Irritable bowel syndrome pathophysiology: Difference between revisions

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*** Recruitment of peripheral silent nociceptors causing increased end organ sensitivity due to hormonal or immune activation<ref name="pmid21537962">{{cite journal |vauthors=Barbara G, Cremon C, De Giorgio R, Dothel G, Zecchi L, Bellacosa L, Carini G, Stanghellini V, Corinaldesi R |title=Mechanisms underlying visceral hypersensitivity in irritable bowel syndrome |journal=Curr Gastroenterol Rep |volume=13 |issue=4 |pages=308–15 |year=2011 |pmid=21537962 |doi=10.1007/s11894-011-0195-7 |url=}}</ref>.  
*** Recruitment of peripheral silent nociceptors causing increased end organ sensitivity due to hormonal or immune activation<ref name="pmid21537962">{{cite journal |vauthors=Barbara G, Cremon C, De Giorgio R, Dothel G, Zecchi L, Bellacosa L, Carini G, Stanghellini V, Corinaldesi R |title=Mechanisms underlying visceral hypersensitivity in irritable bowel syndrome |journal=Curr Gastroenterol Rep |volume=13 |issue=4 |pages=308–15 |year=2011 |pmid=21537962 |doi=10.1007/s11894-011-0195-7 |url=}}</ref>.  
* '''Genetic factors'''   
* '''Genetic factors'''   
*IBS is a complex disease with interactions between genetic and environmental factors.<ref name="pmid24041540">{{cite journal |vauthors=Wouters MM, Lambrechts D, Knapp M, Cleynen I, Whorwell P, Agréus L, Dlugosz A, Schmidt PT, Halfvarson J, Simrén M, Ohlsson B, Karling P, Van Wanrooy S, Mondelaers S, Vermeire S, Lindberg G, Spiller R, Dukes G, D'Amato M, Boeckxstaens G |title=Genetic variants in CDC42 and NXPH1 as susceptibility factors for constipation and diarrhoea predominant irritable bowel syndrome |journal=Gut |volume=63 |issue=7 |pages=1103–11 |year=2014 |pmid=24041540 |doi=10.1136/gutjnl-2013-304570 |url=}}</ref><ref name="pmid11606493">{{cite journal |vauthors=Levy RL, Jones KR, Whitehead WE, Feld SI, Talley NJ, Corey LA |title=Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology |journal=Gastroenterology |volume=121 |issue=4 |pages=799–804 |year=2001 |pmid=11606493 |doi= |url=}}</ref> The role of genetic predisposition in IBS is suggested by epidemiological studies of twins<ref name="pmid20234344">{{cite journal |vauthors=Saito YA, Petersen GM, Larson JJ, Atkinson EJ, Fridley BL, de Andrade M, Locke GR, Zimmerman JM, Almazar-Elder AE, Talley NJ |title=Familial aggregation of irritable bowel syndrome: a family case-control study |journal=Am. J. Gastroenterol. |volume=105 |issue=4 |pages=833–41 |year=2010 |pmid=20234344 |pmc=2875200 |doi=10.1038/ajg.2010.116 |url=}}</ref><ref name="pmid17509102">{{cite journal |vauthors=Lembo A, Zaman M, Jones M, Talley NJ |title=Influence of genetics on irritable bowel syndrome, gastro-oesophageal reflux and dyspepsia: a twin study |journal=Aliment. Pharmacol. Ther. |volume=25 |issue=11 |pages=1343–50 |year=2007 |pmid=17509102 |doi=10.1111/j.1365-2036.2007.03326.x |url=}}</ref> and familial aggregation.<ref name="pmid11606493">{{cite journal |vauthors=Levy RL, Jones KR, Whitehead WE, Feld SI, Talley NJ, Corey LA |title=Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology |journal=Gastroenterology |volume=121 |issue=4 |pages=799–804 |year=2001 |pmid=11606493 |doi= |url=}}</ref><ref name="pmid11606493">{{cite journal |vauthors=Levy RL, Jones KR, Whitehead WE, Feld SI, Talley NJ, Corey LA |title=Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology |journal=Gastroenterology |volume=121 |issue=4 |pages=799–804 |year=2001 |pmid=11606493 |doi= |url=}}</ref><ref name="pmid16271334">{{cite journal |vauthors=Saito YA, Petersen GM, Locke GR, Talley NJ |title=The genetics of irritable bowel syndrome |journal=Clin. Gastroenterol. Hepatol. |volume=3 |issue=11 |pages=1057–65 |year=2005 |pmid=16271334 |doi= |url=}}</ref>
*Investigations show higher concordance of IBS in monozygotic as compared to dizygotic twins, thereby proving the role of genetic factors in IBS.<ref name="pmid11606493">{{cite journal |vauthors=Levy RL, Jones KR, Whitehead WE, Feld SI, Talley NJ, Corey LA |title=Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology |journal=Gastroenterology |volume=121 |issue=4 |pages=799–804 |year=2001 |pmid=11606493 |doi= |url=}}</ref><ref name="pmid17509102">{{cite journal |vauthors=Lembo A, Zaman M, Jones M, Talley NJ |title=Influence of genetics on irritable bowel syndrome, gastro-oesophageal reflux and dyspepsia: a twin study |journal=Aliment. Pharmacol. Ther. |volume=25 |issue=11 |pages=1343–50 |year=2007 |pmid=17509102 |doi=10.1111/j.1365-2036.2007.03326.x |url=}}</ref><ref name="pmid17008364">{{cite journal |vauthors=Bengtson MB, Rønning T, Vatn MH, Harris JR |title=Irritable bowel syndrome in twins: genes and environment |journal=Gut |volume=55 |issue=12 |pages=1754–9 |year=2006 |pmid=17008364 |pmc=1856463 |doi=10.1136/gut.2006.097287 |url=}}</ref><ref name="pmid9707057">{{cite journal |vauthors=Morris-Yates A, Talley NJ, Boyce PM, Nandurkar S, Andrews G |title=Evidence of a genetic contribution to functional bowel disorder |journal=Am. J. Gastroenterol. |volume=93 |issue=8 |pages=1311–7 |year=1998 |pmid=9707057 |doi=10.1111/j.1572-0241.1998.440_j.x |url=}}</ref>
