Commensal bacteria weaken the intestinal barrier by suppressing epithelial neuropilin-1 and Hedgehog signaling [Kommensale Bakterien schwächen die Darmbarriere durch Unterdrückung von epithelialem Neuropilin-1 und Hedgehog-Signalen]

Pontarollo, Giulia; Kollar, Bettina; Man, Amrit; Khuu, My Phung; Kiouptsi, Klytaimnistra; Bayer, Franziska; Brandão, Inês; Zinina, Valeriya V; Hahlbrock, Jennifer; Malinarich, Frano; Mimmler, Maximilian; Bhushan, Sudhanshu; Marini, Federico; Ruf, Wolfram; Belheouane, Meriem; Baines, John F; Endres, Kristina; Reba, Scott M; Raker, Verena K; Deppermann, Carsten; Welsch,Christoph; Bosmann, Markus; Soshnikova, Natalia; Chassaing, Benoit; Bergentall, Mattias; Sommer, Felix; Bäckhed, Fredrik; Reinhardt, Christoph

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 (Nrp1ΔIEC) results in decreased Hh pathway activity and a weakened gut barrier. In addition, Nrp1ΔIEC 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.