Commensal bacteria weaken the intestinal barrier by suppressing epithelial neuropilin-1 and Hedgehog signaling
-
Published:2023-07-06
Issue:7
Volume:5
Page:1174-1187
-
ISSN:2522-5812
-
Container-title:Nature Metabolism
-
language:en
-
Short-container-title:Nat Metab
Author:
Pontarollo GiuliaORCID, Kollar Bettina, Mann Amrit, Khuu My PhungORCID, Kiouptsi KlytaimnistraORCID, Bayer Franziska, Brandão InêsORCID, Zinina Valeriya V.ORCID, Hahlbrock Jennifer, Malinarich Frano, Mimmler MaximilianORCID, Bhushan Sudhanshu, Marini Federico, Ruf WolframORCID, Belheouane MeriemORCID, Baines John F., Endres KristinaORCID, Reba Scott M., Raker Verena K.ORCID, Deppermann CarstenORCID, Welsch ChristophORCID, Bosmann MarkusORCID, Soshnikova NataliaORCID, Chassaing Benoit, Bergentall Mattias, Sommer FelixORCID, Bäckhed Fredrik, Reinhardt ChristophORCID
Abstract
AbstractThe 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.
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Physiology (medical),Endocrinology, Diabetes and Metabolism,Internal Medicine
Reference66 articles.
1. Costea, P. I. et al. Enterotypes in the landscape of gut microbial community composition. Nat. Microbiol. 3, 8–16 (2018). 2. Hooper, L. V. Bacterial contributions to mammalian gut development. Trends Microbiol 12, 129–134 (2004). 3. Reinhardt, C. et al. Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling. Nature 483, 627–631 (2012). 4. Abrams, G. D., Bauer, H. & Sprinz, H. Influence of the normal flora on mucosal morphology and cellular renewal in the ileum. A comparison of germ-free and conventional mice. Lab. Invest. 12, 355–364 (1963). 5. Bayer, F. et al. The interplay between nutrition, innate immunity, and the commensal microbiota in adaptive intestinal morphogenesis. Nutrients 13, 2198 (2021).
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|