*Effects of single nucleotide polymorphisms (SNPs) in genes of IBS patients have been extensively studied. SNPs in genes play an important role in host-microbiota interaction (TLR9, IL-6 and CDH1), immune activation and epithelial barriers.<ref name="pmid20044998">{{cite journal |vauthors=Villani AC, Lemire M, Thabane M, Belisle A, Geneau G, Garg AX, Clark WF, Moayyedi P, Collins SM, Franchimont D, Marshall JK |title=Genetic risk factors for post-infectious irritable bowel syndrome following a waterborne outbreak of gastroenteritis |journal=Gastroenterology |volume=138 |issue=4 |pages=1502–13 |year=2010 |pmid=20044998 |doi=10.1053/j.gastro.2009.12.049 |url=}}</ref><ref name="pmid12477767">{{cite journal |vauthors=Gonsalkorale WM, Perrey C, Pravica V, Whorwell PJ, Hutchinson IV |title=Interleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component? |journal=Gut |volume=52 |issue=1 |pages=91–3 |year=2003 |pmid=12477767 |pmc=1773523 |doi= |url=}}</ref>
*The mutation of type V (alpha subunit) of ''SCN5A''-encoded voltage gated sodium channel associated with congenital prolonged QT syndrome can be correlated with symptoms of Irritable bowel syndrome. IBS patients with moderately severe pain in the abdomen have showed a missense mutation in ''SCN5A'', causing loss of function of this channel, more commonly in patients with IBS associated with constipation.<ref name="pmid16771953">{{cite journal |vauthors=Locke GR, Ackerman MJ, Zinsmeister AR, Thapa P, Farrugia G |title=Gastrointestinal symptoms in families of patients with an SCN5A-encoded cardiac channelopathy: evidence of an intestinal channelopathy |journal=Am. J. Gastroenterol. |volume=101 |issue=6 |pages=1299–304 |year=2006 |pmid=16771953 |doi=10.1111/j.1572-0241.2006.00507.x |url=}}</ref><ref name="pmid19056759">{{cite journal |vauthors=Saito YA, Strege PR, Tester DJ, Locke GR, Talley NJ, Bernard CE, Rae JL, Makielski JC, Ackerman MJ, Farrugia G |title=Sodium channel mutation in irritable bowel syndrome: evidence for an ion channelopathy |journal=Am. J. Physiol. Gastrointest. Liver Physiol. |volume=296 |issue=2 |pages=G211–8 |year=2009 |pmid=19056759 |pmc=2643921 |doi=10.1152/ajpgi.90571.2008 |url=}}</ref>
*There is an established relationship between IBS and polymorphisms in the gene for serotonin transport causing alteration in intestinal peristalsis due to change in the serotonin reuptake efficacy.<ref name="pmid24060757">{{cite journal |vauthors=Grasberger H, Chang L, Shih W, Presson AP, Sayuk GS, Newberry RD, Karagiannides I, Pothoulakis C, Mayer E, Merchant JL |title=Identification of a functional TPH1 polymorphism associated with irritable bowel syndrome bowel habit subtypes |journal=Am. J. Gastroenterol. |volume=108 |issue=11 |pages=1766–74 |year=2013 |pmid=24060757 |pmc=4067697 |doi=10.1038/ajg.2013.304 |url=}}</ref><ref name="pmid21073637">{{cite journal |vauthors=Jun S, Kohen R, Cain KC, Jarrett ME, Heitkemper MM |title=Associations of tryptophan hydroxylase gene polymorphisms with irritable bowel syndrome |journal=Neurogastroenterol. Motil. |volume=23 |issue=3 |pages=233–9, e116 |year=2011 |pmid=21073637 |pmc=3057463 |doi=10.1111/j.1365-2982.2010.01623.x |url=}}</ref><ref name="pmid15138209">{{cite journal |vauthors=Kim HJ, Camilleri M, Carlson PJ, Cremonini F, Ferber I, Stephens D, McKinzie S, Zinsmeister AR, Urrutia R |title=Association of distinct alpha(2) adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders |journal=Gut |volume=53 |issue=6 |pages=829–37 |year=2004 |pmid=15138209 |pmc=1774073 |doi= |url=}}</ref><ref name="pmid15361494">{{cite journal |vauthors=Yeo A, Boyd P, Lumsden S, Saunders T, Handley A, Stubbins M, Knaggs A, Asquith S, Taylor I, Bahari B, Crocker N, Rallan R, Varsani S, Montgomery D, Alpers DH, Dukes GE, Purvis I, Hicks GA |title=Association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome in women |journal=Gut |volume=53 |issue=10 |pages=1452–8 |year=2004 |pmid=15361494 |pmc=1774243 |doi=10.1136/gut.2003.035451 |url=}}</ref> Moreover, changed patterns of interleukin production may be associated with IBS.<ref name="pmid12477767">{{cite journal |vauthors=Gonsalkorale WM, Perrey C, Pravica V, Whorwell PJ, Hutchinson IV |title=Interleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component? |journal=Gut |volume=52 |issue=1 |pages=91–3 |year=2003 |pmid=12477767 |pmc=1773523 |doi= |url=}}</ref>
