Capsazepine-Induced Altered Colonic Mucosal Health Limits Isomalto-oligosaccharide Action in High-Fat Diet-Fed C57BL/6J Mice.

The present study sought to understand the effects of a combination of altered colonic mucosal health (intrarectal capsazepine administration) and high-fat diet (HFD) administration in mice. Furthermore, we also studied whether this combination prevents protective actions of dietary prebiotic, isomaltooligosaccharides. We studied the alterations in intestinal permeability, histological and transcriptional changes, short-chain fatty acid (SCFA) concentrations, and gut microbial abundance. Capsazepine (CPZ) was administered rectally twice a day along with HFD feeding. Following confirmation of CPZ action (loss of TRPA1 and TRPV1-associated nocifensive behavior), the intrarectal dose of CPZ was reduced to once in 2 days up to 8 weeks. Simultaneous intrarectal administration of CPZ exacerbated the HFD (8 weeks feeding)-induced damage to mucosal lining, intestinal permeability, tight junction protein expression, SCFA levels, and gut bacterial abundances. This higher degree of mucosal damage and pathological alteration in colonic mucosa prevented the previously reported protective actions of isomaltooligosaccharides as a prebiotic in HFD-fed mice. Overall, we present evidence that colonic precondition (gut permeability and mucosal lining) is an important factor in determination of HFD-induced changes in the colon, and success of diet-associated interventions (dietary fibers, pre/probiotics, etc.) is dependent on it.