Enteric VIP-producing neurons maintain gut microbiota homeostasis through regulating epithelium fucosylation

Interactions between the enteric nervous system (ENS) and intestinal epithelium are thought to play a vital role in intestinal homeostasis. How the ENS monitors the frontier with commensal and pathogenic microbes while maintaining epithelial function remains unclear. Here, by combining subdiaphragmatic vagotomy with transcriptomics, chemogenetic strategy, and coculture of enteric neuron-intestinal organoid, we show that enteric neurons expressing VIP shape the α1,2-fucosylation of intestinal epithelial cells (IECs). Mechanistically, neuropeptide VIP activates fut2 expression via the Erk1/2-c-Fos pathway through the VIPR1 receptor on IECs. We further demonstrate that perturbation of enteric neurons leads to gut dysbiosis through α1,2-fucosylation in the steady state and results in increased susceptibility to alcohol-associated liver disease (ALD). This was attributed to an imbalance between beneficial Bifidobacterium and opportunistic pathogenic Enterococcus faecalis in ALD. In addition, Bifidobacterium α1,2-fucosidase may promote Bifidobacterium adhesion to the mucosal surface, which restricts Enterococcus faecalis overgrowth and prevents ALD progression. [Display omitted] •Enteric neuron-derived VIP shapes IECs fucosylation and gut microbiota composition•VIP activates fut2 expression in IECs via the Erk1/2-c-Fos pathway•α1,2-fucosidase enhances Bifidobacterial adhesion to fucosyl-conjugated mucus•Bifidobacteria restrict cytolytic E. faecalis growth and prevent ALD progression Lei et al. show that enteric neurons expressing VIP direct a program of gut mucosal fucosylation via the Erk1/2-c-Fos pathway. The reduced abundance of enteric VIPergic neurons leads to the imbalance of abundance between beneficial Bifidobacterium and pathogenic E. faecalis and enhances the susceptibility of ALD.