*SNPs in tumour necrosis factor alpha (TNFα) and genes coding for superfamily member 15 (''TNFSF15'') that are associated with inflammatory bowel disease, have proven associations with IBS.<ref name="pmid22684480">{{cite journal |vauthors=Swan C, Duroudier NP, Campbell E, Zaitoun A, Hastings M, Dukes GE, Cox J, Kelly FM, Wilde J, Lennon MG, Neal KR, Whorwell PJ, Hall IP, Spiller RC |title=Identifying and testing candidate genetic polymorphisms in the irritable bowel syndrome (IBS): association with TNFSF15 and TNFα |journal=Gut |volume=62 |issue=7 |pages=985–94 |year=2013 |pmid=22684480 |doi=10.1136/gutjnl-2011-301213 |url=}}</ref><ref name="pmid21636646">{{cite journal |vauthors=Zucchelli M, Camilleri M, Andreasson AN, Bresso F, Dlugosz A, Halfvarson J, Törkvist L, Schmidt PT, Karling P, Ohlsson B, Duerr RH, Simren M, Lindberg G, Agreus L, Carlson P, Zinsmeister AR, D'Amato M |title=Association of TNFSF15 polymorphism with irritable bowel syndrome |journal=Gut |volume=60 |issue=12 |pages=1671–1677 |year=2011 |pmid=21636646 |pmc=3922294 |doi=10.1136/gut.2011.241877 |url=}}</ref><ref name="pmid22684480" />
*Studies have been conducted to establish associations between neuropeptide S receptor gene (NPSR1) involved in nociception, inflammation and anxiety with abdominal pain.<ref name="pmid19732772">{{cite journal |vauthors=Camilleri M, Carlson P, Zinsmeister AR, McKinzie S, Busciglio I, Burton D, Zucchelli M, D'Amato M |title=Neuropeptide S receptor induces neuropeptide expression and associates with intermediate phenotypes of functional gastrointestinal disorders |journal=Gastroenterology |volume=138 |issue=1 |pages=98–107.e4 |year=2010 |pmid=19732772 |pmc=2813358 |doi=10.1053/j.gastro.2009.08.051 |url=}}</ref> TNF polymorphisms are also associated with post infectious IBS such as rs4263839 in TNFSF15 and IBS, particularly IBS-C.<ref name="pmid21636646">{{cite journal |vauthors=Zucchelli M, Camilleri M, Andreasson AN, Bresso F, Dlugosz A, Halfvarson J, Törkvist L, Schmidt PT, Karling P, Ohlsson B, Duerr RH, Simren M, Lindberg G, Agreus L, Carlson P, Zinsmeister AR, D'Amato M |title=Association of TNFSF15 polymorphism with irritable bowel syndrome |journal=Gut |volume=60 |issue=12 |pages=1671–1677 |year=2011 |pmid=21636646 |pmc=3922294 |doi=10.1136/gut.2011.241877 |url=}}</ref><ref name="pmid22684480">{{cite journal |vauthors=Swan C, Duroudier NP, Campbell E, Zaitoun A, Hastings M, Dukes GE, Cox J, Kelly FM, Wilde J, Lennon MG, Neal KR, Whorwell PJ, Hall IP, Spiller RC |title=Identifying and testing candidate genetic polymorphisms in the irritable bowel syndrome (IBS): association with TNFSF15 and TNFα |journal=Gut |volume=62 |issue=7 |pages=985–94 |year=2013 |pmid=22684480 |doi=10.1136/gutjnl-2011-301213 |url=}}</ref>
*Genes involved in the regulation of hepatic bile acid synthesis such as a functional Klothoβ<ref name="pmid21396369">{{cite journal |vauthors=Wong BS, Camilleri M, Carlson PJ, Guicciardi ME, Burton D, McKinzie S, Rao AS, Zinsmeister AR, Gores GJ |title=A Klothoβ variant mediates protein stability and associates with colon transit in irritable bowel syndrome with diarrhea |journal=Gastroenterology |volume=140 |issue=7 |pages=1934–42 |year=2011 |pmid=21396369 |pmc=3109206 |doi=10.1053/j.gastro.2011.02.063 |url=}}</ref> gene variant also haven proven association with the disease.<ref name="pmid22610000">{{cite journal |vauthors=Wong BS, Camilleri M, Carlson P, McKinzie S, Busciglio I, Bondar O, Dyer RB, Lamsam J, Zinsmeister AR |title=Increased bile acid biosynthesis is associated with irritable bowel syndrome with diarrhea |journal=Clin. Gastroenterol. Hepatol. |volume=10 |issue=9 |pages=1009–15.e3 |year=2012 |pmid=22610000 |pmc=3565429 |doi=10.1016/j.cgh.2012.05.006 |url=}}</ref><ref name="pmid21396369">{{cite journal |vauthors=Wong BS, Camilleri M, Carlson PJ, Guicciardi ME, Burton D, McKinzie S, Rao AS, Zinsmeister AR, Gores GJ |title=A Klothoβ variant mediates protein stability and associates with colon transit in irritable bowel syndrome with diarrhea |journal=Gastroenterology |volume=140 |issue=7 |pages=1934–42 |year=2011 |pmid=21396369 |pmc=3109206 |doi=10.1053/j.gastro.2011.02.063 |url=}}</ref><ref name="pmid21396369">{{cite journal |vauthors=Wong BS, Camilleri M, Carlson PJ, Guicciardi ME, Burton D, McKinzie S, Rao AS, Zinsmeister AR, Gores GJ |title=A Klothoβ variant mediates protein stability and associates with colon transit in irritable bowel syndrome with diarrhea |journal=Gastroenterology |volume=140 |issue=7 |pages=1934–42 |year=2011 |pmid=21396369 |pmc=3109206 |doi=10.1053/j.gastro.2011.02.063 |url=}}</ref>
