Role of Gut Microbiota in the Skeletal Response to PTH

Abstract

Exposed surfaces of mammals are colonized with 100 trillion indigenous bacteria, fungi, and viruses, creating a diverse ecosystem known as the human microbiome. The gut microbiome is the richest microbiome and is now known to regulate postnatal skeletal development and the activity of the major endocrine regulators of bone. Parathyroid hormone (PTH) is one of the bone-regulating hormone that requires elements of the gut microbiome to exert both its bone catabolic and its bone anabolic effects. How the gut microbiome regulates the skeletal response to PTH is object of intense research. Involved mechanisms include absorption and diffusion of bacterial metabolites, such as short-chain fatty acids, and trafficking of immune cells from the gut to the bone marrow. This review will focus on how the gut microbiome communicates and regulates bone marrow cells in order to modulate the skeletal effects of PTH.

Keywords: PTH; SCFA; Th17 cells; bone; microbiome.

Figure 1.

Diagrammatic representation of the mechanism of action of cPTH in bone. Bacterial products such as lipopolysaccharide and flagellin translocate into the intestinal wall where, in concert with PTH, they induce the differentiation of Cd4+ T cells into TNF+ T cells. Intestinal TNF, together with stimuli provided by segmented filamentous bacteria (SFB) induce the expansion of intestinal Th17 cells. TNF+ T cells and Th17 cells, which express the receptor S1PR1, egress from the intestine and enter the blood vessels attracted by the S1PR1 ligand S1P. TNF+ T cells express the chemokine CXCR3 and are attracted to the bone marrow (BM) by CXCL9/10/11 produced by stromal cells. Once in the BM, TNF+ T cells release TNF, which upregulate CCL20, the ligand for the Th17 cell receptor CCR6, causing the homing of circulating Th17 cells into the BM.Th17 cells release Il-17, which induce the production of RANKL by osteoblasts and osteocytes, causing bone loss. Reproduced with Permission from Springer Nature from: Yu M, Malik Tyagi A, Li JY, et al. PTH induces bone loss via microbial-dependent expansion of intestinal TNF+ T cells and Th17 cells. Nat Commun. 2020;11(1):468.

Figure 2.

Diagrammatic representation of the mechanism of action of iPTH in bone. The intestinal microbiota produces butyrate via fermentation of complex carbohydrates. Intestinal butyrate diffuses through the intestinal wall into the systemic circulation, which carries it to distant organs. In the bone marrow (BM), butyrate enhances the differentiation of naïve helper CD4+ cells into regulatory T cells (Tregs) in concert with PTH. The expansion of BM Tregs makes possible for PTH to induce the production of wnt10b by BM CD8+ T cells. Wnt10b activates Wnt signaling in BM stromal cells, causing their proliferation and differentiation into osteoblasts. The expansion of the osteoblastic population results in increased bone formation and improved bone structure.