Irritable bowel syndrome pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
The exact pathogenesis of [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].
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The progression to [disease name] usually involves the [molecular pathway].
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The pathophysiology of [disease/malignancy] depends on the histological subtype.
Pathophysiology
Pathogenesis
- The exact pathogenesis of Irritable Bowel Syndrome (IBS) is uncertain.
- It is thought that IBS is caused by the interaction of various factors:
- Gastrointestinal motor abnormalities- IBS is referred to as ‘spastic colon’ due to changes in colonic motor function. Manometry recordings in studies from the transverse, descending and sigmoid colon showed that spastic colon led to changed patterns of colonic and small intestinal motor function such as increased frequency and irregularity of luminal contractions[1][2][3]. Peak amplitude of high-amplitude propagating contractions (HAPCs)[4] in diarrhea-prone IBS patients[5] were found to be higher, compared to healthy subjects. This led to increased responses to ingestion, CRH(Corticotropin releasing hormone)[6][7], CCK(cholecystokinin)[8] and were associated with abdominal discomfort and accelerated transit through the colon. On the other hand, constipation prone IBS patients[5] showed fewer HAPCs, delayed transit through the colon and decreased motility. One study showed that >90% of HAPCs[8] were associated with abdominal pain.
- CNS dysregulation- The conceptualization of IBS being a brain gut disorder is reinforced by the following-
1) Epidemiological studies that suggest that IBS occurs in individuals who have experienced childhood trauma with symptom exacerbation occurring in patients with emotional disturbances or stress[9]. Traumatic experiences before the age of 18 can directly shape adult connectivity in the executive control network. The effects on structures such as the insula, anterior cingulate cortex and the thalamus have been implicated in the pathophysiology of central pain amplification.[10] IBS has been found to have a high association with pre-existing psychiatric and psychological conditions like anxiety and depression[11]. However, studies have shown that even when patients are not anxious or depressed, the dorsolateral prefrontal cortex activity was reduced, suggesting CNS dysfunction and increased susceptibility to stressors[12].
2) Psychological therapies that act on cerebral cortical sites and antidepressants have proven to be one of the mainstays of therapy for patients. For example, the fact that probiotics can modify signal processing in the brain also supports this theory[13].
3) Studies using advanced brain imaging techniques have analyzed differences in brain activity between patients and healthy controls and have helped us appreciate that the mid-cingulate cortex- responsible for attention processes and responses and the prefrontal cortex-responsible for vigilance and alertness of the human brain could be involved in IBS. Modulation of the mid-cingulate cortex is associated with alterations in the subjective sensations of pain whereas prefrontal cortex modulation may lead to increased perception of visceral pain[10]. Patients with IBS have been found to have aberrant processing of central information[14], with decreased feedback on the emotional arousal network that controls the autonomic modulation of gastrointestinal function[15]. These have been seen as irregularities on diffusion tensor imaging[16] in the white matter of the brain. Rectal balloon distension in patients has shown the increased involvement of regions of the brain associated with attentional and behavioral responses to the arrival of such stimuli[17][18][12].
- Visceral hypersensitivity- Visceral hypersensitivity is an important factor in the pathogenesis of pain perception in IBS patients. IBS is associated with a decreased threshold for perception of visceral stimuli (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. Many factors contribute to visceral hyperalgesia(i.e increased sensitivity of the intestines to normal sensations)- 1. Spinal hyperexcitability due to activation of an N-methyl D aspartate(NMDA) receptor, Nitric oxide and possibly other neurotransmitters. 2. Activation of specific gastrointestinal mediators like kinins and serotonin that lead to afferent nerve fibre sensitisation 3. Central (brainstem and cortical) modulation with increased activation of anterior circulate cortex, thalamus and insula, involved in processing of pain, translating into long term hypersensitivity due to neuroplasticity, causing semipermanent changes in the neural response to all kinds of visceral stimulation. These findings have been proven by brain imaging studies. (e.g. functional magnetic resonance imaging, positron emission tomography) 4. Recruitment of peripheral silent nociceptors causing increased end organ sensitivity due to hormonal or immune activation.
- Immune activation and mucosal inflammation
- Altered gut microbiota
- Gastrointestinal infections- leads to post inflammatory neuroplastic changes and visceral hypersensitivity
- Abnormal serotonin pathways
- Neuroimmune factors
- Genetic factors- Mutations in SCN5A encode alpha subunit of voltage gated sodium channel NaV1.5
- Bile acid malabsorption- causes alteration of the function of an apical ileal bile acid transporter
Genetics
Genetics
- [Disease name] is transmitted in [mode of genetic transmission] pattern.
- Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
- The development of [disease name] is the result of multiple genetic mutations.
Associated Conditions
Gross Pathology
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
- On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
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.
- ↑ Kellow JE, Phillips SF (1987). "Altered small bowel motility in irritable bowel syndrome is correlated with symptoms". Gastroenterology. 92 (6): 1885–93. PMID 3569764.
- ↑ 5.0 5.1 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 10.0 10.1 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.
- ↑ Mearin F, Lacy BE, Chang L, Chey WD, Lembo AJ, Simren M, Spiller R (2016). "Bowel Disorders". Gastroenterology. doi:10.1053/j.gastro.2016.02.031. PMID 27144627.
- ↑ 12.0 12.1 Larsson MB, Tillisch K, Craig AD, Engström M, Labus J, Naliboff B, Lundberg P, Ström M, Mayer EA, Walter SA (2012). "Brain responses to visceral stimuli reflect visceral sensitivity thresholds in patients with irritable bowel syndrome". Gastroenterology. 142 (3): 463–472.e3. doi:10.1053/j.gastro.2011.11.022. PMC 3288538. PMID 22108191.
- ↑ Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat B, Guyonnet D, Legrain-Raspaud S, Trotin B, Naliboff B, Mayer EA (2013). "Consumption of fermented milk product with probiotic modulates brain activity". Gastroenterology. 144 (7): 1394–401, 1401.e1–4. doi:10.1053/j.gastro.2013.02.043. PMC 3839572. PMID 23474283.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Elsenbruch S, Rosenberger C, Enck P, Forsting M, Schedlowski M, Gizewski ER (2010). "Affective disturbances modulate the neural processing of visceral pain stimuli in irritable bowel syndrome: an fMRI study". Gut. 59 (4): 489–95. doi:10.1136/gut.2008.175000. PMID 19651629.