Irritable Bowel Syndrome is caused by a complex interaction of various factors such as intrinsic gastrointestinal factors, CNS dysregulation and psychosocial factors, genetic, and environmental factors. Intrinsic gastrointestinal factors include motor abnormalities, visceral hypersensitivity, immune activation, mucosal inflammation, altered gut microbiota, and abnormal serotonin pathways. Visceral hypersensitivity refers to a decreased threshold for the perception of visceral stimuli that affects spinal excitability, brain stem and cortical modulation, activation of specific gastrointestinal mediators, and recruitment of peripheral silent nociceptors. Immune activation and mucosal inflammation involves an interaction of lymphocytes, mast cells, and proinflammatory cytokines. Environmental factors encompass dietary changes and infections. Psychosocial factors such as stress, anxiety, and depression directly shape adult connectivity in the executive control network consisting of structures such as the insula, anterior cingulate cortex, and the thalamus. Semipermanent or permanent changes in complex neural circuits lead to central pain amplification contributing to abdominal pain in IBS patients. The dorsolateral prefrontal cortex activity (responsible for vigilance and alertness of the human brain) and the mid-cingulate cortex (engaged in attention pathways and responses) is reduced in IBS patients. This reduction may lead to alterations in the subjective sensations of pain. Genetic factors also play a role in IBS. IBS has a high twin concordance and familial aggregation. IBS is associated with single nucleotide polymorphisms (SNPs) in genes involved in immune activation, neuropeptide hormone function, oxidative stress, nociception, permeability of the GI tract, host-microbiota interaction, inflammation, and TNF activity.

IBS occurs as a result of an interplay between four main factors:

• Diet
  • Fermentable oligosaccharides, monosaccharides, disaccharides, and polyols (FODMAPs) are present in stone fruits, artificial sweeteners, lactose-containing foods, and legumes. Changes in diet such as increased amounts (FODMAPs) can alter gut microflora.^[1]
    • Fermentation and osmotic effects of FODMAPs produce abdominal discomfort and diarrhea in IBS.
    • FODMAPs yield carbon dioxide, methane, and hydrogen that are responsible for bloating.
  • Osmotically active carbohydrate by products lead to diarrhea by enhancing intestinal contractions and precipitating fluid secretion.^{[2][3][4][5][6][7][8]}
•  Infection
  • Infectious gastroenteritis triggers micro inflammation and up to one third of irritable bowel syndrome cases follow acute gastroenteritis.
  • Micro inflammation of the gut causes activation of the lymphocytes, mast cells and pro inflammatory cytokines that stimulate the enteric nervous system and lead to abnormal visceral and motor responses within the gastrointestinal tract.
  • Immune activation due to GI infection also increases enteroendocrine cells, calprotectin-positive macrophages, intraepithelial lymphocytes, and lamina propria T cells which contribute directly to abdominal pain perception. ^{[9][10][11][12][13][14][15][16][17]}
  • The role of small intestinal bacterial overgrowth syndrome is strongest when testing with glucose breath tests (relative risk = 4.2) or jejunal aspirates (relative risk = 3.0) are compared among patients with IBS and controls^[18].

• 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 altered colonic and small intestinal motor function, such as increased frequency and irregularity of luminal contractions.
  • Motor changes lead to symptoms of diarrhea and constipation.^[19][20][21]
    • 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. ^{[22][23][24][25][26]}
    • 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.^[25]
  • Visceral hypersensitivity:
    • IBS is associated with a decreased threshold for perception of visceral stimuli (i.e. visceral hypersensitivity)^[25][27][28]
    • 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^{[29][30][31][32]}.
    • Visceral hypersensitivity contributes to IBS by involving the following:
      • Spinal hyperexcitability
        • Secondary to activation of neurotransmitters such as:
        • N-methyl D aspartate (NMDA) receptor
        • Nitric oxide
      • Activation of specific gastrointestinal mediators that lead to afferent nerve fiber sensitization:
        • Kinins
        • Serotonin
      • 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.^[27][33]
      • Recruitment of peripheral silent nociceptors cause increased end organ sensitivity due to
        • Hormonal activation ( increased serotonin affects gastrointestinal motility and visceral pain perception)
        • Immune activation(recruitment of inflammatory mediators)^[27]

