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Summary: The vagus nerve is proposed to enable communication between the gut microbiome and the brain, but activity-based evidence is lacking. We find that mice reared germ-free exhibit decreased vagal tone relative to colonized controls, which is reversed via microbiota restoration. Perfusing antibiotics into the small intestines of conventional mice, but not germ-free mice, acutely decreases vagal activity which is restored upon re-perfusion with intestinal filtrates from conventional, but not germ-free, mice. Microbiome-dependent short-chain fatty acids, bile acids, and 3-indoxyl sulfate indirectly stimulate vagal activity in a receptor-dependent manner. Serial perfusion of each metabolite class activates both shared and distinct neuronal subsets with varied response kinetics. Metabolite-induced and receptor-dependent increases in vagal activity correspond with the activation of brainstem neurons. Results from this study reveal that the gut microbiome regulates select metabolites in the intestinal lumen that differentially activate vagal afferent neurons, thereby enabling the microbial modulation of chemosensory signals for gut-brain communication.

Background and Aims: The Cancer Genome Atlas (TCGA) project has identified HER2 mutations or amplification in 7% of colon cancers. In addition to HER2 mutations, colon cancer patients also possess co-occurring mutations in genes such as APC. Here, we investigated the role of HER2 and APC mutations on the crypt-villus architecture of the intestinal epithelium, localization of secretory cells, and expression of intestinal stem cell markers. Methods: We generated a HER2 transgenic mouse (HER2V777L Tg) possessing an activating mutation commonly found in colorectal cancer patients, HER2V777L, using transcription activator-like effector nucleases–based gene editing technology. We expressed the HER2V777L transgene in mouse small intestine and colon using Lgr5-Cre and Villin-Cre recombinases. In addition, we analyzed Lgr5-Cre; APCmin; HER2V777L Tg mice by morphologic and gene expression assays on intestinal sections and organoids derived from the epithelium. Results: HER2V777L expression resulted in hypertrophic crypt formation with expanded zones of proliferation. Proximal intestinal villi showed increased abundance of multiple differentiated lineages including extensive intermediate cell differentiation, as evidenced by MUC2/MMP7 co-immunofluorescence and transmission electron microscopy. HER2V777L expression in the context of APC loss resulted in further enhancement and expansion of the proliferative crypt compartment. Conclusions: We established an epithelial intrinsic role for HER2V777L on enhanced cellular proliferation. Additionally, we determined that HER2 and APC mutations, when combined, promote enhanced proliferation of intestinal crypts.