Irritable bowel syndrome pathophysiology: Difference between revisions
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***Changes in the motor function of the [[Colon (anatomy)|colon]] are responsible for producing the gastrointestinal symptoms of IBS such as altered bowel habits and abdominal pain.<ref name="pmid18456567" /> | ***Changes in the motor function of the [[Colon (anatomy)|colon]] are responsible for producing the gastrointestinal symptoms of IBS such as altered bowel habits and abdominal pain.<ref name="pmid18456567" /> | ||
**'''Visceral hypersensitivity:''' | **'''Visceral hypersensitivity:''' | ||
**IBS is associated with a decreased threshold for perception of visceral stimuli (i.e. visceral hypersensitivity).<ref name="pmid18456567" /><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><ref name="pmid2323511">{{cite journal |vauthors=Whitehead WE, Holtkotter B, Enck P, Hoelzl R, Holmes KD, Anthony J, Shabsin HS, Schuster MM |title=Tolerance for rectosigmoid distention in irritable bowel syndrome |journal=Gastroenterology |volume=98 |issue=5 Pt 1 |pages=1187–92 |year=1990 |pmid=2323511 |doi= |url=}}</ref>[[Rectum|Rectal]] distension produces painful and non-painful sensations at lower volumes in IBS patients as compared to healthy controls, suggesting the presence of afferent pathway disturbances in visceral innervation<ref name="pmid7797041">{{cite journal |vauthors=Mertz H, Naliboff B, Munakata J, Niazi N, Mayer EA |title=Altered rectal perception is a biological marker of patients with irritable bowel syndrome |journal=Gastroenterology |volume=109 |issue=1 |pages=40–52 |year=1995 |pmid=7797041 |doi= |url=}}</ref><ref name="pmid2338274">{{cite journal |vauthors=Prior A, Maxton DG, Whorwell PJ |title=Anorectal manometry in irritable bowel syndrome: differences between diarrhoea and constipation predominant subjects |journal=Gut |volume=31 |issue=4 |pages=458–62 |year=1990 |pmid=2338274 |pmc=1378424 |doi= |url=}}</ref><ref name="pmid17919487">{{cite journal |vauthors=Posserud I, Syrous A, Lindström L, Tack J, Abrahamsson H, Simrén M |title=Altered rectal perception in irritable bowel syndrome is associated with symptom severity |journal=Gastroenterology |volume=133 |issue=4 |pages=1113–23 |year=2007 |pmid=17919487 |doi=10.1053/j.gastro.2007.07.024 |url=}}</ref><ref name="pmid12055583">{{cite journal |vauthors=Bouin M, Plourde V, Boivin M, Riberdy M, Lupien F, Laganière M, Verrier P, Poitras P |title=Rectal distention testing in patients with irritable bowel syndrome: sensitivity, specificity, and predictive values of pain sensory thresholds |journal=Gastroenterology |volume=122 |issue=7 |pages=1771–7 |year=2002 |pmid=12055583 |doi= |url=}}</ref>. | |||
**The factors which contribute to visceral hyperalgesia (i.e increased sensitivity of the intestines to normal sensations) are as follows: | |||
**'''[[Spinal cord|Spinal]] hyperexcitability''' | |||
**Secondary to activation of an [[NMDA receptor|N-methyl D aspartate (NMDA) receptor]], [[nitric oxide]] and possibly other neurotransmitters. | |||
**'''Activation of specific gastrointestinal mediators''' such as [[kinins]] and [[serotonin]] that lead to afferent nerve fiber sensitization. | |||
**'''Central ([[Brain stem|brainstem]] and [[Cerebral cortex|cortical]]) modulation''' with increased activation of anterior cingulate cortex, [[thalamus]] and [[Insular cortex|insula]]. | |||
**These structures are involved in processing of pain. | |||
**Cortical and brain stem modulation translate into long term hypersensitivity due to neuroplasticity. | |||
**Semi permanent changes(seen on functional magnetic resonance imaging and positron emission tomography) in the neural response to visceral stimulation contribute to visceral hypersensitivity.''<ref name="pmid21537962" /><ref name="pmid10784583">{{cite journal |vauthors=Mertz H, Morgan V, Tanner G, Pickens D, Price R, Shyr Y, Kessler R |title=Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention |journal=Gastroenterology |volume=118 |issue=5 |pages=842–8 |year=2000 |pmid=10784583 |doi= |url=}}</ref> '' | |||
**'''Recruitment of peripheral silent nociceptors''' cause increased end organ sensitivity due to hormonal or immune activation<ref name="pmid21537962" />. | |||
{{familytree/start |summary=PE diagnosis Algorithm.}} | {{familytree/start |summary=PE diagnosis Algorithm.}} | ||