• 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.^{[34][35][36][37][38][39][36]}
  • IBS patients have higher mucosal counts of lymphocytes (T cells, B cells), mast cells and immune mediators such as prostanoids, proteases, cytokines and histamines.^{[36][40][41][42][43]}
    • 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.^{[35][37][44][45]}
      • IBS patients with diarrhea have enhanced mucosal humoral activity, associated with activation and proliferation of B cells and immunoglobulin production, identified by microarray profiling.^[45]
      • IBS patients with severe disease have an increase in lymphocyte infiltration in the myentric plexus.^[37]
      • 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.^[35]
      • Stool in patients with diarrhea prominent IBS demonstrates high levels of serine protease activity, which is produced by lymphocytes.^[46][47]
      • In response to high levels of serine protease, there is increased visceral pain and colonic cellular permeability. ^[46]
      • Serine protease inhibitors prevent effects mediated by high levels of serine protease in IBS patients.^[47][46]
    • Mast cells:
      •  IBS leads to an increased number of mast cells in IBS patients in the jejunum, terminal ileum and colon.^[39]
      • Higher numbers of activated mast cells are found in proximity to colonic nerve fibres in the mucosa of the gastrointestinal tract of IBS patients. ^[39][38]
    • Proinflammatory cytokines:
      • Cytokines are protein mediators of the immune response. Increased levels of cytokines have been found in IBS patients.^[42][43]
      • Higher amounts of tumor necrosis factor are produced by the peripheral blood mononuclear cells of IBS patients.^[36][48]
      • Other cytokines such as interleukin 1β, interleukin 6, interleukin10, and TNFα are raised in IBS patients.
      • Increased concentration of cytokines is directly proportional to the severity and frequency of pain.^[36][48][49]
      • The TNF antagonist infliximab counteracts pain in IBS patients, proving TNF involvement in mechanical hypersensitivity of the colonic afferent nerve endings.^[49]
  • 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.^{[40][50][51][52][53][54][13][55]}
    • 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. ^[56][57][58]
    • Altered gut microbiota causes increased colonic hypersensitivity. ^[59]
  • 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.^{[60][61][62][63][64][65][66]}
    • Serotonin affects gastrointestinal motility and visceral pain perception. Spontaneous release of 5-HT correlates with abdominal pain severity.^[67]
    • 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.^{[68][69][70][71]}
    • 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.^[72][73]

  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.^[74][75]
  • 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. ^[76]
  • 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.^[77][78]
  • 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.^[79][80]
  • 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.^[77][81][82]
  • Psychological stress also impacts the release of gut proinflammatory cytokines, contributing to pain in IBS patients.^[34]

  Genetic factors

  • IBS has high twin concordance and familial aggregation:^{[83][84][85][86][87][88]}
    • IBS has higher concordance in monozygotic as compared to dizygotic twins.^{[83][84][85][89]}
    • Individuals with a biologic relative with IBS have two times a higher risk of developing IBS. ^[90]
  • 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.^[91][92]
    • Mutation of type V (alpha subunit) of SCN5A-encoded voltage gated sodium channel causes IBS.^[93][94]
    • Genome wide DNA methylation profiling is impaired in IBS and this involves genes linked to neuropeptide hormone function and oxidative stress.^[95]
    • IBS causes mutation in the neuropeptide S receptor gene (NPSR1) involved in nociception, inflammation and anxiety with abdominal pain.^[96]
    • Genes involved in the regulation of hepatic bile acid synthesis such as a functional Klothoβ gene are mutated in IBS.^[97][98]
  • TNF polymorphisms:
    • SNPs in tumour necrosis factor alpha (TNFα) and genes coding for superfamily member 15 (TNFSF15) have proven associations with IBS.^{[92][99][100]}
    • TNF polymorphisms are also associated with post infectious IBS such as rs4263839 in TNFSF15 and IBS, particularly IBS associated with constipation.^[99][100]

  Associated conditions

  Several medical comorbidities appear with greater frequency in IBS patients.

  Headache, Fibromyalgia, and Depression

  IBS patients may be identified with comorbidities such as headache, fibromyalgia and depression.^{[101][102][103]}

  Inflammatory Bowel Disease

  • IBS and IBD are interrelated diseases, as patients with IBD experience IBS-like symptoms when their IBD is in remission.^{[104][105][106]}
  • IBS is believed to be a type of low-grade inflammatory bowel disease as serum markers associated with inflammation have also been found in patients with IBS.^[107]
  • IBS patients are16.3 times more likely to develop IBD.^[108]

  Abdominal Surgery

  • IBS patients are 87% more likely to undergo abdominal and pelvic surgery, and three times more likely to undergo gallbladder surgery.^[109]
  • IBS patients were twice as likely to undergo hysterectomy.^[110]

  Endometriosis

  There is a statistically significant link between migraine headaches, IBS, and endometriosis.^[111]

  Medical conditions that accompany IBS

  Several medical comorbidities appear with greater frequency in IBS patients.

  Headache, Fibromyalgia, and Depression

  IBS patients may be identified with comorbidities such as headache, fibromyalgia and depression.^{[102][103][112]}

  Inflammatory Bowel Disease

  • IBS and IBD are interrelated diseases, as patients with IBD experience IBS-like symptoms when their IBD is in remission.^{[104][105][106]}
  • IBS is believed to be a type of low-grade inflammatory bowel disease as serum markers associated with inflammation have also been found in patients with IBS .^[107]
  • IBS patients are16.3 times more likely to develop IBD.^[108]

  Abdominal Surgery

  • IBS patients are 87% more likely to undergo abdominal and pelvic surgery, and three times more likely to undergo gallbladder surgery.^[109]
  • IBS patients were twice as likely to undergo hysterectomy.^[110]

  Endometriosis

  There is a statistically significant link between migraine headaches, IBS, and endometriosis.^[111]

  Gross Pathology

  • On gross pathology, the GI tract appears normal in IBS.

  Microscopic Pathology

  Microscopic changes that may be found in IBS patients are as follows:^{[37][39][60][113][16][114][115][116][117][118][119][120]}

  LOCATION	LAYER OF INTESTINE INVOLVED	MAST CELLS	T LYMPHOCYTES	ENTEROCHROMAFFIN CELLS
  Rectum	Mucosa	+++/-	+/-	+/-
  Terminal ileum	Mucosa	–	++	–
  Cecum	Mucosa	++	–	–
  Colon	Muscularis externa	+/-	–	–
  Jejunum	Myentric plexus	++	–	–

  References

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