色氨酸肠道菌群代谢物通过激活“外源性化合物感受器”参与骨质疏松症发生的机制研究

骨质疏松症是一种临床常见疾病，主要病理机制为成骨细胞参与的骨形成和破骨细胞参与的骨吸收失衡。肠道菌群是一类人体的共生生物，参与多种生理病理过程。色氨酸经肠道菌群代谢产生多种吲哚衍生物。申请人前期实验发现，绝经后血清吲哚乙酸（I3AA）水平明显低于绝经前，且I3AA水平和女性骨密度具有显著相关性。申请人进一步实验证实，部分吲哚衍生物调节破骨细胞分化和功能，且吲哚、吲哚丙酸、吲哚甲酸、吲哚乙醛可明显激活“外源性化合物感受器”（包括PXR/AhR/CAR）。基于上述结果，申请人推测，绝经前后色氨酸代谢相关肠道菌群丰度改变、血清色氨酸代谢物水平异常参与骨质疏松的发生。在本课题中，申请人团队拟通过进一步实验在绝经前后女性和卵巢切除/假手术小鼠模型中明确色氨酸代谢相关肠道菌群及血清代谢物变化、色氨酸代谢肠道菌群/代谢物对小鼠骨量的调控作用及其分子机制。

Osteoporosis is a common clinical disorder, which is resulted from imbalance between bone formation by osteoblasts and bone resorption by osteoclasts. Gut microbiota is the complex community of microorganisms that live in the digestive tracts of humans that are involved in many pathology and pathogenesis processes. Tryptophan can be metabolized by the gut bacteria into indole derivatives, such as indole (Ind), indoxyl-3-sulfate (I3S), indole-3-propionic acid (IPA), indole-3-aldehyde (I3A), indole-3-acetic acid (I3AA). In our preliminary experiments we found that serum I3AA levels from postmenopausal women were lower than that from premenopausal women and Pearson correlation analysis indicated that BMD (bone mineral density) was significantly correlated with serum I3AA level. Further we found that part of these indole derivatives modulated osteoclasts differentiation and function. RT-qPCR results showed microbiota derived tryptophan derivatives activated xenobiotic sensors including PXR, AhR and CAR. We thus speculate that menopause caused shift of composition of gut microbiota and subsequently altered gut microbiota derived tryptophan metabolites are involved in pathogenesis of osteoporosis. In this project the research team will try to investigate changes of composition of gut microbiota and related tryptophan metabolites. In this way we want to elucidate the effect of tryptophan metabolism related gut microbiota and tryptophan metabolites on bone metabolism.