{{familytree | | | | | | | | | |,|-| A01 |-| A02 | | | |A01=[[Spinal cord|Spinal]] hyperexcitability |A02= Activation of <br>• [[NMDA receptor|N-methyl D aspartate (NMDA) receptor]] <br>• [[nitric oxide]] }} | {{familytree | | | | | | | | | |,|-| A01 |-| A02 | | | |A01=[[Spinal cord|Spinal]] hyperexcitability |A02= Activation of <br>• [[NMDA receptor|N-methyl D aspartate (NMDA) receptor]] <br>• [[nitric oxide]] }} | ||
| Line 47: | Line 57: | ||
{{familytree/end}} | {{familytree/end}} | ||
<br><br><br> | <br><br><br> | ||
*'''Immune activation and mucosal inflammation'''{{Family tree/start}} | |||
{{Family tree/start}} | |||
{{Family tree | A01 |-|-| A02 |-|-|-| A03 | |A01= '''Mast cells'''| A02= '''IMMUNE ACTIVATION AND MUCOSAL INFLAMMATION'''| A03='''Lymphocytes'''}} | {{Family tree | A01 |-|-| A02 |-|-|-| A03 | |A01= '''Mast cells'''| A02= '''IMMUNE ACTIVATION AND MUCOSAL INFLAMMATION'''| A03='''Lymphocytes'''}} | ||
Revision as of 17:41, 30 October 2017
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Irritable bowel syndrome Microchapters |
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Differentiating Irritable bowel syndrome from other Diseases |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
The exact pathogenesis of Irritable bowel syndrome (IBS) is not fully understood.
It is believed to be caused by the complex interaction of various factors such as gastrointestinal motor abnormalities, CNS dysregulation, visceral hypersensitivity, immune activation, mucosal inflammation of the GI tract, altered gut microflora and abnormal serotonin pathways.
Pathophysiology
Pathogenesis
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 | |||||||||||||||||||||||||||||
- Intrinsic gastrointestinal factors
- 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 IBS leads to changed patterns of colonic and small intestinal motor function, such as increased frequency and irregularity of luminal contractions.
- Motor changes lead to symptoms of diarrhea and constipation.[1][2][3]
- Diarrhea-prone IBS patients have increased responses to ingestion, CRH (corticotropin releasing hormone), CCK (cholecystokinin), which increase the peak amplitude of high-amplitude propagating contractions (HAPCs) and lead to abdominal discomfort with accelerated transit through the colon. [4][5][6][7][8]
- Constipation-prone IBS patients show fewer high-amplitude propagating contractions (HAPCs) as compared to diarrhea prone IBS patients, delayed transit through the colon and decreased motility.
- Changes in the motor function of the colon are responsible for producing the gastrointestinal symptoms of IBS such as altered bowel habits and abdominal pain.[7]
- Visceral hypersensitivity:
- IBS is associated with a decreased threshold for perception of visceral stimuli (i.e. visceral hypersensitivity).[7][9][10]Rectal distension produces painful and non-painful sensations at lower volumes in IBS patients as compared to healthy controls, suggesting the presence of afferent pathway disturbances in visceral innervation[11][12][13][14].
- The factors which contribute to visceral hyperalgesia (i.e increased sensitivity of the intestines to normal sensations) are as follows:
- Spinal hyperexcitability
- Secondary to activation of an N-methyl D aspartate (NMDA) receptor, nitric oxide and possibly other neurotransmitters.
- Activation of specific gastrointestinal mediators such as kinins and serotonin that lead to afferent nerve fiber sensitization.
