Gut microbiota induce IGF-1 and promote bone formation and growth

Abstract

Appreciation of the role of the gut microbiome in regulating vertebrate metabolism has exploded recently. However, the effects of gut microbiota on skeletal growth and homeostasis have only recently begun to be explored. Here, we report that colonization of sexually mature germ-free (GF) mice with conventional specific pathogen-free (SPF) gut microbiota increases both bone formation and resorption, with the net effect of colonization varying with the duration of colonization. Although colonization of adult mice acutely reduces bone mass, in long-term colonized mice, an increase in bone formation and growth plate activity predominates, resulting in equalization of bone mass and increased longitudinal and radial bone growth. Serum levels of insulin-like growth factor 1 (IGF-1), a hormone with known actions on skeletal growth, are substantially increased in response to microbial colonization, with significant increases in liver and adipose tissue IGF-1 production. Antibiotic treatment of conventional mice, in contrast, decreases serum IGF-1 and inhibits bone formation. Supplementation of antibiotic-treated mice with short-chain fatty acids (SCFAs), products of microbial metabolism, restores IGF-1 and bone mass to levels seen in nonantibiotic-treated mice. Thus, SCFA production may be one mechanism by which microbiota increase serum IGF-1. Our study demonstrates that gut microbiota provide a net anabolic stimulus to the skeleton, which is likely mediated by IGF-1. Manipulation of the microbiome or its metabolites may afford opportunities to optimize bone health and growth.

Bioinformatic analysis of endogenous and exogenous small RNAs on lipoproteins

“…DNA isolates were then concentrated to 10 μL with DNA Clean and Concentrate-5 (Zymo). To measure bacterial DNA content, 1 ng of E. coli DNA was serially diluted (1:5) 5 times for an effective detection range of 1 ng to 0.32 pg and bacterial DNA was amplified by real-time PCR using a previously described [16] eubacteria primer set: Forward 5ʹ-ACTCCTACGGGAGGCAGCAGT-3ʹ and Reverse 5ʹ-ATTACCGCGGCTGTGGC-3ʹ. Likewise, bacterial DNA content was assessed from 4 μL of plasma DNA isolates (40%) or 4 mL of molecular grade water.…”

Epithelial Barrier Function in Gut-Bone Signaling

“…Decreases in the mucin layers have been shown to compromise the intestinal barrier function leading to increases in intestinal permeability and microbe penetration [129]. All of the effects of dysbiosis on the gut barrier function can also lead to systemic changes in the body including bone loss [130–132]. …”

“…This increase in bone density was attributed to a decrease in osteoclast, as well as, inflammatory cytokines in the bone and bone marrow in the germ free mice vs conventionally raised mice [132]. However, the effects of microbiome on bone density, as determined by studies using germ free mice, are not consistent across mouse strains and/or sex [136][8][130][132]. In addition, the impact of the microbiota changes on the epithelial barrier were not been fully examined.…”

Immunology of Gut-Bone Signaling

“…Specifically, dysbiosis can lead to the promotion of osteoclast differentiation and resorptive activity through the activation of pro-inflammatory T helper 17 (T H 17) cells, resulting in reduced bone mass (190). Moreover, Yan et al (191) found that colonization of conventional specific pathogen-free gut microbiota in germ-free mice increased bone formation and resorption, suggesting that the gut microbiota can have a critical effect on bone remodeling. This link between dysbiosis and bone health can have important implications in infant and adult humans.…”