Time-restricted feeding promotes glucagon-like peptide-1 secretion and regulates appetite via tryptophan metabolism of gut Lactobacillus in pigs

Previous clinical trials have shown that time-restricted feeding can be involved in regulating the metabolic health of humans and animals. However, the underlying mechanism has not been fully explored. In this study, the pig model was employed to simulate four prevalent human eating habits, with the aim of investigating the impact of gut microbiota and microbial metabolites on gut hormone secretion and appetite regulation. Compared to the ad libitum feeding (ALF) pattern, three time-restricted feeding patterns reduced total food intake and eating time. Meanwhile, three time-restricted feeding patterns induced elevated levels of serum and hypothalamic glucagon-like peptide-1 (GLP-1), while suppressing reward-related circuits in the hypothalamus. It is noteworthy that the early time-restricted feeding (eTRF) pattern increased the number of intestinal enteroendocrine cells (EECs) compared to ALF. Metagenomic and metabonomic analyses revealed that three time-restricted feeding patterns induced colonization of Lactobacillus and significantly increased the levels of its metabolite, indole-3-lactic acid (ILA). Dietary supplementation with ILA exhibited an increasing trend in fasting serum GLP-1 level of piglets. In vitro studies with pig intestinal organoids showed the Lactobacillus metabolite ILA enhanced GLP-1 secretion through the promotion of intestinal stem cell differentiation into EECs, rather than activating the ability of EECs to secrete GLP-1. Overall, time-restricted feeding promoted GLP-1 secretion and affected long-term appetite regulation by promoting the colonization of Lactobacillus and modulating microbial tryptophan metabolism.