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

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 c...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 113; no. 47; pp. E7554 - E7563
Main Authors Yan, Jing, Herzog, Jeremy W., Tsang, Kelly, Brennan, Caitlin A., Bower, Maureen A., Garrett, Wendy S., Sartor, Balfour R., Aliprantis, Antonios O., Charles, Julia F.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 22.11.2016
SeriesPNAS Plus
Subjects
Adipose tissue
Antibiotics
Biological Sciences
Colonization
Fatty acids
Homeostasis
Insulin-like growth factors
Metabolism
Metabolites
Microorganisms
PNAS Plus
microbiota
IGF-1
bone
SCFA
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Summary: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.
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Edited by Jeffrey I. Gordon, Washington University School of Medicine in St. Louis, St. Louis, MO, and approved October 14, 2016 (received for review May 30, 2016)
1Present address: Merck Research Laboratories, 33 Ave Louis Pasteur, Boston, MA 02115.
Author contributions: J.Y., J.W.H., A.O.A., and J.F.C. designed research; J.Y., J.W.H., K.T., C.A.B., and J.F.C. performed research; J.W.H., C.A.B., M.A.B., W.S.G., and B.R.S. contributed new reagents/analytic tools; J.Y., C.A.B., W.S.G., A.O.A., and J.F.C. analyzed data; and J.Y., A.O.A., and J.F.C. wrote the paper.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1607235113