Gut microbial metabolite alleviates osteoporosis by attenuating AKT-NFATc1 signaling pathway and ROS production.

Abstract

Postmenopausal osteoporosis is a prevalent bone disorder characterized by an imbalance in bone homeostasis following estrogen decline, which leads to progressive bone loss. Research has shown that estrogen deprivation-induced osteoporosis (OVX) is partly dependent on the gut microbiota and its metabolites, a process that can be therapeutically targeted through supplementation with probiotics or the metabolites themselves. Multiple studies have revealed the multifaceted roles of indole and its derivatives in bone health and the pathophysiology of skeletal disorders. These compounds are exclusively synthesized from tryptophan by the gut microbiota. However, the underlying mechanisms and relationships of gut microbiota-derived indole and its derivatives in osteoporosis remain unclear. Our study aimed to explore the influence and mechanism of gut microbiota-derived indole and its derivatives on the development of osteoporosis. In this study, we confirmed that the gut microbiota was altered in OVX mouse model, which was manifested as decreased Lactobacillus genus in the gut and reduced levels of the related indoleacetic acid (IAA) in serum. IAA was significantly positively correlated with bone mass and the abundance of Lactobacillus genus. Specifically, IAA inhibited RANKL-induced PI3K-AKT signaling activation and ROS production, reduced NFATc1 nuclear translocation in BMMs, eventually suppressed osteoclast formation and bone resorption function. The agonist SC-79 restored the IAA-inhibited osteoclast formation. In vivo, daily IAA supplementation conferred protection from OVX-induced bone loss by significantly attenuating osteoclast resorption and enhancing Nrf2 expression. Overall, we elucidated the mechanisms of osteoclastogenesis during osteoporosis to facilitate the development of a new therapy using gut microbial metabolite IAA in addition to the existing therapeutics.