*Data from studies suggest that the genome as well as genome-wide methylation of DNA plays an important role in IBS. Genome wide DNA methylation profiling is different in patients as compared to healthy controls, especially involving genes linked to neuropeptide hormone function and oxidative stress.<ref name="pmid26670691">{{cite journal |vauthors=Mahurkar S, Polytarchou C, Iliopoulos D, Pothoulakis C, Mayer EA, Chang L |title=Genome-wide DNA methylation profiling of peripheral blood mononuclear cells in irritable bowel syndrome |journal=Neurogastroenterol. Motil. |volume=28 |issue=3 |pages=410–22 |year=2016 |pmid=26670691 |pmc=4760882 |doi=10.1111/nmo.12741 |url=}}</ref>


* '''Immune activation and mucosal inflammation'''
* '''Immune activation and mucosal inflammation'''
Line 92: Line 103:
*** Serotonin(5-HT) is an important neurotransmitter produced by the enterochromaffin cells in the colon,<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="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="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> in response to chemical and mechanical stimuli(short chain fatty acids produced by gastrointestinal microflora and food) and is increased in IBS patients with diarrhea as compared to controls.<ref name="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,<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="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="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> in response to chemical and mechanical stimuli(short chain fatty acids produced by gastrointestinal microflora and food) and is increased in IBS patients with diarrhea as compared to controls.<ref name="pmid15822040">{{cite journal |vauthors=Dunlop SP, Coleman NS, Blackshaw E, Perkins AC, Singh G, Marsden CA, Spiller RC |title=Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome |journal=Clin. Gastroenterol. Hepatol. |volume=3 |issue=4 |pages=349–57 |year=2005 |pmid=15822040 |doi= |url=}}</ref><ref name="pmid16401466">{{cite journal |vauthors=Atkinson W, Lockhart S, Whorwell PJ, Keevil B, Houghton LA |title=Altered 5-hydroxytryptamine signaling in patients with constipation- and diarrhea-predominant irritable bowel syndrome |journal=Gastroenterology |volume=130 |issue=1 |pages=34–43 |year=2006 |pmid=16401466 |doi=10.1053/j.gastro.2005.09.031 |url=}}</ref><ref name="pmid23222853">{{cite journal |vauthors=Gershon MD |title=5-Hydroxytryptamine (serotonin) in the gastrointestinal tract |journal=Curr Opin Endocrinol Diabetes Obes |volume=20 |issue=1 |pages=14–21 |year=2013 |pmid=23222853 |pmc=3708472 |doi=10.1097/MED.0b013e32835bc703 |url=}}</ref><ref name="pmid23872499">{{cite journal |vauthors=Shekhar C, Monaghan PJ, Morris J, Issa B, Whorwell PJ, Keevil B, Houghton LA |title=Rome III functional constipation and irritable bowel syndrome with constipation are similar disorders within a spectrum of sensitization, regulated by serotonin |journal=Gastroenterology |volume=145 |issue=4 |pages=749–57; quiz e13–4 |year=2013 |pmid=23872499 |doi=10.1053/j.gastro.2013.07.014 |url=}}</ref>   
*** Serotonin affects gastrointestinal motility and influences CNS transmission of information. It is known that the spontaneous release of 5-HT is markedly elevated in IBS patients, regardless of bowel habit and directly correlates with abdominal pain severity.<ref name="pmid21427712">{{cite journal |vauthors=Cremon C, Carini G, Wang B, Vasina V, Cogliandro RF, De Giorgio R, Stanghellini V, Grundy D, Tonini M, De Ponti F, Corinaldesi R, Barbara G |title=Intestinal serotonin release, sensory neuron activation, and abdominal pain in irritable bowel syndrome |journal=Am. J. Gastroenterol. |volume=106 |issue=7 |pages=1290–8 |year=2011 |pmid=21427712 |doi=10.1038/ajg.2011.86 |url=}}</ref>   
*** Serotonin affects gastrointestinal motility and influences CNS transmission of information. It is known that the spontaneous release of 5-HT is markedly elevated in IBS patients, regardless of bowel habit and directly correlates with abdominal pain severity.