Gut dysregulation drives bone damage in tibial dyschondroplasia by disrupting glucose homeostasis

作者：Shucheng Huang, Tingting Xu, Pan Chen, Chaodong Zhang, Aftab Shaukat, Luxi Lin, Ke Yue, Qinqin Cao, Xishuai Tong, Kaili liu, Yanfeng He, Jing-fei Xie, Fang Liu, Cai Zhang, Huaiyong Zhang · 发表于：Research Square · 年份：2022 · DOI：10.21203/rs.3.rs-1829937/v1 · 研究领域：Peroxisome Proliferator-Activated Receptors、Metabolism, Diabetes, and Cancer、Connective tissue disorders research

Abstract Tibial dyschondroplasia (TD) with multiple incentives is a metabolic skeletal disease that occurs in fast-growing broilers. Perturbations in the gut microbiota (GM) have been shown to affect bone homeostasis and the mechanisms by which GM modulates bone metabolism in TD broilers remain unrevealed. Here, by using a broiler model of TD, we noted elevated blood glucose (GLU) levels in TD broilers, accompanied by altered pancreatic structure and its secretory function, and damaged intestinal barrier function. Importantly, fecal microbiota transplantation (FMT) of gut microbes from normal donors could rehabilitate the GM and depress the elevation of GLU in TD broilers, high GLU level is a predisposing cause of bone disease, suggesting that GM dysbiosis-mediated hyperglycemia might involve in bone regulation. 16s rRNA gene sequencing and short-chain fatty acids analysis revealed that the significantly increased genera Blautia and Coprococcus -derived metabolite butyric acid regulated GLU levels in TD broilers by binding to GPR109A on the pancreas. Tibial studies showed reduced expression of vascular regulatory factors (including PI3K, AKT and VEFGA) based on transcriptional analysis and inhibited vascular distribution contributed to non-vascularization of cartilage in the proximal tibial growth plate in TD broilers with elevated GLU. Additionally, the total flavonoids of Rhizoma drynariae treatment further validated the improvement of bone homeostasis in TD broilers by reg...