Microbial Tryptophan Metabolites Ameliorate Ovariectomy‐Induced Bone Loss by Repairing Intestinal AhR‐Mediated Gut‐Bone Signaling Pathway

Abstract Microbial tryptophan (Trp) metabolites acting as aryl hydrocarbon receptor (AhR) ligands are shown to effectively improve metabolic diseases via regulating microbial community. However, the underlying mechanisms by which Trp metabolites ameliorate bone loss via gut‐bone crosstalk are largely unknown. In this study, supplementation with Trp metabolites, indole acetic acid (IAA), and indole‐3‐propionic acid (IPA), markedly ameliorate bone loss by repairing intestinal barrier integrity in ovariectomy (OVX)‐induced postmenopausal osteoporosis mice in an AhR‐dependent manner. Mechanistically, intestinal AhR activation by Trp metabolites, especially IAA, effectively repairs intestinal barrier function by stimulating Wnt/β‐catenin signaling pathway. Consequently, enhanced M2 macrophage by supplementation with IAA and IPA secrete large amount of IL‐10 that expands from intestinal lamina propria to bone marrow, thereby simultaneously promoting osteoblastogenesis and inhibiting osteoclastogenesis in vivo and in vitro. Interestingly, supplementation with Trp metabolites exhibit negligible ameliorative effects on both gut homeostasis and bone loss of OVX mice with intestinal AhR knockout (Villin Cre Ahr fl/fl ). These findings suggest that microbial Trp metabolites may be potential therapeutic candidates against osteoporosis via regulating AhR‐mediated gut‐bone axis.