Reconstitution of the host holobiont in germ-free born male rats acutely increases bone growth and affects marrow cellular content

Physiol Genomics. 2021 Dec 1;53(12):518-533. doi: 10.1152/physiolgenomics.00017.2021. Epub 2021 Oct 29.


Integration of microbiota in a host begins at birth and progresses during adolescence, forming a multidirectional system of physiological interactions. Here, we present an instantaneous effect of natural, bacterial gut colonization on the acceleration of longitudinal and radial bone growth in germ-free born, 7-wk-old male rats. Changes in bone mass and structure were analyzed after 10 days following the onset of colonization through cohousing with conventional rats and revealed unprecedented acceleration of bone accrual in cortical and trabecular compartments, increased bone tissue mineral density, improved proliferation and hypertrophy of growth plate chondrocytes, bone lengthening, and preferential deposition of periosteal bone in the tibia diaphysis. In addition, the number of small in size adipocytes increased, whereas the number of megakaryocytes decreased, in the bone marrow of conventionalized germ-free rats indicating that not only bone mass but also bone marrow environment is under control of gut microbiota signaling. The changes in bone status paralleled with a positive shift in microbiota composition toward short-chain fatty acids (SCFA)-producing microbes and a considerable increase in cecal SCFA concentrations, specifically butyrate. Furthermore, reconstitution of the host holobiont increased hepatic expression of IGF-1 and its circulating levels. Elevated serum levels of 25-hydroxy vitamin D and alkaline phosphatase pointed toward an active process of bone formation. The acute stimulatory effect on bone growth occurred independently of body mass increase. Overall, the presented model of conventionalized germ-free rats could be used to study microbiota-based therapeutics for combatting dysbiosis-related bone disorders.

Keywords: IGF-1; bone; bone marrow adipocytes; gut microbiome; short-chain fatty acids.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Animals
  • Bacteria / genetics*
  • Bacteria / metabolism*
  • Bone Density / physiology
  • Bone Development / physiology*
  • Bone Marrow Cells / metabolism*
  • Cell Proliferation / physiology
  • Chondrocytes / metabolism
  • Coprophagia
  • Dysbiosis
  • Fatty Acids, Volatile / analysis
  • Fatty Acids, Volatile / metabolism
  • Feces / microbiology
  • Gastrointestinal Microbiome / genetics*
  • Germ-Free Life*
  • Host Microbial Interactions / genetics*
  • Male
  • Osteogenesis / physiology*
  • RNA, Ribosomal, 16S / genetics
  • Rats
  • Rats, Sprague-Dawley


  • Fatty Acids, Volatile
  • RNA, Ribosomal, 16S

Associated data

  • figshare/10.6084/m9.figshare.16606889.v1