<ref name="pmid21427712">{{cite journal |vauthors=Cremon C, Carini G, Wang B, Vasina V, Cogliandro RF, De Giorgio R, Stanghellini V, Grundy D, Tonini M, De Ponti F, Corinaldesi R, Barbara G |title=Intestinal serotonin release, sensory neuron activation, and abdominal pain in irritable bowel syndrome |journal=Am. J. Gastroenterol. |volume=106 |issue=7 |pages=1290–8 |year=2011 |pmid=21427712 |doi=10.1038/ajg.2011.86 |url=}}</ref>   
*** Serotonin plays a vital role in visceral perception and motility and its increased production contributes to postprandial symptoms in IBS patients, hence providing the rationale for the therapeutic efficacy of 5-HT 3 receptor antagonists and 5-HT 4 receptor agonists on symptoms in IBS patients.<ref name="pmid17241888">{{cite journal |vauthors=Gershon MD, Tack J |title=The serotonin signaling system: from basic understanding to drug development for functional GI disorders |journal=Gastroenterology |volume=132 |issue=1 |pages=397–414 |year=2007 |pmid=17241888 |doi=10.1053/j.gastro.2006.11.002 |url=}}</ref><ref name="pmid22071696">{{cite journal |vauthors=Camilleri M |title=Pharmacology of the new treatments for lower gastrointestinal motility disorders and irritable bowel syndrome |journal=Clin. Pharmacol. Ther. |volume=91 |issue=1 |pages=44–59 |year=2012 |pmid=22071696 |doi=10.1038/clpt.2011.261 |url=}}</ref>  
*** Serotonin plays a vital role in visceral perception and motility and its increased production contributes to postprandial symptoms in IBS patients, hence providing the rationale for the therapeutic efficacy of 5-HT 3 receptor antagonists and 5-HT 4 receptor agonists on symptoms in IBS patients.<ref name="pmid17241888">{{cite journal |vauthors=Gershon MD, Tack J |title=The serotonin signaling system: from basic understanding to drug development for functional GI disorders |journal=Gastroenterology |volume=132 |issue=1 |pages=397–414 |year=2007 |pmid=17241888 |doi=10.1053/j.gastro.2006.11.002 |url=}}</ref><ref name="pmid22071696">{{cite journal |vauthors=Camilleri M |title=Pharmacology of the new treatments for lower gastrointestinal motility disorders and irritable bowel syndrome |journal=Clin. Pharmacol. Ther. |volume=91 |issue=1 |pages=44–59 |year=2012 |pmid=22071696 |doi=10.1038/clpt.2011.261 |url=}}</ref>


==Genetics==
==Genetics==

Revision as of 18:57, 24 October 2017

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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.

OR


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

OR

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 understood 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 from the transverse, descending and sigmoid colon have shown that spastic colon leads 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) in diarrhea-prone IBS patients is higher, compared to healthy subjects.[4][5]
    • Diarrhea prone IBS patients have increased responses to ingestion, CRH(Corticotropin releasing hormone)[6][7], CCK(cholecystokinin)[8] and present with abdominal discomfort and accelerated transit through the colon.
    • On the other hand, constipation prone IBS patients show fewer HAPCs, delayed transit through the colon and decreased motility.[4]
    • It has been demonstrated that more than 90% of HAPCs are associated with abdominal pain.[8]
  • CNS dysregulation
    • The conceptualization of IBS being a brain gut disorder is reinforced by the following:
      • Epidemiological studies 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 is reduced, pointing directly towards CNS dysfunction and increased susceptibility to stressors.[12]
      • Psychological therapies that act on cerebral cortical sites and antidepressants have proven to be one of the mainstays of therapy for patients. The role of probiotics in modifying signal processing in the brain also proves that IBS is a brain gut disorder. [13]
      • Studies using advanced brain imaging techniques have analyzed differences in brain activity 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) are involved in IBS. [10]
      • 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 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[4][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):
      • Spinal hyperexcitability due to activation of an N-methyl D aspartate(NMDA) receptor, Nitric oxide and possibly other neurotransmitters.
      • Activation of specific gastrointestinal mediators like kinins and serotonin that lead to afferent nerve fiber sensitization.
      • 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]
      • Recruitment of peripheral silent nociceptors causing increased end organ sensitivity due to hormonal or immune activation[20].
