SRP404108 PRJNA893378 GSE216386 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. Overall design: 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. GSE216386 pubmed 36300928