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

IBS is caused by the 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 and mucosal inflammation, altered gut microbiota and abnormal serotonin pathways. Visceral hypersensitivity is 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/permanent changes in complex neural circuits lead to central pain amplification and contribute 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, which may lead to alterations in the subjective sensations of pain. Genetic factors also play a role in IBS. It has high twin concordance and familial aggregation. It 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.

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
 
 
 
  • Environmental 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][9]
    •  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. [10][11][12][13][14][15][16][17][18]
  • 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.[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
    • Activation of specific gastrointestinal mediators 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.[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]


 
 
 
 
 
 
 
 
 
 
 
 
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