- Central (brainstem and cortical) modulation with increased activation of anterior cingulate cortex, thalamus and insula.
- These structures are involved in processing of pain.
- Cortical and brain stem modulation translate into long term hypersensitivity due to neuroplasticity.
- Semi permanent changes(seen on functional magnetic resonance imaging and positron emission tomography) in the neural response to visceral stimulation contribute to visceral hypersensitivity.[9][15]
- Recruitment of peripheral silent nociceptors cause increased end organ sensitivity due to hormonal or immune activation[9].
- Motor abnormalities:
| 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 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
- Immune activation and mucosal inflammation
Mast cells IMMUNE ACTIVATION AND MUCOSAL INFLAMMATION Lymphocytes Proinflammatory cytokines - 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.[16][17][18][19][20][21][18]
- IBS patients have higher mucosal counts of lymphocytes (T cells, B cells), mast cells and immune mediators such as prostanoids, proteases, cytokines and histamines.[18][22][23][24][25]
- 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.[17][19][26][27]
- IBS patients with diarrhea have enhanced mucosal humoral activity, associated with activation and proliferation of B cells and immunoglobulin production, identified by microarray profiling.[27]
- IBS patients with severe disease have an increase in lymphocyte infiltration in the myentric plexus.[19]
- 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.[17]
- Stool in patients with diarrhea prominent IBS demonstrates high levels of serine protease activity, which is produced by lymphocytes.[28][29]
- In response to high levels of serine protease, there is increased visceral pain and colonic cellular permeability. [28]
- Serine protease inhibitors prevent effects mediated by high levels of serine protease in IBS patients.[29][28]
- Mast cells:
- IBS leads to an increased number of mast cells in IBS patients in the jejunum, terminal ileum and colon.[21]
- Higher numbers of activated mast cells are found in proximity to colonic nerve fibres in the mucosa of the gastrointestinal tract of IBS patients. [21][20]
- Proinflammatory cytokines:
- Cytokines are protein mediators of the immune response. Increased levels of cytokines have been found in IBS patients.[25][24]
- Higher amounts of tumor necrosis factor are produced by the peripheral blood mononuclear cells of IBS patients.[30][18]
- Other cytokines such as interleukin 1β, interleukin 6, interleukin 10, and TNFα are raised in IBS patients.
- Increased concentration of cytokines is directly proportional to the severity and frequency of pain.[18][31][30]
- The TNF antagonist infliximab counteracts pain in IBS patients, proving TNF involvement in mechanical hypersensitivity of the colonic afferent nerve endings . [31]
- 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.[22][32] [33][34][35][36][37][38]
- 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. [39][40][41]
- Altered gut microbiota causes increased colonic hypersensitivity. [42]
- 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.[43][44][45][46][47][48][49]
- Serotonin affects gastrointestinal motility and visceral pain perception. Spontaneous release of 5-HT correlates with abdominal pain severity.[50]
- 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.[51][52][53][54]
- Increased serotonin 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.[55][56]
Psychosocial factors and CNS dysregulation
- Symptom exacerbation occurs in IBS patients with emotional disturbances,stress, anxiety or depression. Traumatic experiences before 18 years of age 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.[57][58]
- 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, seen on advanced brain imaging techniques as irregularities in the mid- cingulate cortex and prefrontal cortex on diffusion tensor imaging. [59]
- prefrontal cortex modulation may lead to increased perception of visceral pain.
- Modulation of the mid-cingulate cortex is associated with alterations in the subjective sensations of pain.[60][61]
- Patients with IBS have aberrant processing of central information, with decreased feedback on the emotional arousal network that controls the autonomic activity of the gastrointestinal tract and changes gut motility.[62][63]
- IBS is a brain gut disorder as rectal distension in patients causes increased engagement of regions of the brain associated with attentional and behavioral responses.[60][64][65]
- Psychological stress also impacts the release of gut proinflammatory cytokines, contributing to pain in IBS patients.[16]
Genetics
- IBS has high twin concordance and familial aggregation:[66][67][68][69][70][71]
- Single nucleotide polymorphisms (SNPs) in genes:
- IBS has SNPs in genes playing an important role in host-microbiota interaction (TLR9, IL-6 and CDH1), immune activation and epithelial barriers.
