Obesity is associated with impaired intestinal barrier function and dysbiosis of the gut microbiota. Spermidine, a polyamine that acts as an autophagy inducer, has important benefits in patients with aging-associated diseases and metabolic dysfunction. However, the mechanism of spermidine on obesity remains unclear. Here, we show that spermidine intake is negatively correlated with obesity in both humans and mice. Spermidine supplementation causes a significant loss of weight and improves insulin resistance in diet-induced obese (DIO) mice. These effects are associated with the alleviation of metabolic endotoxemia and enhancement of intestinal barrier function, which might be mediated through autophagy pathway and TLR4-mediated microbial signaling transduction. Moreover, spermidine causes the significant alteration of microbiota composition and function. Microbiota depletion compromises function, while transplantation of spermidine-altered microbiota confers protection against obesity. These changes might partly be driven by an SCFAproducing bacterium, Lachnospiraceae NK4A136 group, which was decreased in obese subjects and subsequently increased by spermidine. Notably, the change of Lachnospiraceae NK4A136 group is significantly correlated with enhanced gut barrier function induced by spermidine. Our results indicate that spermidine supplementation may serve as a viable therapy for obesity.

ReviewOBESITY BIOLOGY AND INTEGRATED PHYSIOLOGY ► We summarize the impact of several novel antidiabetic drugs (e.g., DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists) on macrophage polarization and obesity-induced IR. ► We discuss the link between gut microbiota and its metabolites and macrophages in obesity-induced IR.

Non‐alcoholic fatty liver disease (NAFLD) is one of the most prevalent metabolic disorders worldwide, along with obesity and type 2 diabetes. NAFLD involves a series of liver abnormalities from simple hepatic steatosis to non‐alcoholic steatohepatitis, which can ultimately lead to liver cirrhosis and cancer. The gut–liver axis plays an important role in the development of NAFLD, which depends mainly on regulation of the gut microbiota and its bacterial products. These intestinal bacterial species and their metabolites, including bile acids, tryptophan catabolites, and branched‐chain amino acids, regulate adipose tissue and intestinal homeostasis and contribute to the pathogenesis of NAFLD/non‐alcoholic steatohepatitis. In this review, the current evidence regarding the key role of the gut microbiota and its metabolites in the pathogenesis and development of NAFLD is highlighted, and the advances in the progression and applied prospects of gut microbiota‐targeted dietary and exercise therapies is also discussed.

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