Microbial osteoporosis: The interplay between the gut microbiota and bones via host metabolism and immunity

Abstract

The complex relationship between intestinal microbiota and host is a novel field in recent years. A large number of studies are being conducted on the relationship between intestinal microbiota and bone metabolism. Bone metabolism consisted of bone absorption and formation exists in the whole process of human growth and development. The nutrient components, inflammatory factors, and hormone environment play important roles in bone metabolism. Recently, intestinal microbiota has been found to influence bone metabolism via influencing the host metabolism, immune function, and hormone secretion. Here, we searched relevant literature on Pubmed and reviewed the effect of intestinal microbiota on bone metabolism through the three aspects, which may provide new ideas and targets for the clinical treatment of osteoporosis.

Keywords: bone formation; bone resorption; intestinal microbiota; osteoporosis.

Figure 1

(a) Disorders of intestinal microbiota can increase the permeability of intestinal cell, which caused more LPS into the circulation system. LPS can upregulate the inflammatory mediators, interleukin (IL)‐1, cyclooxygenase (COX)‐2, and TNF in the bone metaphyseal region. (b) Disorders of intestinal microbiota can increase gut PH and decrease calcium absorption

Figure 2

(a) Bile acids experienced a “gut‐liver axis” and were transformed to the secondary bile acid under the influence of anaerobic bacteria. (b) Through FXP and TGR5 signaling, intestinal microbial components can change the amount and the type of secondary bile acid. (c) Some types of secondary bile acid are agonists of the membrane‐bound G‐protein‐coupled receptor (TGR5). Stimulation of TGR5 can increase the production of glucagon‐like peptide‐1 (GLP‐1), a kind of enterogenous hormone, which can active thyroid C cells proliferation and promote the secretion of calcitonin, thus inhibiting bone resorption. GLP‐1 also can stimulate the proliferation of osteoblast and inhibit osteoclast.(Sandoval & D'Alessio, 2015) (d) LCA can damage osteoblasts mitochondrial and reduce cell viability. As a mild VDR ligand, LCA can reduce the gene expression of osteocalcin and RANKL

Figure 3

(a) SCFAs owns the ability to influence Tregs development through membrane protein (SLC5A8, GPR41, GPR43, GPR109A), which can promote an anti‐inflammatory environment. GPR109A,(Furusawa et al., 2013) activated by butyrate, suppresses intestinal inflammation by induction of IL‐18 secretion; GPR43,(Smith et al., 2013) activated by acetate promotes resolution of intestinal inflammation by inducing apoptosis of inflammatory cells; GPR41, activated(Lührs et al., 2002) by butyrate, suppresses intestinal inflammation via inhibition of NF‐kB activation; LC5A8,(Thangaraju et al., 2010) suppresses intestinal inflammation via inhibition of histone deacetylase (HDAC). (b). Enterochromaffin cells are responsible for the synthesis of 5HT that is partially modulated by GM as SCFAs increase the synthesis of 5HT.(Reigstad et al., 2015)

Figure 4

(a) Th17 cells produce a pro‐osteoclastogenic effect. SFB influenced the expression of antimicrobial proteins RegIIIg participating in Th17 cell polarization; SFB induced Th17 cell differentiation by intestinal epithelial cells production of serum amyloid A that might affect DC cytokine; Th17 cell differentiation depended on MHCII‐dependent antigen presentation of SFB antigens by intestinal dendritic cells; Bacteroides fragilis prevented the differentiation of Th17 cells by polysaccharide A. (b) Tregs regulated the formation of osteoclast. Treg cell differentiation was induced by short‐chain fatty acids, leading to epigenetic changes to stabilize the program; Clostridium genus provided bacterial antigens and a TGF‐b‐rich environment, resulting in the expansion of systemic Tregs. (c). NLRs bind to bacterial peptides and attract receptor interaction protein (RIP2), stimulating the NF‐kB signaling pathway, which can induce osteoclastogenesis through chemokines and cytokines

Figure 5

(a) Spore‐forming microbes can fully regulate serotonin levels, which regulates osteoblasts proliferation through Htr1b/PKA/CREB/cyclins signaling. (b)Specific microbiota can affect systematic level of leptin, which may influence bone mass depending on the regulation of sympathetic nervous system through brain serotonin