  • Genetic factors
  • IBS is a complex disease with interactions between genetic and environmental factors.[26][27] The role of genetic predisposition in IBS is suggested by epidemiological studies of twins[28][29] and familial aggregation.[27][27][30]
  • Investigations show higher concordance of IBS in monozygotic as compared to dizygotic twins, thereby proving the role of genetic factors in IBS.[27][29][31][32]
  • 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.[33][34]
  • 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.[35][36]
  • 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.[37][38][39][40] Moreover, changed patterns of interleukin production may be associated with IBS.[34]
  • 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.[41][42][41]
  • Studies have been conducted to establish associations between neuropeptide S receptor gene (NPSR1) involved in nociception, inflammation and anxiety with abdominal pain.[43] TNF polymorphisms are also associated with post infectious IBS such as rs4263839 in TNFSF15 and IBS, particularly IBS-C.[42][41]
  • Genes involved in the regulation of hepatic bile acid synthesis such as a functional Klothoβ[44] gene variant also haven proven association with the disease.[45][44][44]
  • Data from studies suggest that the genome as well as genome-wide methylation of DNA plays an important role in IBS. Genome wide DNA methylation profiling is different in patients as compared to healthy controls, especially involving genes linked to neuropeptide hormone function and oxidative stress.[46]


  • 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.[47][48][49][50][51][52][49]
    • Moreover, 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.[47]
    • 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. [49][53][54][55][56]
    • Lymphocytes:
      •  Patients with IBS have increased B lymphocyte activation in the blood.[57] However, activation of humoral immunity in IBS is specific for the gastrointestinal tract[58] as increased numbers of lymphocytes have been found in the small intestine and colon of patients.[48][50]
      • In addition to this, IBS patients with diarrhea[58] 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,[50] 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.[48]
      • Examination of stool in patients with diarrhea prominent IBS have high levels of serine protease activity.[59][60]When fecal extracts are intra colonically infused into mice, there is increased visceral pain and colonic cellular permeability. [59]
      • Serine protease inhibitors prevent effects mediated by high levels of serine protease. 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.[60][59]
    • Mast cells:
      •  Studies have shown an increased number of mast cells in IBS patients in the jejunum, terminal ileum and colon.[52]
      • Higher numbers of activated mast cells are found in proximity to colonic nerve fibres in the mucosa of the gastrointestinal tract of IBS patients. [52][51]
    • Proinflammatory cytokines:
      • Cytokines are proteinaceous mediators of the immune response.  Increased levels of cytokines have been found in IBS patients.[56][55]
      • Higher amounts of of tumor necrosis factor are produced by the peripheral blood mononuclear cells of IBS patients.[61][49]
      • In studies conducted using 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. [62]
      • 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.[49][62][61]
    • Altered gut microbiota
      •  It is postulated that altered fecal microflora may be associated with IBS.[63][53] There are numerous studies that suggest that altered fecal microflora in IBS patients differ from healthy controls. [64][65][66][67][68]
      • Inoculation of germ free animals with fecal microbiota from IBS patients has demonstrated increased colonic hypersensitivity, as compared to samples inoculated from healthy controls. [69]
      • Studies have also shown that the fecal microbiota in patients with post infectious IBS differs markedly from healthy controls, with decrease in the diversity of the fecal microbiome, correlated with increased numbers of CD8 and CD4RA-positive intraepithelial lymphocytes. [70]
      • IBS patients who have undergone colonoscopy, with sampling from the colon and terminal ileum have been found to have colonic spirochaetosis with a unique pathology of increased lymphoid follicles and eosinophils as compared to healthy controls.[71]
      • IBS with diarrhea is sometimes preceded by acute enteric infections and therefore, benefit from probiotics that serve to alter metabolism and composition of the microflora.[72][73]  Administration of probiotics in patients decreases flatulence relative to Lactobacillus.[74] A probiotic yogurt containing a mixture of Bacteroides species has been shown to improve symptoms in IBS patients.[75]
      • Studies have been conducted suggesting that the switching on of a T-helper-2 immune-cell response may cause increased susceptibility to IBS after acute GI infection.[76][77]
    • Abnormal serotonin pathways
      • Serotonin(5-HT) is an important neurotransmitter produced by the enterochromaffin cells in the colon,[78][79][80] 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.[81][82][83][84]
      • 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.[85]
      • 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.[86][87]

Genetics

  • IBS is a complex disease with interactions between genetic and environmental factors.[26][27] The role of genetic predisposition in IBS is suggested by epidemiological studies of twins[28][29] and familial aggregation.[27][27][30]
  • Investigations show higher concordance of IBS in monozygotic as compared to dizygotic twins, thereby proving the role of genetic factors in IBS.[27][29][31][32]
  • 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.[33][34]
  • 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.[35][36]
  • 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.[37][38][39][40] Moreover, changed patterns of interleukin production may be associated with IBS.[34]
  • 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.[41][42][41]
  • Studies have been conducted to establish associations between neuropeptide S receptor gene (NPSR1) involved in nociception, inflammation and anxiety with abdominal pain.[43] TNF polymorphisms are also associated with post infectious IBS such as rs4263839 in TNFSF15 and IBS, particularly IBS-C.[42][41]
  • Genes involved in the regulation of hepatic bile acid synthesis such as a functional Klothoβ[44] gene variant also haven proven association with the disease.[45][44][44]
  • Data from studies suggest that the genome as well as genome-wide methylation of DNA plays an important role in IBS. Genome wide DNA methylation profiling is different in patients as compared to healthy controls, especially involving genes linked to neuropeptide hormone function and oxidative stress.[46]

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. ↑ 4.0 4.1 4.2 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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  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 8.0 8.1 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.
  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.
  10. ↑ 10.0 10.1 10.2 Gupta A, Kilpatrick L, Labus J, Tillisch K, Braun A, Hong JY, Ashe-McNalley C, Naliboff B, Mayer EA (2014). "Early adverse life events and resting state neural networks in patients with chronic abdominal pain: evidence for sex differences". Psychosom Med. 76 (6): 404–12. doi:10.1097/PSY.0000000000000089. PMC 4113723. PMID 25003944.
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  14. ↑ 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.
  15. ↑ Hall GB, Kamath MV, Collins S, Ganguli S, Spaziani R, Miranda KL, Bayati A, Bienenstock J (2010). "Heightened central affective response to visceral sensations of pain and discomfort in IBS". Neurogastroenterol. Motil. 22 (3): 276–e80. doi:10.1111/j.1365-2982.2009.01436.x. PMID 20003075.
  16. ↑ Ellingson BM, Mayer E, Harris RJ, Ashe-McNally C, Naliboff BD, Labus JS, Tillisch K (2013). "Diffusion tensor imaging detects microstructural reorganization in the brain associated with chronic irritable bowel syndrome". Pain. 154 (9): 1528–41. doi:10.1016/j.pain.2013.04.010. PMC 3758125. PMID 23721972.
