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Chapter 4 76 Irritable bowel syndrome pathophysiology Several mechanisms have been hypothesized to play a role in the pathogenesis of IBS, including disturbances in microbiota, low-grade inflammation, immune activation, intestinal barrier dysfunction and altered bile salt absorption. Discussing these mechanisms separately is beyond the scope of this article. A thorough overview is provided in a recent review article. 5 We would like to emphasise that IBS is a heterogeneous disease. Even identical symptoms are likely caused by different processes. 5 Grouping IBS patients on the basis of stool pattern thus promotes heterogeneity, resulting in varying results with different cohorts. This aspect is also relevant when studying the role of TRP channels in visceral pain generation in IBS. Indeed, low-grade mucosal inflammation has been proposed as an important pathophysiological factor in IBS. 6 Researchers have since demonstrated a sensitizing effect of inflammatory mediators on various TRP channels, as will be discussed below. It is important to note that inflammation does not seem to be required to maintain visceral sensitization, as two recent clinical studies investigating the effects of mesalazine in IBS failed to demonstrate any benefits. 7,8 On the other hand, post-inflammatory sensitization can provide a theoretical explanation for IBS-like symptoms after gastro- enteritis, known as post-infectious IBS, and after achieving endoscopic and biochemical remission in inflammatory bowel disease (IBD). However, it would be inadequate to assume inflammation as the sole driving factor of visceral hypersensitivity. Shortcomings of our current knowledge on TRP channel sensitization should be recognized. Sensory innervation of the intestine Nociceptive signalling from the oesophagus to the proximal colon is conducted through the vagal nerve. Information from mid to distal colon and rectosigmoid is carried by the lumbar splanchnic and sacral pelvic nerves. The vagal nerve contains the peripheral terminals of pseudo-unipolar neurons with their cell bodies located in the nodose ganglia. Visceral sensory information from the vagal nerve supply is transduced into the solitary nuclei located in the medulla oblongata. The splanchnic and pelvic nerves contain axons of pseudo-unipolar neurons arising from a dorsal root ganglion (DRG). Peripheral sensory information from this supply is transduced into the dorsal horn of the spinal cord and ascends via the spinothalamic tract. 9 Peripheral nociceptive signalling is extensively modulated by the central nervous system, resulting in suppression or augmentation of the nociceptive input. These central processes determine whether nociceptive signalling (sensing and transmitting noxious stimuli) is perceived as pain (unpleasant experience). 10