Irritable bowel syndrome pathophysiology: Difference between revisions

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{{Family tree | | | | | | B01 | | | |B01= '''[[Proinflammatory]] [[cytokines]]'''}}
{{Family tree | | | | | | B01 | | | |B01= '''[[Proinflammatory]] [[cytokines]]'''}}
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*IBS in patients with history of inflammatory bowel disease, celiac disease or microscopic colitis points towards the fact that immune activation and local GI 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 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 mucosal counts of ''lymphocytes'' (T cells, B cells), ''mast cells'' and immune ''mediators'' such as prostanoids, proteases, cytokines and 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>
* 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:'''
**Activation of humoral immunity in IBS is specific for the gastrointestinal tract. Increased number of lymphocytes have been found in the small intestine and colon of 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>
**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" />
**[[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.<ref name="pmid12454854" />
**[[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" />
**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>
**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>
**In response to high levels of serine protease, there is increased visceral pain and colonic cellular permeability. <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" />
**Serine protease inhibitors prevent effects mediated by high levels of serine protease in IBS patients.<ref name="pmid18194983" /><ref name="pmid18924448" />
**[[Serine protease]] inhibitors prevent effects mediated by high levels of [[serine protease]] in [[Irritable bowel syndrome|IBS]] patients.<ref name="pmid18194983" /><ref name="pmid18924448" />
**'''Mast cells:'''
**'''Mast cells:'''
**  IBS leads to an increased number of mast cells in IBS patients in the jejunum, terminal ileum and colon.<ref name="pmid14988823" />
**  [[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" />
** 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" /><ref name="pmid17005763" />
** 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" />
** '''Proinflammatory cytokines:'''
** '''Proinflammatory cytokines:'''
** Cytokines are protein mediators of the immune response.  Increased levels of cytokines have been found in IBS patients.<ref name="pmid12631663" /><ref name="pmid19711225" />
** [[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="pmid12631663" /><ref name="pmid19711225" />
** 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" />
** 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="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" />
** Other cytokines such as interleukin 1β, interleukin 6, interleukin 10, and TNFα are raised in IBS patients.
** 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.
** Increased concentration of cytokines is directly proportional to the severity and frequency of pain.<ref name="pmid17383420" /><ref name="pmid25063707" /><ref name="pmid16472586" />
** Increased concentration of [[Cytokine|cytokines]] is directly proportional to the severity and frequency of pain.<ref name="pmid17383420" /><ref name="pmid25063707" /><ref name="pmid16472586" />
** The TNF antagonist infliximab counteracts pain in IBS patients, proving TNF involvement in mechanical hypersensitivity of the 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'''
** Fecal microflora in IBS patients differ from healthy individuals. Some IBS patients have colonic spirochaetosis, with a unique pathology of increased lymphoid follicles and 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 GI infection alters gut microflora switches on a T-helper-2 immune-cell response with increased numbers of CD8 and CD4RA-positive intraepithelial lymphocytes, causing increased susceptibility to the development of 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 microbiota causes increased 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>
* '''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 stimuli (short chain fatty acids produced by gastrointestinal microflora ) and mechanical stimuli ( food) and is increased in 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(5-HT) is an important neurotransmitter produced by the enterochromaffin cells in the colon, in response to chemical stimuli (short chain fatty acids produced by gastrointestinal microflora ) and mechanical stimuli ( food) and is increased in 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>   

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

Overview

IBS 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
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
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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