Gut Metabolite Indoleacrylic Acid Suppresses Osteoclast Formation by AHR mediated NF-κB Signaling Pathway

Bone homeostasis relies on the coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts. Disruption of this balance leads to osteoporosis, a highly prevalent bone disease with substantial health impacts in middle-aged and older adults. There is accumulating evidence linking the development of osteoporosis to alterations in the gut microbiota and its metabolite profile. The gut metabolite indole and its derivatives were shown to have beneficial effects in multiple metabolic diseases. However, their effects on bone homeostasis remain unclear. This study identified alterations in the gut microbiota and decreases in levels of tryptophan metabolites in an ovariectomized (OVX) estrogen deficiency-induced osteoporosis mouse model, characterized by decreased abundance of Lactobacillus and Clostridium species in the gut and reduced serum levels of indoleacrylic acid (IA), indoleacetic acid (IAA), and indolepropionic acid (IPA). IA showed a significant positive correlation with bone mass. Specifically, IA inhibited RANKL-induced aryl hydrocarbon receptor (AhR) and c-Fos expression, reducing nuclear translocation of p-p65 in bone marrow macrophages (BMMs), ultimately resulting in suppression of osteoclast resorption activity. AhR acts as a key positive regulator in the process of osteoclastogenesis, and its overexpression restored IA-mediated inhibition of osteoclast formation. In vivo, daily IA supplementation protected mice against OVX-induced bone loss, with higher PINP and lower CTX-1 levels. Taken together, these findings identified IA as a promising therapeutic candidate capable of suppressing osteoclastogenesis through an AhR-dependent mechanism, providing mechanistic insight and a potential strategy for the treatment of postmenopausal osteoporosis.