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General introduction 15 1 controls. In addition, this study demonstrated that supernatants of rectal biopsies of IBS patients, but not healthy controls, sensitized TRPA1 and TRPV4 in murine sensory neurons. 53 Whereas several TRP channels exhibit pro-nociceptive properties, there are indications that TRPM8 has anti-nociceptive effects. TRPM8 can be activated by several factors including low temperatures and cooling compounds, e.g. menthol, the main constituent of peppermint oil . TRPM8 has been suggested to exhibit antinociceptive properties by impeding the mechano- and sensory effects of TRPA1 and TRPV1 by cross- desensitization. 54 Moreover, results from an animal colitis model suggest that TRPM8 activation by agonist icilin can reduce cytokine and chemokine levels and as such, also has an anti-inflammatory effect. 55 Taken together, these results implicate that TRPM8 may be able to counteract abdominal pain and thereby may have therapeutic applications. However, more data on this topic, in particular from in vivo studies, is warranted to comprehend the exact role of TRP channels and their interaction in visceral nociceptive processing and immune function. Intestinal dysbiosis is another factor that can contribute to sensitization of nerves and is associated with IBS, at least in subgroups of patients. A microbiota signature that has been confirmed by several comprehensive studies is the increased Firmicutes/Bacteroidetes ratio 56 , a relative depletion of Bifidobacteria and a general lower diversity of the microbiota. 57 It should however be noted that these findings could not be confirmed in all studies. In addition, changes in microbial metabolic activity 58 and a microbial signature associated with symptoms severity 59 have been found. The microbiome perturbations can impact the intestinal epithelium and its underlying immune system. Growing evidence moreover supports bidirectional interactions between the gut microbiome and the brain. 60-63 Data in support of this brain-gut- microbiome axis originate mainly from animal studies. For example, colonization of germfree mice with the bowel contents of IBS patients did result in immune activation, increased intestinal permeability, and anxious behavior that was not related to GI symptoms. 63,64 In recent years, evidence is also emerging from human data, such as brain-imaging studies, which found changes in brain activation patterns following administration of a probiotic. 65,66 Another process that was found to be altered in a subset of IBS patients is central pain modulation. Intestinal nociceptive signals are transduced to the central nervous system where they are modulated extensively. This central pain modulation is a balance between inhibition and facilitation of the painful stimulus and a key determinant of