Commensal Bacteria Weaken the Intestinal Barrier by Suppressing Epithelial Neuropilin-1 and Hedgehog Signaling

Overview

Journal Nat Metab

Publisher Springer Nature

Specialty Endocrinology

Date 2023 Jul 6

PMID 37414930

Authors

Giulia Pontarollo

Bettina Kollar

Amrit Mann

My Phung Khuu

Klytaimnistra Kiouptsi

Franziska Bayer

Ines Brandao

Valeriya V Zinina

Jennifer Hahlbrock

Frano Malinarich

Maximilian Mimmler

Sudhanshu Bhushan

Federico Marini

Wolfram Ruf

Meriem Belheouane

John F Baines

Kristina Endres

Scott M Reba

Verena K Raker

Carsten Deppermann

Christoph Welsch

Markus Bosmann

Natalia Soshnikova

Benoit Chassaing

Mattias Bergentall

Felix Sommer

Fredrik Backhed

Christoph Reinhardt

Affiliations

Soon will be listed here.

Abstract

The gut microbiota influences intestinal barrier integrity through mechanisms that are incompletely understood. Here we show that the commensal microbiota weakens the intestinal barrier by suppressing epithelial neuropilin-1 (NRP1) and Hedgehog (Hh) signaling. Microbial colonization of germ-free mice dampens signaling of the intestinal Hh pathway through epithelial Toll-like receptor (TLR)-2, resulting in decreased epithelial NRP1 protein levels. Following activation via TLR2/TLR6, epithelial NRP1, a positive-feedback regulator of Hh signaling, is lysosomally degraded. Conversely, elevated epithelial NRP1 levels in germ-free mice are associated with a strengthened gut barrier. Functionally, intestinal epithelial cell-specific Nrp1 deficiency (Nrp1) results in decreased Hh pathway activity and a weakened gut barrier. In addition, Nrp1 mice have a reduced density of capillary networks in their small intestinal villus structures. Collectively, our results reveal a role for the commensal microbiota and epithelial NRP1 signaling in the regulation of intestinal barrier function through postnatal control of Hh signaling.

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