- SNPs cause inflammation and increased permeability of the GI tract, leading to abdominal discomfort and increased motility.[74][75]
- Mutation of type V (alpha subunit) of SCN5A-encoded voltage gated sodium channel causes IBS.[76][77]
- Genome wide DNA methylation profiling is impaired in IBS and this involves genes linked to neuropeptide hormone function and oxidative stress.[78]
- IBS causes mutation in the neuropeptide S receptor gene (NPSR1) involved in nociception, inflammation and anxiety with abdominal pain.[79]
- Genes involved in the regulation of hepatic bile acid synthesis such as a functional Klothoβ gene are mutated in IBS.[80][81]
- TNF polymorphisms:
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
- ↑ 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.
- ↑ Kumar D, Wingate DL (1985). "The irritable bowel syndrome: a paroxysmal motor disorder". Lancet. 2 (8462): 973–7. PMID 2865504.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Fukudo S, Nomura T, Hongo M (1998). "Impact of corticotropin-releasing hormone on gastrointestinal motility and adrenocorticotropic hormone in normal controls and patients with irritable bowel syndrome". Gut. 42 (6): 845–9. PMC 1727153. PMID 9691924.
- ↑ 7.0 7.1 7.2 Camilleri M, McKinzie S, Busciglio I, Low PA, Sweetser S, Burton D, Baxter K, Ryks M, Zinsmeister AR (2008). "Prospective study of motor, sensory, psychologic, and autonomic functions in patients with irritable bowel syndrome". Clin. Gastroenterol. Hepatol. 6 (7): 772–81. doi:10.1016/j.cgh.2008.02.060. PMC 2495078. PMID 18456567.
- ↑ Kellow JE, Phillips SF (1987). "Altered small bowel motility in irritable bowel syndrome is correlated with symptoms". Gastroenterology. 92 (6): 1885–93. PMID 3569764.
- ↑ 9.0 9.1 9.2 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 16.0 16.1 Coëffier M, Gloro R, Boukhettala N, Aziz M, Lecleire S, Vandaele N, Antonietti M, Savoye G, Bôle-Feysot C, Déchelotte P, Reimund JM, Ducrotté P (2010). "Increased proteasome-mediated degradation of occludin in irritable bowel syndrome". Am. J. Gastroenterol. 105 (5): 1181–8. doi:10.1038/ajg.2009.700. PMID 19997094.
- ↑ 17.0 17.1 17.2 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.
- ↑ 18.0 18.1 18.2 18.3 18.4 Liebregts T, Adam B, Bredack C, Röth A, Heinzel S, Lester S, Downie-Doyle S, Smith E, Drew P, Talley NJ, Holtmann G (2007). "Immune activation in patients with irritable bowel syndrome". Gastroenterology. 132 (3): 913–20. doi:10.1053/j.gastro.2007.01.046. PMID 17383420.
- ↑ 19.0 19.1 19.2 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.
- ↑ 20.0 20.1 Guilarte M, Santos J, de Torres I, Alonso C, Vicario M, Ramos L, Martínez C, Casellas F, Saperas E, Malagelada JR (2007). "Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum". Gut. 56 (2): 203–9. doi:10.1136/gut.2006.100594. PMC 1856785. PMID 17005763.
- ↑ 21.0 21.1 21.2 Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, Pasquinelli G, Morselli-Labate AM, Grady EF, Bunnett NW, Collins SM, Corinaldesi R (2004). "Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome". Gastroenterology. 126 (3): 693–702. PMID 14988823.
- ↑ 22.0 22.1 Marshall JK, Thabane M, Garg AX, Clark WF, Moayyedi P, Collins SM (2010). "Eight year prognosis of postinfectious irritable bowel syndrome following waterborne bacterial dysentery". Gut. 59 (5): 605–11. doi:10.1136/gut.2009.202234. PMID 20427395.
- ↑ Wensaas KA, Langeland N, Hanevik K, Mørch K, Eide GE, Rortveit G (2012). "Irritable bowel syndrome and chronic fatigue 3 years after acute giardiasis: historic cohort study". Gut. 61 (2): 214–9. doi:10.1136/gutjnl-2011-300220. PMID 21911849.
