Gut microbiota modulates osteoclast glutathione synthesis and mitochondrial biogenesis in mice subjected to ovariectomy

Abstract

Objectives

Osteoporosis is a common bone disease in the elderly mainly regulated by osteoblasts (OBs) and osteoclasts (OCs). The gut microbiota has been recognized as an important factor in many physiological and pathological processes in the host. Thus, we hypothesize that the gut microbiota is necessary for postmenopausal osteoporosis and that germ‐free (GF) mice are protected from osteoporosis.

Material and Methods

Osteoporosis models were established by performing ovariectomy (OVX) in mice. Bone mass was measured by micro‐CT, and gut microbiota were assessed by 16s rDNA sequencing. Reactive oxygen species (ROS) were detected by dihydroethidium (DHE) staining in vivo and 2’,7'‐dichlorodihydrofluorescein diacetate (DCFH‐DA) staining in vitro.

Results

Firmicutes and Bacteroidetes in the intestine are pivotal in OC differentiation, and the Firmicutes/Bacteroidetes ratio (F/B ratio) is a specific indicator of osteoporosis. Furthermore, we found that Firmicutes and Bacteroidetes affect the de novo synthesis of glutathione (GSH) by regulating its key enzyme glutamate–cysteine ligase catalytic subunit (Gclc) and inhibiting mitochondrial biogenesis and ROS accumulation via the cAMP response element‐binding (CREB) pathway. In addition, supplementing OVX mice with the probiotic Lactobacillus salivarius LI01 from the Firmicutes phylum prevented osteoporosis.

Conclusions

Our results reveal that GSH plays a vital role in OVX‐induced bone loss, and probiotics that affect GSH metabolism are potential therapeutic targets for overcoming osteoporosis.

Abstract

Gut microbiota regulates osteoclast differentiation and mitochondrial biogenesis via GSH de novo synthesis.