  17. ↑ Elsenbruch S, Rosenberger C, Bingel U, Forsting M, Schedlowski M, Gizewski ER (2010). "Patients with irritable bowel syndrome have altered emotional modulation of neural responses to visceral stimuli". Gastroenterology. 139 (4): 1310–9. doi:10.1053/j.gastro.2010.06.054. PMID 20600024.
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  19. ↑ 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.
  20. ↑ 20.0 20.1 20.2 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.
  21. ↑ Mertz H, Naliboff B, Munakata J, Niazi N, Mayer EA (1995). "Altered rectal perception is a biological marker of patients with irritable bowel syndrome". Gastroenterology. 109 (1): 40–52. PMID 7797041.
  22. ↑ Prior A, Maxton DG, Whorwell PJ (1990). "Anorectal manometry in irritable bowel syndrome: differences between diarrhoea and constipation predominant subjects". Gut. 31 (4): 458–62. PMC 1378424. PMID 2338274.
  23. ↑ Posserud I, Syrous A, Lindström L, Tack J, Abrahamsson H, Simrén M (2007). "Altered rectal perception in irritable bowel syndrome is associated with symptom severity". Gastroenterology. 133 (4): 1113–23. doi:10.1053/j.gastro.2007.07.024. PMID 17919487.
  24. ↑ Bouin M, Plourde V, Boivin M, Riberdy M, Lupien F, Laganière M, Verrier P, Poitras P (2002). "Rectal distention testing in patients with irritable bowel syndrome: sensitivity, specificity, and predictive values of pain sensory thresholds". Gastroenterology. 122 (7): 1771–7. PMID 12055583.
  25. ↑ Mertz H, Morgan V, Tanner G, Pickens D, Price R, Shyr Y, Kessler R (2000). "Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention". Gastroenterology. 118 (5): 842–8. PMID 10784583.
  26. ↑ 26.0 26.1 Wouters MM, Lambrechts D, Knapp M, Cleynen I, Whorwell P, Agréus L, Dlugosz A, Schmidt PT, Halfvarson J, Simrén M, Ohlsson B, Karling P, Van Wanrooy S, Mondelaers S, Vermeire S, Lindberg G, Spiller R, Dukes G, D'Amato M, Boeckxstaens G (2014). "Genetic variants in CDC42 and NXPH1 as susceptibility factors for constipation and diarrhoea predominant irritable bowel syndrome". Gut. 63 (7): 1103–11. doi:10.1136/gutjnl-2013-304570. PMID 24041540.
  27. ↑ 27.0 27.1 27.2 27.3 27.4 27.5 27.6 27.7 Levy RL, Jones KR, Whitehead WE, Feld SI, Talley NJ, Corey LA (2001). "Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology". Gastroenterology. 121 (4): 799–804. PMID 11606493.
  28. ↑ 28.0 28.1 Saito YA, Petersen GM, Larson JJ, Atkinson EJ, Fridley BL, de Andrade M, Locke GR, Zimmerman JM, Almazar-Elder AE, Talley NJ (2010). "Familial aggregation of irritable bowel syndrome: a family case-control study". Am. J. Gastroenterol. 105 (4): 833–41. doi:10.1038/ajg.2010.116. PMC 2875200. PMID 20234344.
  29. ↑ 29.0 29.1 29.2 29.3 Lembo A, Zaman M, Jones M, Talley NJ (2007). "Influence of genetics on irritable bowel syndrome, gastro-oesophageal reflux and dyspepsia: a twin study". Aliment. Pharmacol. Ther. 25 (11): 1343–50. doi:10.1111/j.1365-2036.2007.03326.x. PMID 17509102.
  30. ↑ 30.0 30.1 Saito YA, Petersen GM, Locke GR, Talley NJ (2005). "The genetics of irritable bowel syndrome". Clin. Gastroenterol. Hepatol. 3 (11): 1057–65. PMID 16271334.
  31. ↑ 31.0 31.1 Bengtson MB, Rønning T, Vatn MH, Harris JR (2006). "Irritable bowel syndrome in twins: genes and environment". Gut. 55 (12): 1754–9. doi:10.1136/gut.2006.097287. PMC 1856463. PMID 17008364.
  32. ↑ 32.0 32.1 Morris-Yates A, Talley NJ, Boyce PM, Nandurkar S, Andrews G (1998). "Evidence of a genetic contribution to functional bowel disorder". Am. J. Gastroenterol. 93 (8): 1311–7. doi:10.1111/j.1572-0241.1998.440_j.x. PMID 9707057.
  33. ↑ 33.0 33.1 Villani AC, Lemire M, Thabane M, Belisle A, Geneau G, Garg AX, Clark WF, Moayyedi P, Collins SM, Franchimont D, Marshall JK (2010). "Genetic risk factors for post-infectious irritable bowel syndrome following a waterborne outbreak of gastroenteritis". Gastroenterology. 138 (4): 1502–13. doi:10.1053/j.gastro.2009.12.049. PMID 20044998.
  34. ↑ 34.0 34.1 34.2 34.3 Gonsalkorale WM, Perrey C, Pravica V, Whorwell PJ, Hutchinson IV (2003). "Interleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component?". Gut. 52 (1): 91–3. PMC 1773523. PMID 12477767.
