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The gut microbiome has emerged as a key regulator of host metabolism, and its dysregulation is implicated in obesity. This study investigated the therapeutic potential of Piper sarmentosum Roxb. aqueous extract (PSRW) on metabolic dysfunction and gut microbiota composition in a high-fat diet (HFD)-induced obese rat model. Methods: HFD-induced obese male Wistar rats received PSRW, simvastatin, or their combination for 12 weeks. Serum lipids (TC, TG, HDL, LDL), liver enzymes (AST, ALT), and renal markers were measured, and gut microbiota were profiled by 16S rRNA (V4) sequencing with PICRUSt2\/KEGG functional prediction. The phenolic composition of the same extract was characterized by HPLC in a companion study. Results: PSRW did not cause weight loss but significantly lowered serum TC, AST, and ALT, with efficacy comparable to simvastatin and significantly lower TG than control, though not significantly different from HFD. Co-administration of PSRW and simvastatin produced a greater reduction in TC and liver enzymes than either agent alone. HFD shifted microbial community structure and enriched pro-inflammatory phyla such as Desulfobacterota; PSRW partially reversed these changes, suppressing obesogenic Lachnospiraceae genera while enriching beneficial microbes including Dwaynesavagella, and functionally reprogrammed taxa such as Kineothrix and Muribaculum from detrimental to protective associations. HFD enriched microbial glycosphingolipid biosynthesis, whereas the PSRW simvastatin combination uniquely enhanced glycine, serine, and threonine metabolism. Conclusions:P. sarmentosum extract ameliorates HFD-induced dyslipidemia and hepatotoxicity, and these effects are accompanied by remodeling of the composition and predicted functional capacity of the gut microbiome. Its ability to act in combination with statins highlights its potential as a candidate complementary therapy for hyperlipidemia and NAFLD.<\/jats:p>","DOI":"10.3390\/nu18162667","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T15:48:36Z","timestamp":1786722516000},"page":"2667","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modulatory Effects of Piper sarmentosum Roxb. Aqueous Extract on Gut Microbiota and Obesity in a High-Fat Diet Rat Model"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9163-3682","authenticated-orcid":false,"given":"Romteera","family":"Kittichaiworakul","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5392-9062","authenticated-orcid":false,"given":"Patcharawadee","family":"Thongkumkoon","sequence":"additional","affiliation":[{"name":"Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5537-1023","authenticated-orcid":false,"given":"Chutima S.","family":"Vaddhanaphuti","sequence":"additional","affiliation":[{"name":"Cluster of Innovative Research for Translational Medicine in Non-Communicable Diseases (CIRTM-NCDs), Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"},{"name":"Innovative Research Unit of Epithelial Transport and Regulation, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Worarat","family":"Rojanaverawong","sequence":"additional","affiliation":[{"name":"Cluster of Innovative Research for Translational Medicine in Non-Communicable Diseases (CIRTM-NCDs), Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"},{"name":"Innovative Research Unit of Epithelial Transport and Regulation, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"},{"name":"Office of Research Administration, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sawannee","family":"Sutheeworapong","sequence":"additional","affiliation":[{"name":"Systems Biology and Bioinformatics Research Unit, Pilot Plant Development and Training Institute, King Mongkut\u2019s University of Technology Thonburi, Bangkok 10150, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rawiwan","family":"Wongpoomchai","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0695-6682","authenticated-orcid":false,"given":"Sivamoke","family":"Dissook","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Horwitz, A., and Birk, R. 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