Microbial Metabolite Trimethylamine N-Oxide PromotesCampylobacter jejuniInfection by Escalating Intestinal Inflammation, Epithelial Damage, and Barrier Disruption

Abstract

ABSTRACTThe interactions betweenCampylobacter jejuni, a critical foodborne cause of gastroenteritis, and the intestinal microbiota during infection are not completely understood. The crosstalk betweenC. jejuniand its host is impacted by the gut microbiota through mechanisms of competitive exclusion, microbial metabolites, or immune response. To investigate the role of gut microbiota onC. jejunipathogenesis, we examined campylobacteriosis in the IL10KO mouse model, which was characterized by an increase in the relative abundance of intestinal proteobacteria,E. coli, and inflammatory cytokines duringC. jejuniinfection. We also found a significantly increased abundance of microbial metabolite Trimethylamine N-Oxide (TMAO) in the colonic lumens of IL10KO mice. We further investigated the effects of TMAO onC. jejunipathogenesis. We determined thatC. jejunisenses TMAO as a chemoattractant and the administration of TMAO promotesC. jejuniinvasion into Caco-2 monolayers. TMAO also increased the transmigration ofC. jejuniacross polarized monolayers of Caco-2 cells, decreased TEER, and increasedC. jejuni-mediated intestinal barrier damage. Interestingly, TMAO treatment and presence duringC. jejuniinfection of Caco-2 cells synergistically caused an increased inflammatory cytokine expression, specifically IL-1β and IL-8. These results establish thatC. jejuniutilizes microbial metabolite TMAO for increased virulence during infection.