Osteopontin Exacerbates High-Fat Diet-induced Metabolic Disorders in a microbiome-dependent Manner

Gut microbiota is involved in metabolic disorders. However, microbiome-based therapeutic interventions are not always effective, which might be due to interference of the host factors. Here, we first identified a strong positive correlation between OPN levels and BMI in humans. Next, we confirmed that OPN could aggravate high-fat diet induced metabolic disorders in mice. Importantly, we found that fecal microbiota transplantation from OPN-deficient mice significantly alleviated metabolic disorders in WT mice. OPN directly induces remodeling of the gut microbiota both in vitro and in vivo. These findings indicate that OPN could contribute to metabolic disorders by inducing an alteration of gut microbiota. OPN regulated the relative abundance of Lactobacillus by decreasing the adhesion of Lactobacillus to intestinal epithelial cells through Notch signaling pathway. These data identify OPN may serve as a potential pharmaceutical target for weight control and metabolic disorders treatment. Specific pathogen-free female mice and OPN-deficient mice (B6.129S6(Cg)-Spp1tm1Blh/J) of same background (C57BL/6J) were both originally from Jackson Laboratory (Bar Harbor, Maine, USA). Four-week-old female wild-type (WT) mice and OPN-deficient (KO) mice were sacrificed after a 24-week continuing high-fat diet (HFD, 60 kcal percent fat, cat#D12492; from Research Diets, Inc) or a normal diet (ND) containing approximately 4% kcal fat.

肠道菌群（gut microbiota）与代谢紊乱密切相关。然而，基于微生物组的治疗干预手段并非总能奏效，其潜在原因可能在于宿主因素的干扰。本研究首先在人群中证实，OPN水平与体质量指数（BMI）存在显著正相关。随后，我们在小鼠模型中验证了OPN可加重高脂饮食诱导的代谢紊乱。重要的是，我们发现将OPN敲除小鼠的粪便菌群移植给野生型（wild-type, WT）小鼠，可显著缓解受体小鼠的代谢紊乱症状。OPN可在体外（in vitro）与体内（in vivo）直接诱导肠道菌群的结构重塑。上述研究结果表明，OPN可通过改变肠道菌群组成参与代谢紊乱的发生发展。OPN可通过Notch信号通路（Notch signaling pathway）降低乳杆菌属（Lactobacillus）对肠上皮细胞的黏附能力，从而调控该菌属的相对丰度。本研究数据证实，OPN有望成为体重控制与代谢紊乱治疗的潜在药物靶点。本研究使用的无特定病原体（specific pathogen-free, SPF）雌性小鼠，以及背景品系为C57BL/6J的OPN敲除小鼠（品系编号：B6.129S6(Cg)-Spp1tm1Blh/J），均购自美国杰克逊实验室（Jackson Laboratory，位于美国缅因州巴尔港）。将4周龄的野生型（WT）雌性小鼠及OPN敲除（KO）雌性小鼠分别施以为期24周的持续高脂饮食（high-fat diet, HFD，脂肪供能占比60%，货号D12492，购自Research Diets, Inc公司）或脂肪供能占比约4%的正常饮食（normal diet, ND），造模结束后处死小鼠。