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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature Metabolism |
| Vol/bind | 5 |
| Udgave nummer | 7 |
| Sider (fra-til) | 1174-1187 |
| Antal sider | 25 |
| ISSN | 2522-5812 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:We are grateful to K.-P. Derreth, N. Hörmann and C. Karwot (CTH, University Medical Center Mainz) for expert technical assistance. We thank U. Walter (CTH, University Medical Center Mainz) for helpful discussions. We are thankful to S.M. Reba, R. Rojas, C. Herding and W.H. Boom (Department of Medicine, Case Western Reserve University & University Hospitals and Cleveland Clinic and Cleveland Medical Center) for providing the Tlr2-flox mouse line. We thank M. Radsak (Department of Medicine III, University Medical Center Mainz) for providing global Tlr4-deficient mice. We thank A.T. Gewirtz (Georgia State University) for providing small intestinal tissue specimens from GF and CONV-R Tlr5 mice. We express our gratitude to D. Kaiserlian (Inserm Rhône-Alpes, CEDE) for the MODE-K small intestinal epithelial cell line. We are grateful to T. Nikolova and T.G. Hofmann (Institute of Toxicology, University Medical Center Mainz) for the use of their microscope. We thank K. Farquharson (Pulmonary Center, Department of Medicine, Boston University School of Medicine) for reading the final version of the paper. This work was supported by the computing infrastructure provided by the Core Facility Bioinformatics and by the Histology Core Facility at the University Medical Center Mainz. The project was funded by a research grant from the Stiftung Pathobiochemie und Molekulare Diagnostik, the CTH Junior Group Translational Research in Thrombosis and Hemostasis (Federal Ministry of Education and Research (BMBF) 01EO1003 and 01EO1503), Deutsche Forschungsgemeinschaft (German Research Foundation) individual grants to C.R. (RE 3450/3-1, RE 3450/5-1, RE 3450/5-2), a project grant from the Wilhelm Sander-Stiftung (no. 2019.107.1) to C.R., an intramural project grant from the Naturwissenschaftlich-Medizinisches Forschungszentrum to C.R., a project grant from the Boehringer Ingelheim Foundation (cardio consortium ‘novel and neglected cardiovascular risk factors’) to C.R., and a CTH Pre-Doctoral Fellowship to I.B. (BMBF 01EO1003). N.S. acknowledges funding by the Heisenberg Program, DFG SO 1738/1-1 and by DFG SO 1738/3-1. C.R. acknowledges funding from the Forschungsinitiative Rheinland-Pfalz and ReALity. C.R. was awarded a Fellowship from the Gutenberg Research College at the Johannes Gutenberg-University Mainz. K.K. is supported by the German Center for Cardiovascular Research (DZHK) ‘Promotion of women scientists’ Excellence Programme and is a member of Young DZHK. C.D. and C.R. are DZHK Scientists and W.R. is Principal Investigator at DZHK. C.D., W.R. and C.R. are Principal Investigators at the BMBF Cluster4Future CurATime (CurATime project microbAIome; 03ZU1202CA). W.R., M. Bosmann and C.R. are members of the Centre for Translational Vascular Biology at the University Medical Center Mainz. W.R., V.K.R., C.D., M. Bosmann, N.S. and C.R. are members of the Research Center for Immunotherapy at the University Medical Center Mainz. M.P.K. and V.V.Z. are enrolled in the Mainz Research School of Translational Biomedicine (TRANSMED) at the University Medical Center Mainz. J.F.B. was supported by the DFG through Collaborative Research Center 1182 ‘Origin and Function of Metaorganisms’ (grant no. SFB1182, Project A2) and Excellence Cluster ‘Precision Medicine in Chronic Inflammation PMI)’ (grant no. EXC2167). −/−
Funding Information:
We are grateful to K.-P. Derreth, N. Hörmann and C. Karwot (CTH, University Medical Center Mainz) for expert technical assistance. We thank U. Walter (CTH, University Medical Center Mainz) for helpful discussions. We are thankful to S.M. Reba, R. Rojas, C. Herding and W.H. Boom (Department of Medicine, Case Western Reserve University & University Hospitals and Cleveland Clinic and Cleveland Medical Center) for providing the Tlr2-flox mouse line. We thank M. Radsak (Department of Medicine III, University Medical Center Mainz) for providing global Tlr4 -deficient mice. We thank A.T. Gewirtz (Georgia State University) for providing small intestinal tissue specimens from GF and CONV-R Tlr5−/−mice. We express our gratitude to D. Kaiserlian (Inserm Rhône-Alpes, CEDE) for the MODE-K small intestinal epithelial cell line. We are grateful to T. Nikolova and T.G. Hofmann (Institute of Toxicology, University Medical Center Mainz) for the use of their microscope. We thank K. Farquharson (Pulmonary Center, Department of Medicine, Boston University School of Medicine) for reading the final version of the paper. This work was supported by the computing infrastructure provided by the Core Facility Bioinformatics and by the Histology Core Facility at the University Medical Center Mainz. The project was funded by a research grant from the Stiftung Pathobiochemie und Molekulare Diagnostik, the CTH Junior Group Translational Research in Thrombosis and Hemostasis (Federal Ministry of Education and Research (BMBF) 01EO1003 and 01EO1503), Deutsche Forschungsgemeinschaft (German Research Foundation) individual grants to C.R. (RE 3450/3-1, RE 3450/5-1, RE 3450/5-2), a project grant from the Wilhelm Sander-Stiftung (no. 2019.107.1) to C.R., an intramural project grant from the Naturwissenschaftlich-Medizinisches Forschungszentrum to C.R., a project grant from the Boehringer Ingelheim Foundation (cardio consortium ‘novel and neglected cardiovascular risk factors’) to C.R., and a CTH Pre-Doctoral Fellowship to I.B. (BMBF 01EO1003). N.S. acknowledges funding by the Heisenberg Program, DFG SO 1738/1-1 and by DFG SO 1738/3-1. C.R. acknowledges funding from the Forschungsinitiative Rheinland-Pfalz and ReALity. C.R. was awarded a Fellowship from the Gutenberg Research College at the Johannes Gutenberg-University Mainz. K.K. is supported by the German Center for Cardiovascular Research (DZHK) ‘Promotion of women scientists’ Excellence Programme and is a member of Young DZHK. C.D. and C.R. are DZHK Scientists and W.R. is Principal Investigator at DZHK. C.D., W.R. and C.R. are Principal Investigators at the BMBF Cluster4Future CurATime (CurATime project microbAIome; 03ZU1202CA). W.R., M. Bosmann and C.R. are members of the Centre for Translational Vascular Biology at the University Medical Center Mainz. W.R., V.K.R., C.D., M. Bosmann, N.S. and C.R. are members of the Research Center for Immunotherapy at the University Medical Center Mainz. M.P.K. and V.V.Z. are enrolled in the Mainz Research School of Translational Biomedicine (TRANSMED) at the University Medical Center Mainz. J.F.B. was supported by the DFG through Collaborative Research Center 1182 ‘Origin and Function of Metaorganisms’ (grant no. SFB1182, Project A2) and Excellence Cluster ‘Precision Medicine in Chronic Inflammation PMI)’ (grant no. EXC2167).
Publisher Copyright:
© 2023, The Author(s).