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 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.
Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
Jing
J
Yan
National Gnotobiotic Rodent Resource Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
Jeremy W
JW
Herzog
Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
Kelly
K
Tsang
Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115.
Caitlin A
CA
Brennan
National Gnotobiotic Rodent Resource Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
Maureen A
MA
Bower
Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115.|Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.|Broad Institute of MIT and Harvard University, Cambridge, MA 02141.
Wendy S
WS
Garrett
National Gnotobiotic Rodent Resource Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
Balfour R
BR
Sartor
Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
Antonios O
0000-0002-8744-2535
AO
Aliprantis
Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; JFCHARLES@partners.org.
Julia F
JF
Charles
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001846:Bone Development; D001842:Bone and Bones / Q000378:metabolism*; D005232:Fatty Acids, Volatile / Q000378:metabolism; D005260:Female; D000069196:Gastrointestinal Microbiome; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D010012:Osteogenesis; D013047:Specific Pathogen-Free Organisms
D005232:Fatty Acids, Volatile; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I
IGF-1; SCFA; bone; microbiota