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Theranostics 2021; 11(17):8605-8623. doi:10.7150/thno.63749 This issue Cite

Research Paper

Probiotics Stimulate Bone Formation in Obese Mice via Histone Methylations

Jyotirmaya Behera¹, Jessica Ison¹, Michael J. Voor^2,3, Neetu Tyagi^1✉

1. Bone Biology Laboratory, Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40202 USA
2. Department of Orthopaedic Surgery, School of Medicine, University of Louisville, Louisville, KY 40202 USA
3. Department of Bioengineering, Speed School of Engineering, University of Louisville, Louisville, KY 40202 USA

✉ Corresponding author: Neetu Tyagi, Ph.D., F.A.P.S, Associate Professor, Bone Biology Laboratory, Department of Physiology, Health Sciences Centre, A-1201, University of Louisville, Louisville, KY 40202. Phone: 502-852-4145; Fax: 502-852-6239; E-mail: n0tyag01edu. More

Abstract

Rationale: Manipulation of the gut microbiome can prevent pathologic bone loss. However, the effects of probiotics on mitochondrial epigenetic remodeling and skeletal homeostasis in the high-fat diet (HFD)-linked obesity remains to be explored. Here, we examined the impact of probiotics supplementation on mitochondrial biogenesis and bone homeostasis through the histone methylation mechanism in HFD fed obese mice.

Methods: 16S rRNA gene sequencing was performed to study the microbiota composition in the gut and microbial dysbiosis in obese mouse model. High resolution (microPET/CT) imaging was performed to demonstrate the obese associated colonic inflammation. Obese-associated upregulation of target miRNA in osteoblast was investigated using a microRNA qPCR array. Osteoblastic mitochondrial mass was evaluated using confocal imaging. Overexpression of mitochondrial transcription factor (Tfam) was used to investigate the glycolysis and mitochondrial bioenergetic metabolism using Tfam-transgenic (Tg) mice fed on HFD. The bone formation and mechanical strength was evaluated by microCT analysis and three-point bending analysis.

Results: High-resolution imaging (µ-CT) and mechanical testing revealed that probiotics induced a significant increase of trabecular bone volume and bone mechanical strength respectively in obese mice. Probiotics or Indole-3-propionic acid (IPA) treatment directly to obese mice, prevents gut inflammation, and improved osteoblast mineralization. Mechanistically, probiotics treatment increases mitochondrial transcription factor A (Tfam) expression in osteoblasts by promoting Kdm6b/Jmjd3 histone demethylase, which inhibits H3K27me3 epigenetic methylation at the Tfam promoter. Furthermore, Tfam-transgenic (Tg) mice, fed with HFD, did not experience obesity-linked reduction of glucose uptake, mitochondrial biogenesis and mineralization in osteoblasts.

Conclusions: These results suggest that the probiotics mediated changes in the gut microbiome and its derived metabolite, IPA are potentially be a novel agent for regulating bone anabolism via the gut-bone axis.

Keywords: gut microbiota, osteoblasts mineralization, histone methylation, mitochondrial biogenesis, bone loss

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