Excitation of colonic afferent nerves by fecal supernatants from gastrointestinal disease patients
Abu Omar, Amal
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Increased excitability of extrinsic afferent nerves has emerged as an important mechanism of visceral pain during inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). While host-derived mediators have been the main focus of studies investigating this increased excitability, little is understood regarding the role of intestinal microbiota in pain development in IBD and IBS. Therefore, to examine the role of the microbiota in pain in these disorders, this thesis aimed to determine the effects of fecal supernatants (FS) from patients with active IBD (5 Crohn’s disease (CD) and 7 ulcerative colitis (UC)) patients and 6 healthy volunteers (HV) on colonic afferent nerves. Additionally, the effects of FS from 5 IBS patients were characterized before and after a low fermentable carbohydrate diet (LFD) that has been shown to improve the symptoms of IBS patients. The effects of FS were assessed using ex-vivo extracellular recordings of colonic afferent nerves of the distal colon of control mice. FS from HV decreased the basal firing frequency and the mechanosensitivity of afferent nerves compared to vehicle controls (P< 0.001, and P<0.01 respectively). Conversely, FS from IBD patients increased the basal firing frequency of afferent nerves compared to vehicle controls (P<0.0001 in both CD and UC FS samples). Furthermore, FS from CD augmented the mechanosensitivity of the afferent units compared to vehicle controls (P<0.05), with a significant effect on high threshold (HT) afferent units (P<0.001). These effects were inhibited when I blocked the activity of bacterial proteases. In contrast to CD FS, UC FS reduced the mechanosensitivity of colonic afferent nerves (P<0.05). IBS FS also increased the basal firing frequency of afferent nerves (P<0.001) and increased the mechanosensitivity of the HT afferents (P<0.05) compared to vehicle controls. These effects were induced by both histamine and proteases. Excitingly, FS from the same IBS patients who followed a LFD decreased the basal firing frequency (P<0.01) and blocked the excitatory effect of IBS FS on mechanosensitivity of HT afferent units. Together, these results suggest that FS from IBD and IBS patients contain microbial mediators that could exacerbate pain by activating colonic afferent nerves and increasing afferent input to the CNS. Additionally, a LFD may reduce pain in IBS by modulating the production of these microbial mediators.