PTH induces bone loss via microbial-dependent expansion of intestinal TNF+ T cells and Th17 cells

• Type of Material: Article
• Authors: Mingcan Yu, Emory University; Abdul Malik Tyagi, Emory University; Jau-Yi Li, Emory University; Jonathan Adams, Emory University; Timothy L. Denning, Georgia State University; M. Neale Weitzmann, Emory University; Rheinallt Jones, Emory University; Roberto Pacifici, Emory University
• Language: English
• Date: 2020-01-24
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © 2020, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-019-14148-4
• Title of Journal or Parent Work: Nature Communications
• Volume: 11
• Issue: 1
• Start Page: 468
• End Page: 468
• Grant/Funding Information: MNW was also supported by a grant from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (5I01BX000105).; This study was supported by grants from the National Institutes of Health (RP:DK112946, DK108842, and RR028009; RMJ: DK098391; MNW: AG062334, AR068157 and AR070091).
• Keywords: Science & Technology - Other Topics; Hyperparathyroidism; Anabolic activity; T(H)17 Cells; PTH/PTHRP Receptor; Segmented filamentous bacteria; Disease; Parathyroid hormone; Multidisciplinary Sciences; Beta; Secondary; Intermittent; Science & Technology
• Research Categories: Biology, Microbiology; Health Sciences, Immunology; Biology, Molecular; Health Sciences, Nutrition

Abstract

Bone loss is a frequent but not universal complication of hyperparathyroidism. Using antibiotic-treated or germ-free mice, we show that parathyroid hormone (PTH) only caused bone loss in mice whose microbiota was enriched by the Th17 cell-inducing taxa segmented filamentous bacteria (SFB). SFB+ microbiota enabled PTH to expand intestinal TNF+ T and Th17 cells and increase their S1P-receptor-1 mediated egress from the intestine and recruitment to the bone marrow (BM) that causes bone loss. CXCR3-mediated TNF+ T cell homing to the BM upregulated the Th17 chemoattractant CCL20, which recruited Th17 cells to the BM. This study reveals mechanisms for microbiota-mediated gut–bone crosstalk in mice models of hyperparathyroidism that may help predict its clinical course. Targeting the gut microbiota or T cell migration may represent therapeutic strategies for hyperparathyroidism.