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This study aimed to systematically evaluate the therapeutic effects of pepper leaf extracts (PLE), spinach extracts (SE), and obeticholic acid (OCA) on HFD-induced metabolic dysfunction in mice. Methods: Integrated phenotypic, histopathological, gut microbial, bile acid, and metabolomic analyses were applied to evaluate the intervention effects. Results: Our results demonstrated that 16-week dietary intervention with PLE, SE, or OCA all effectively mitigated HFD-induced obesity, pathological adipose remodeling, hepatic steatosis, systemic insulin resistance, and intestinal barrier dysfunction. Mechanistically, PLE effectively restored intestinal barrier integrity and reshaped the dysbiotic gut microbiota, with a marked enrichment of beneficial bacterial taxa closely linked to intestinal barrier maintenance, and normalized the disrupted cecal bile acid profile in HFD-fed mice. Furthermore, untargeted metabolomic analysis revealed that PLE reprogrammed disordered systemic metabolism, with significant modulation of key pathways involved in bile acid homeostasis, amino acid metabolism, and energy metabolism. Conclusions: In summary, this study provides evidence that PLE effectively attenuates HFD-induced metabolic disorders through modulation of the gut microbiota\u2013bile acid\u2013metabolome axis and restoration of intestinal barrier integrity. The superior therapeutic efficacy of PLE compared with SE and OCA, coupled with its favorable safety profile, positions PLE as a promising novel natural candidate for the prevention and treatment of obesity and its associated metabolic complications.<\/jats:p>","DOI":"10.3390\/nu18071105","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T12:11:59Z","timestamp":1774872719000},"page":"1105","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pepper Leaf Extracts Alleviate HFD-Induced Metabolic Disorders via Microbiota-Driven Intestinal Barrier Repair and Bile Acid Reprogramming"],"prefix":"10.3390","volume":"18","author":[{"given":"Ning","family":"Xu","sequence":"first","affiliation":[{"name":"College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China"},{"name":"Sanya Institute of China Agricultural University, Sanya 572025, China"},{"name":"Frontier Technology Research Institute of China Agricultural University in Shenzhen, Shenzhen 518000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suxia","family":"Shen","sequence":"additional","affiliation":[{"name":"College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China"},{"name":"Sanya Institute of China Agricultural University, Sanya 572025, China"},{"name":"Frontier Technology Research Institute of China Agricultural University in Shenzhen, Shenzhen 518000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaotian","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China"},{"name":"Sanya Institute of China Agricultural University, Sanya 572025, China"},{"name":"Frontier Technology Research Institute of China Agricultural University in Shenzhen, Shenzhen 518000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Zeng","sequence":"additional","affiliation":[{"name":"College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China"},{"name":"Sanya Institute of China Agricultural University, Sanya 572025, China"},{"name":"Frontier Technology Research Institute of China Agricultural University in Shenzhen, Shenzhen 518000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haifeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"BGI Precision Nutrition (Shenzhen) Technology Co., Ltd., Shenzhen 518083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6231-293X","authenticated-orcid":false,"given":"Xiaojun","family":"Liao","sequence":"additional","affiliation":[{"name":"College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China"},{"name":"Sanya Institute of China Agricultural University, Sanya 572025, China"},{"name":"Frontier Technology Research Institute of China Agricultural University in Shenzhen, Shenzhen 518000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China"},{"name":"Sanya Institute of China Agricultural University, Sanya 572025, China"},{"name":"Frontier Technology Research Institute of China Agricultural University in Shenzhen, Shenzhen 518000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1016\/S0140-6736(19)30041-8","article-title":"Health effects of dietary risks in 195 countries, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017","volume":"393","author":"Collaborators","year":"2019","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Dhurandhar, Y., Tomar, S., Das, A., Prajapati, J.L., Singh, A.P., Bodake, S.H., and Namdeo, K.P. 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