- causes alteration of the function of an apical ileal bile acid transporter

Genetics

Genetics

  • [Disease name] is transmitted in [mode of genetic transmission] pattern.
  • Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
  • The development of [disease name] is the result of multiple genetic mutations.

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].

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