Alleviation of high-fat diet-induced lipid metabolism disorders: Role of quinoa peptides in inhibiting high-activity BSH-producing gut microbiota and modulating of BA-FXR/TGR5 signaling

Abstract Background: Lipid metabolism disorders contribute significantly to various metabolic diseases and are closely related to gut microbiota dysbiosis. Our previous study showed that oral gavage of quinoa peptides (QPep) restored gut microbiota composition and alleviated liver lipid metabolism disorders in high-fat diet (HFD)-induced obese mice. Nevertheless, the precise mechanisms are still not fully understood. This study aimed to clarify how QPep improve lipid metabolism disorders in HFD mice. Results: Oral gavage of QPep significantly attenuated HFD-induced metabolic disorders in mice, as evidenced by reduced body weight gain and adipose mass, improved serum lipid profiles, decreased hepatic lipid accumulation, and ameliorated impaired glucose homeostasis. The microbiota clearance and fecal microbiota transplantation experiments demonstrated that the beneficial effect of QPep on lipid metabolism disorders depends on the gut microbiota. QPep selectively suppressed gut bacteria that encode bile salt hydrolase (BSH), with high enzymatic activity, reducing intestinal BSH activity while preserving conjugated bile acids (BAs). These accumulated conjugated BAs served as natural FXR antagonists, inhibiting the ileal FXR-FGF15 signaling pathway and stimulating hepatic BAs synthesis by upregulating CYP7A1/CYP27A1. Concurrently, the altered BAs profile strongly activated TGR5 in epididymal white adipose and ileum tissues, reprogramming systemic lipid metabolism and alleviating metabolic disorders. Conclusions: This study reveals a novel mechanism by which bioactive peptides derived from quinoa protein ameliorate lipid metabolism disorders via gut microbiota-BAs crosstalk. These findings demonstrate the potential of quinoa peptides as functional ingredients for metabolic syndrome management and suggest a strategy for precise gut microbiota regulation through dietary interventions.

摘要 背景：脂质代谢紊乱显著参与多种代谢性疾病的发生发展，且与肠道菌群失调紧密关联。本团队前期研究显示，灌胃藜麦肽（QPep）可恢复高脂饮食（HFD）诱导肥胖小鼠的肠道菌群组成，并缓解肝脏脂质代谢紊乱。然而，其确切作用机制仍未完全阐明。本研究旨在明确QPep改善高脂饮食小鼠脂质代谢紊乱的具体途径。
结果：灌胃QPep可显著减轻高脂饮食诱导的小鼠代谢紊乱，具体体现为体重增长减缓、脂肪组织重量降低、血清脂质谱改善、肝脏脂质堆积减少，以及葡萄糖稳态受损状况得到改善。菌群清除与粪便菌群移植实验证实，QPep对脂质代谢紊乱的有益作用依赖于肠道菌群。QPep可选择性抑制携带高活性胆汁盐水解酶（BSH）的肠道细菌，降低肠道BSH活性，同时保留结合型胆汁酸（BAs）。这些蓄积的结合型胆汁酸可作为天然的法尼醇X受体（FXR）拮抗剂，抑制回肠FXR-FGF15信号通路，并通过上调CYP7A1/CYP27A1的表达促进肝脏胆汁酸合成。与此同时，经重塑的胆汁酸谱可强烈激活附睾白色脂肪组织与回肠组织中的TGR5受体，重编程全身脂质代谢并缓解代谢紊乱。
结论：本研究揭示了藜麦蛋白源生物活性肽通过肠道菌群-胆汁酸互作改善脂质代谢紊乱的全新机制。上述研究结果证实了藜麦肽作为代谢综合征管理功能性成分的潜力，并为通过膳食干预实现精准肠道菌群调控提供了可行策略。