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Edited by Lora V. Hooper, University of Texas Southwestern Medical Center, Dallas, TX, and approved August 16, 2018 (received for review January 4, 2018)
Significance
Growing evidence suggests that prominent changes in the gut microbial communities (dysbiosis) play a key role in the development of allergic disorders, but the underlying mechanisms remain largely unknown. Here, we used a murine model of human allergic contact dermatitis to demonstrate a regulatory role of the adaptor mitochondrial antiviral signaling (MAVS) RIG-I–like receptors on disease outcome by modulating gut barrier function and bacterial ecology. Our results highlight an unexpected role of the RIG-I–MAVS pathway in maintenance of intestinal barrier function and modulation of gut commensal flora to prevent the development of inflammatory diseases such as allergy. These data provide a rationale for manipulating the gut microbiota as a therapeutic intervention in subjects at risk of developing allergy.
Abstract
Prominent changes in the gut microbiota (referred to as “dysbiosis”) play a key role in the development of allergic disorders, but the underlying mechanisms remain unknown. Study of the delayed-type hypersensitivity (DTH) response in mice contributed to our knowledge of the pathophysiology of human allergic contact dermatitis. Here we report a negative regulatory role of the RIG-I–like receptor adaptor mitochondrial antiviral signaling (MAVS) on DTH by modulating gut bacterial ecology. Cohousing and fecal transplantation experiments revealed that the dysbiotic microbiota of Mavs−/− mice conferred a proallergic phenotype that is communicable to wild-type mice. DTH sensitization coincided with increased intestinal permeability and bacterial translocation within lymphoid organs that enhanced DTH severity. Collectively, we unveiled an unexpected impact of RIG-I–like signaling on the gut microbiota with consequences on allergic skin disease outcome. Primarily, these data indicate that manipulating the gut microbiota may help in the development of therapeutic strategies for the treatment of human allergic skin pathologies.
Footnotes
↵1Present address: MaaT Pharma, 69007 Lyon, France.
↵2A.D. and M.C. contributed equally to this work.
↵3Present address: Department of Immunity, Virus and Infammation (IVI), Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, University of Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, 69008 Lyon, France.
- ↵4To whom correspondence should be addressed. Email: marie-cecile.michallet{at}lyon.unicancer.fr.
Author contributions: E.P., S.D., O.D., M.P., G.L., J.M., and M.-C.M. designed research; E.P., A.D., S.D., L.M., L.B., M.G., C.M., D.B., J.-P.R., S.L., M.P., E.K., A.C., C.B., U.R., M.H., and M.-C.M. performed research; E.P., S.D., O.D., M.P., G.L., J.M., and M.-C.M. analyzed data; and E.P., A.D., M.C., A.B.-B., J.C.M., C.C., G.T., J.M., and M.-C.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1722372115/-/DCSupplemental.
Published under the PNAS license.
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MAVS deficiency induces gut dysbiotic microbiota conferring a proallergic phenotype
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