Irritable bowel syndrome pathophysiology: Difference between revisions

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==Genetics==
==Genetics==
*[Disease name] is transmitted in [mode of genetic transmission] pattern.
*IBS is a complex disease with interactions between genetic and environmental factors. The role of genetic predisposition in IBS is suggested by epidemiological studies of twins and familial aggregation.
*Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
*Investigations show higher concordance of IBS in monozygotic as compared to dizygotic twins, hence proving the role of genetic factors in IBS.
*The development of [disease name] is the result of multiple genetic mutations.
*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.
*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.  
*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. Moreover, changed patterns of interleukin production may be associated with IBS.
*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.
*Studies have been conducted to establish associations between neuropeptide S receptor gene (NPSR1) involved in nociception, inflammation and anxiety with abdominal pain. TNF polymorphisms are also associated with post infectious IBS such as rs4263839 in TNFSF15 and IBS, particularly IBS-C.  
*Genes involved in the regulation of hepatic bile acid synthesis such as a functional Klothoβ gene variant also haven proven association with the disease.
*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.  .
==Associated Conditions==
==Associated Conditions==



Revision as of 18:11, 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].

OR

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].
  • Immune activation and mucosal inflammation
    • The high prevalence of IBS in patients with history of inflammatory bowel disease, celiac disease or microscopic colitis points towards the fact that immune activation and mucosal inflammation play an important role in the pathogenesis of IBS.[26][27][28][29][30][31][28]
    • Moreover, psychological stress can significantly impact the release of proinflammatory cytokines, thereby affecting intestinal permeability and reinforcing a functional link existing between immune activation, psychological symptoms and symptoms in patients with IBS.[26]
    • Patients are found to have higher mucosal counts of lymphocytes (T cells, B cells), mast cells and immune mediators such as prostanoids, proteases, cytokines and histamines. [28][32][33][34][35]
    • Lymphocytes:
      •  Patients with IBS have increased B lymphocyte activation in the blood.[36] However, activation of humoral immunity in IBS is specific for the gastrointestinal tract[37] as increased numbers of lymphocytes have been found in the small intestine and colon of patients.[27][29]
      • In addition to this, IBS patients with diarrhea[37] have enhanced mucosal humoral activity, associated with activation and proliferation of B cells and immunoglobulin production, identified by microarray profiling.
      • IBS patients with severe disease have an increase in lymphocyte infiltration in the myentric plexus,[29] in studies where full-thickness jejunal biopsies were obtained.
      • Mediators released by lymphocytes include histamine, proteases and nitric oxide. The stimulation of the enteric nervous system by these mediators leads to abnormal visceral and motor responses within the gastrointestinal tract.[27]
      • Examination of stool in patients with diarrhea prominent IBS have high levels of serine protease activity.[38][39]When fecal extracts are intra colonically infused into mice, there is increased visceral pain and colonic cellular permeability. [38]
      • 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.[39][38]
    • Mast cells:
      •  Studies have shown an increased number of mast cells in IBS patients in the jejunum, terminal ileum and colon.[31]
      • Higher numbers of activated mast cells are found in proximity to colonic nerve fibres in the mucosa of the gastrointestinal tract of IBS patients. [31][30]
    • Proinflammatory cytokines:
      • Cytokines are proteinaceous mediators of the immune response.  Increased levels of cytokines have been found in IBS patients.[35][34]
      • Higher amounts of of tumor necrosis factor are produced by the peripheral blood mononuclear cells of IBS patients.[40][28]
      • In studies conducted using supernatants from cultured peripheral blood mononuclear cells in IBS patients,the TNF antagonist infliximab has been found to block the mechanical hypersensitivity of the mouse colonic afferent nerve endings. [41]
      • 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.[28][41][40]
    • Altered gut microbiota
      •  It is postulated that altered fecal microflora may be associated with IBS.[42][32] There are numerous studies that suggest that altered fecal microflora in IBS patients differ from healthy controls. [43][44][45][46][47]
      • Inoculation of germ free animals with fecal microbiota from IBS patients has demonstrated increased colonic hypersensitivity, as compared to samples inoculated from healthy controls. [48]
      • 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. [49]
      • 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.[50]
      • 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.[51][52]  Administration of probiotics in patients decreases flatulence relative to Lactobacillus.[53] A probiotic yogurt containing a mixture of Bacteroides species has been shown to improve symptoms in IBS patients.[54]
      • 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.[55][56]
    • Abnormal serotonin pathways
      • Serotonin(5-HT) is an important neurotransmitter produced by the enterochromaffin cells in the colon,[57][58][59] 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.[60][61][62][63]
      • 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.[64]
      • 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.[65][66]

Genetics

  • IBS is a complex disease with interactions between genetic and environmental factors. The role of genetic predisposition in IBS is suggested by epidemiological studies of twins and familial aggregation.
  • Investigations show higher concordance of IBS in monozygotic as compared to dizygotic twins, hence proving the role of genetic factors in IBS.
  • 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.
  • 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.
  • 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. Moreover, changed patterns of interleukin production may be associated with IBS.
  • 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.
  • Studies have been conducted to establish associations between neuropeptide S receptor gene (NPSR1) involved in nociception, inflammation and anxiety with abdominal pain. TNF polymorphisms are also associated with post infectious IBS such as rs4263839 in TNFSF15 and IBS, particularly IBS-C.
  • Genes involved in the regulation of hepatic bile acid synthesis such as a functional Klothoβ gene variant also haven proven association with the disease.
  • 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. .

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

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