Tryptophan-Restricted Intermittent Diet Alleviates Estrogen Deficiency-Induced Osteoporosis via Regulating Coupling Effects of "Gut-Bone" Axis.

Osteoporosis (OP) is a chronic and severe skeletal metabolic disorder resulting from excessive bone erosion activity and compromised bone formation. Emerging evidence highlights that the "gut-bone" axis plays a critical role in maintaining bone homeostasis via modulating gut microbiota and relevant metabolites. Individually, diet-derived tryptophan acts as one of the primary environmental factors that modulate the microbiota-bone crosstalk. Nevertheless, the promising modulatory mechanism of the "diet-microbiome-bone" axis remains unknown during OP progression. In this regard, the study focused on the dominant role of tryptophan-restricted intermittent diet during estrogen deficiency-induced OP. Upon these findings, micro-computed tomography (μCT) evaluation and histomorphometric analysis have confirmed that treatment with tryptophan-restricted intermittent diet effectively mitigated bone loss and improved bone microarchitecture. To unravel the underlying mechanism, we performed 16S rDNA gene sequencing and untargeted metabolomics to confirm the alteration of microbial community composition and metabolite profiles. Additionally, biotin was further identified as a significant microbiota-derived metabolite involved in M1 macrophage polarization and mature osteoclast apoptosis when administered with tryptophan-restricted intermittent diet. Thus, we summarized that treatment with tryptophan-restricted intermittent diet could perform a protective function during OP via modulating the coupling effects of gut microbiota and bone homeostasis, which may provide a potential therapeutic strategy for OP.