- ↑ 24.0 24.1 Mearin F, Perelló A, Balboa A, Perona M, Sans M, Salas A, Angulo S, Lloreta J, Benasayag R, García-Gonzalez MA, Pérez-Oliveras M, Coderch J (2009). "Pathogenic mechanisms of postinfectious functional gastrointestinal disorders: results 3 years after gastroenteritis". Scand. J. Gastroenterol. 44 (10): 1173–85. doi:10.1080/00365520903171276. PMID 19711225.
- ↑ 25.0 25.1 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.
- ↑ Ohman L, Lindmark AC, Isaksson S, Posserud I, Strid H, Sjövall H, Simrén M (2009). "B-cell activation in patients with irritable bowel syndrome (IBS)". Neurogastroenterol. Motil. 21 (6): 644–50, e27. doi:10.1111/j.1365-2982.2009.01272.x. PMID 19222763.
- ↑ 27.0 27.1 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.
- ↑ 28.0 28.1 28.2 Bueno L (2008). "Protease activated receptor 2: a new target for IBS treatment". Eur Rev Med Pharmacol Sci. 12 Suppl 1: 95–102. PMID 18924448.
- ↑ 29.0 29.1 Gecse K, Róka R, Ferrier L, Leveque M, Eutamene H, Cartier C, Ait-Belgnaoui A, Rosztóczy A, Izbéki F, Fioramonti J, Wittmann T, Bueno L (2008). "Increased faecal serine protease activity in diarrhoeic IBS patients: a colonic lumenal factor impairing colonic permeability and sensitivity". Gut. 57 (5): 591–9. doi:10.1136/gut.2007.140210. PMID 18194983.
- ↑ 30.0 30.1 Dinan TG, Quigley EM, Ahmed SM, Scully P, O'Brien S, O'Mahony L, O'Mahony S, Shanahan F, Keeling PW (2006). "Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker?". Gastroenterology. 130 (2): 304–11. doi:10.1053/j.gastro.2005.11.033. PMID 16472586.
- ↑ 31.0 31.1 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.
- ↑ Walker MM, Talley NJ, Inganäs L, Engstrand L, Jones MP, Nyhlin H, Agréus L, Kjellstrom L, Öst Å, Andreasson A (2015). "Colonic spirochetosis is associated with colonic eosinophilia and irritable bowel syndrome in a general population in Sweden". Hum. Pathol. 46 (2): 277–83. doi:10.1016/j.humpath.2014.10.026. PMID 25540866.
- ↑ Kassinen A, Krogius-Kurikka L, Mäkivuokko H, Rinttilä T, Paulin L, Corander J, Malinen E, Apajalahti J, Palva A (2007). "The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects". Gastroenterology. 133 (1): 24–33. doi:10.1053/j.gastro.2007.04.005. PMID 17631127.
- ↑ Malinen E, Rinttilä T, Kajander K, Mättö J, Kassinen A, Krogius L, Saarela M, Korpela R, Palva A (2005). "Analysis of the fecal microbiota of irritable bowel syndrome patients and healthy controls with real-time PCR". Am. J. Gastroenterol. 100 (2): 373–82. doi:10.1111/j.1572-0241.2005.40312.x. PMID 15667495.
- ↑ Rajilić-Stojanović M, Biagi E, Heilig HG, Kajander K, Kekkonen RA, Tims S, de Vos WM (2011). "Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome". Gastroenterology. 141 (5): 1792–801. doi:10.1053/j.gastro.2011.07.043. PMID 21820992.
- ↑ 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 (2011). "Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome". Gastroenterology. 141 (5): 1782–91. doi:10.1053/j.gastro.2011.06.072. PMC 3417828. PMID 21741921.
- ↑ Jeffery IB, O'Toole PW, Öhman L, Claesson MJ, Deane J, Quigley EM, Simrén M (2012). "An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota". Gut. 61 (7): 997–1006. doi:10.1136/gutjnl-2011-301501. PMID 22180058.
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