  35. ↑ 35.0 35.1 Locke GR, Ackerman MJ, Zinsmeister AR, Thapa P, Farrugia G (2006). "Gastrointestinal symptoms in families of patients with an SCN5A-encoded cardiac channelopathy: evidence of an intestinal channelopathy". Am. J. Gastroenterol. 101 (6): 1299–304. doi:10.1111/j.1572-0241.2006.00507.x. PMID 16771953.
  36. ↑ 36.0 36.1 Saito YA, Strege PR, Tester DJ, Locke GR, Talley NJ, Bernard CE, Rae JL, Makielski JC, Ackerman MJ, Farrugia G (2009). "Sodium channel mutation in irritable bowel syndrome: evidence for an ion channelopathy". Am. J. Physiol. Gastrointest. Liver Physiol. 296 (2): G211–8. doi:10.1152/ajpgi.90571.2008. PMC 2643921. PMID 19056759.
  37. ↑ 37.0 37.1 Grasberger H, Chang L, Shih W, Presson AP, Sayuk GS, Newberry RD, Karagiannides I, Pothoulakis C, Mayer E, Merchant JL (2013). "Identification of a functional TPH1 polymorphism associated with irritable bowel syndrome bowel habit subtypes". Am. J. Gastroenterol. 108 (11): 1766–74. doi:10.1038/ajg.2013.304. PMC 4067697. PMID 24060757.
  38. ↑ 38.0 38.1 Jun S, Kohen R, Cain KC, Jarrett ME, Heitkemper MM (2011). "Associations of tryptophan hydroxylase gene polymorphisms with irritable bowel syndrome". Neurogastroenterol. Motil. 23 (3): 233–9, e116. doi:10.1111/j.1365-2982.2010.01623.x. PMC 3057463. PMID 21073637.
  39. ↑ 39.0 39.1 Kim HJ, Camilleri M, Carlson PJ, Cremonini F, Ferber I, Stephens D, McKinzie S, Zinsmeister AR, Urrutia R (2004). "Association of distinct alpha(2) adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders". Gut. 53 (6): 829–37. PMC 1774073. PMID 15138209.
  40. ↑ 40.0 40.1 Yeo A, Boyd P, Lumsden S, Saunders T, Handley A, Stubbins M, Knaggs A, Asquith S, Taylor I, Bahari B, Crocker N, Rallan R, Varsani S, Montgomery D, Alpers DH, Dukes GE, Purvis I, Hicks GA (2004). "Association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome in women". Gut. 53 (10): 1452–8. doi:10.1136/gut.2003.035451. PMC 1774243. PMID 15361494.
  41. ↑ 41.0 41.1 41.2 41.3 41.4 41.5 Swan C, Duroudier NP, Campbell E, Zaitoun A, Hastings M, Dukes GE, Cox J, Kelly FM, Wilde J, Lennon MG, Neal KR, Whorwell PJ, Hall IP, Spiller RC (2013). "Identifying and testing candidate genetic polymorphisms in the irritable bowel syndrome (IBS): association with TNFSF15 and TNFα". Gut. 62 (7): 985–94. doi:10.1136/gutjnl-2011-301213. PMID 22684480.
  42. ↑ 42.0 42.1 42.2 42.3 Zucchelli M, Camilleri M, Andreasson AN, Bresso F, Dlugosz A, Halfvarson J, Törkvist L, Schmidt PT, Karling P, Ohlsson B, Duerr RH, Simren M, Lindberg G, Agreus L, Carlson P, Zinsmeister AR, D'Amato M (2011). "Association of TNFSF15 polymorphism with irritable bowel syndrome". Gut. 60 (12): 1671–1677. doi:10.1136/gut.2011.241877. PMC 3922294. PMID 21636646.
  43. ↑ 43.0 43.1 Camilleri M, Carlson P, Zinsmeister AR, McKinzie S, Busciglio I, Burton D, Zucchelli M, D'Amato M (2010). "Neuropeptide S receptor induces neuropeptide expression and associates with intermediate phenotypes of functional gastrointestinal disorders". Gastroenterology. 138 (1): 98–107.e4. doi:10.1053/j.gastro.2009.08.051. PMC 2813358. PMID 19732772.
  44. ↑ 44.0 44.1 44.2 44.3 44.4 44.5 Wong BS, Camilleri M, Carlson PJ, Guicciardi ME, Burton D, McKinzie S, Rao AS, Zinsmeister AR, Gores GJ (2011). "A Klothoβ variant mediates protein stability and associates with colon transit in irritable bowel syndrome with diarrhea". Gastroenterology. 140 (7): 1934–42. doi:10.1053/j.gastro.2011.02.063. PMC 3109206. PMID 21396369.
  45. ↑ 45.0 45.1 Wong BS, Camilleri M, Carlson P, McKinzie S, Busciglio I, Bondar O, Dyer RB, Lamsam J, Zinsmeister AR (2012). "Increased bile acid biosynthesis is associated with irritable bowel syndrome with diarrhea". Clin. Gastroenterol. Hepatol. 10 (9): 1009–15.e3. doi:10.1016/j.cgh.2012.05.006. PMC 3565429. PMID 22610000.
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  48. ↑ 48.0 48.1 48.2 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.
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  50. ↑ 50.0 50.1 50.2 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.
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  56. ↑ 56.0 56.1 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.
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  58. ↑ 58.0 58.1 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.
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  62. ↑ 62.0 62.1 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.
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