Microbiota dysbiosis and mucosal hyperinnervation contribute to intestinal hyperalgesia in a mouse model of postinfectious irritable bowel syndrome.

Abstract

Postinfectious irritable bowel syndrome (PI-IBS) is defined by persistent gastrointestinal symptoms that follow recovery from an episode of infectious enteritis, which worsen after experiencing psychological stress. Mucosal neurite outgrowth stimulated by neurotrophins and serotonin/5-hydroxytryptamine receptor subtype 7 (5-HT₇) activation is linked to visceral hypersensitivity. Rifaximin (RFX) is a poorly absorbed antibiotic that improves IBS symptoms; however, the exact mechanisms remain unclear. The aims are to evaluate changes in microbiota and neuroplasticity in PI-IBS mice after RFX treatment and the analgesic effects of combined treatment with a novel 5-HT₇ antagonist, CYY1005 (CYY). A mouse model with dual triggers of Giardia postinfection and water avoidance stress exhibited intestinal hyperalgesia, as measured by visceromotor responses (VMRs). Higher Shannon diversity and increased relative abundances of Lachnospiraceae, Dehalobacteriaceae, and Ruminococcus gnavus were observed in the microbiota of PI-IBS mice, which were restored to baseline after RFX treatment. Reduced VMRs were associated with attenuated mucosal neurite outgrowth and brain-derived neurotrophic factor (BDNF) expression after RFX treatment. BDNF/high affinity tropomyosin receptor kinase B activation induced mTOR-dependent nerve fiber elongation and upregulated tryptophan hydroxylase 2 and 5-HT₇ expression via Rac1/ROCK pathway in SH-SY5Y neuron cultures. Combined treatment with RFX and CYY reduced VMRs to levels comparable with those of the control groups. Finally, bacteria-free colonic mouse supernatants induced neurite elongation in SH-SY5Y cells, which was inhibited by neutralizing anti-BDNF antibodies. In conclusion, microbiota restoration by RFX treatment attenuated BDNF-induced neurite outgrowth and alleviated visceral hypersensitivity in mice. Analgesic combinations of RFX and a 5-HT₇ receptor antagonist reduced intestinal nociception to baseline levels.NEW & NOTEWORTHY A mouse model of postinfectious IBS was developed using dual triggers of Giardia postinfection and water avoidance stress to mimic diverse risk factors. Rifaximin treatment reduced intestinal hyperalgesia and was associated with decreased mucosal neurite outgrowth and brain-derived neurotrophic factor (BDNF) expression. BDNF activation induced nerve fiber elongation and upregulated 5-HT₇ expression via separate signaling pathways. Analgesic combinations of RFX and a 5-HT₇ receptor antagonist reduced intestinal nociception to baseline.