Akkermansia muciniphilaidentified as key strain to function in pathogen invasion and intestinal stem cell proliferation through Wnt signaling pathway

Abstract

ABSTRACTAs the largest mucosal surface, the gut has built a physical, chemical, microbial and immune barrier to protect the body against pathogen invasion. The disturbance of gut microbiota aggravates pathogenic bacteria invasion and gut barrier injury. Fecal microbiota transplantation (FMT) is a promising treatment for microbiome-related disorders, where probiotic strain engraftment is a significant factor influencing FMT outcomes. The aim of this research was to explore the effect of FMT on antibiotic-induced microbiome-disordered (AIMD) model infected with enterotoxigenicEscherichia coli(ETEC). We used piglet, mouse and intestinal organoid models to explore the protective effects and mechanisms of FMT on ETEC infection. The results showed that FMT regulated gut microbiota and enhanced the protection of AIMD piglets against ETEC K88 challenge, as demonstrated by reduced intestinal pathogen colonization and alleviated gut barrier injury.Akkermansia muciniphila(A. muciniphila) andBacteroides fragilis(B. fragilis) were identified as two strains that may play key roles in FMT. We further investigated the alleviatory effects of these two strains on ETEC infection in AIMD mice model, which revealed thatA. muciniphilaandB. fragilisrelieved ETEC-induced intestinal inflammation by maintaining the proportion of Treg/Th17 cells and epithelial damage by moderately activating the Wnt/β-catenin signaling pathway, while the effect ofA. muciniphilawas better thanB. fragilis. We therefore identified whetherA. muciniphilaprotected against ETEC infection using basal-out and apical-out intestinal organoid models.A. muciniphiladid protect the Lgr5+intestinal stem cells and stimulate proliferation and differentiation of intestinal epithelium, and the protective effects ofA. muciniphilawas reversed by Wnt inhibitor. FMT alleviated ETEC-induced gut barrier injury and intestinal inflammation in AIMD model.A. muciniphila was identified as key strain in FMT to promote proliferation and differentiation of intestinal stem cells by mediating the Wnt/β-catenin signaling pathway.