4.7 Article

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

期刊

CELL HOST & MICROBE
卷 30, 期 10, 页码 1417-+

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CELL PRESS
DOI: 10.1016/j.chom.2022.09.001

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资金

  1. NIH [R01HL160927, R21AA025724, R21AI128206, R21AI159194, R01DK115406, R01DK131442, P50 AA024337, P20 GM113226, R01AA023190]

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Interactions between the enteric nervous system and intestinal epithelium are crucial for intestinal homeostasis, particularly in monitoring the contact between commensal and pathogenic microbes. This study reveals that enteric neurons regulate the fucosylation of intestinal epithelial cells through the neuropeptide VIP. Perturbation of enteric neurons leads to gut dysbiosis and increased susceptibility to alcohol-associated liver disease.
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 alpha 1,2-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 alpha 1,2-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 alpha 1,2-fucosidase may promote Bifidobacterium adhesion to the mucosal surface, which restricts Enterococcus faecalis overgrowth and prevents ALD progression.

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