{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T09:47:34Z","timestamp":1780393654436,"version":"3.54.1"},"reference-count":41,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T00:00:00Z","timestamp":1740960000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Southwest Minzu University Graduate Innovative scientific research project","award":["ZD2023254"],"award-info":[{"award-number":["ZD2023254"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Foods"],"abstract":"<jats:p>The consumption of an unbalanced diet, such as a high-fat diet, is strongly associated with hyperlipidemia and significantly contributes to the development of cardiovascular and cerebrovascular diseases, which are the leading causes of death worldwide. Globally, about 17.9 million people die of cardiovascular disease each year (WHO 2023). Probiotics have emerged as a promising intervention to alleviate hyperlipidemia. Therefore, this study investigates the effects of Lactobacillus fermentum 166 (LF-166), isolated from yak yogurt in the Sichuan Tibetan area, on lipid metabolism in the liver and gut microbiota of high-fat-diet-induced hyperlipidemic mice. The results revealed that the Lactobacillus fermentum 166 (LF-166) treatment reduced the body weight and decreased the blood and liver lipid levels in these mice. Based on the histopathological findings, LF-166 could alleviate liver steatosis and colon injury. Additionally, 16S rRNA sequencing of the mice\u2019s colonic contents showed that LF-166 reduced the Firmicutes\/Bacteroidetes (F\/B) value and enhanced the richness and diversity of the gut microbiota. LF-166 regulated hepatic lipid metabolism through the up-regulation of the genes Lxr, Ampk\u03b1, Fxr, Hsl, and Atgl and the down-regulation of C\/ebp\u03b1 and Ppar\u03b3 in the liver; it also regulated intestinal lipid metabolism by up-regulating Abcg5 and Abcg8 in the ileum and down-regulating the expression of the genes Npc1l1, Asbt, and Ibabp. Thus, LF-166 may inhibit hyperlipidemia progression by modulating the expression of key genes involved in hepatic lipid metabolism, influencing the intestinal microbiota through the liver\u2013gut axis, and regulating systemic lipid metabolism.<\/jats:p>","DOI":"10.3390\/foods14050867","type":"journal-article","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T05:41:51Z","timestamp":1741066911000},"page":"867","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Lactobacillus fermentum 166, Derived from Yak Yogurt from Tibetan Areas of Sichuan, Improves High-Fat-Diet-Induced Hyperlipidemia by Modulating Gut Microbiota and Liver- and Gut-Related Pathways"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6425-7634","authenticated-orcid":false,"given":"Shiqi","family":"Zhang","sequence":"first","affiliation":[{"name":"College of Pharmacy and Food, Southwest Minzu University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limei","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Food, Southwest Minzu University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3486-1936","authenticated-orcid":false,"given":"Chenglin","family":"Zhu","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Food, Southwest Minzu University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Food, Southwest Minzu University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Fu","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Food, Southwest Minzu University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiming","family":"Shuang","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Food, Southwest Minzu University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5331-1895","authenticated-orcid":false,"given":"Lianhong","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Food, Southwest Minzu University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/35025203","article-title":"Atherosclerosis","volume":"407","author":"Lusis","year":"2000","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1161\/CIRCRESAHA.117.311849","article-title":"Reducing the Global Burden of Cardiovascular Disease, Part 2: Prevention and Treatment of Cardiovascular Disease","volume":"121","author":"Leong","year":"2017","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e613","DOI":"10.1016\/S2214-109X(19)30070-1","article-title":"Mortality and cardiovascular and respiratory morbidity in individuals with impaired FEV1 (PURE): An international, community-based cohort study","volume":"7","author":"Duong","year":"2019","journal-title":"Lancet Glob. Health"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/nrgastro.2017.32","article-title":"Lipid droplets and liver disease: From basic biology to clinical implications","volume":"14","author":"Gluchowski","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Mkadem, W., Belguith, K., Oussaief, O., ElHatmi, H., Indio, V., Savini, F., De Cesare, A., and Boudhrioua, N. (2023). Systematic approach to select lactic acid bacteria from spontaneously fermented milk able to fight Listeria monocytogenes and Staphylococcus aureus. Food Biosci., 51.","DOI":"10.1016\/j.fbio.2022.102275"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1007\/s12275-018-7548-y","article-title":"Intestinal microbiota and the immune system in metabolic diseases","volume":"56","author":"Sittipo","year":"2018","journal-title":"J. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"0363","DOI":"10.34133\/research.0363","article-title":"Remodeling Intestinal Microbiota Alleviates Severe Combined Hyperlipidemia-Induced Nonalcoholic Steatohepatitis and Atherosclerosis in LDLR-\/- Hamsters","volume":"7","author":"Miao","year":"2024","journal-title":"Research"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1016\/j.fshw.2023.02.021","article-title":"The protective effects of Levilactobacillus brevis FZU0713 on lipid metabolism and intestinal microbiota in hyperlipidemic rats","volume":"12","author":"Fan","year":"2023","journal-title":"Food Sci. Hum. Wellness"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4885","DOI":"10.3390\/ijms12084885","article-title":"The chemical composition and nitrogen distribution of Chinese yak (Maiwa) milk","volume":"12","author":"Li","year":"2011","journal-title":"Int. J. Mol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Feng, F., Yang, G., Ma, X., Zhang, J., Huang, C., Ma, X., La, Y., Yan, P., Zhandui, P., and Liang, C. (2024). Polymorphisms within the PRKG1 Gene of Gannan Yaks and Their Association with Milk Quality Characteristics. Foods, 13.","DOI":"10.3390\/foods13121913"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Zhu, K., Tan, F., Mu, J., Yi, R., Zhou, X., and Zhao, X. (2019). Anti-Obesity Effects of Lactobacillus fermentum CQPC05 Isolated from Sichuan Pickle in High-Fat Diet-Induced Obese Mice through PPAR-\u03b1 Signaling Pathway. Microorganisms, 7.","DOI":"10.3390\/microorganisms7070194"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Qian, Y., Song, J.-L., Yi, R., Li, G., Sun, P., Zhao, X., and Huo, G. (2018). Preventive effects of Lactobacillus plantarum YS4 on constipation induced by activated carbon in mice. Appl. Sci., 8.","DOI":"10.3390\/app8030363"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5971","DOI":"10.1039\/D1FO04316A","article-title":"Lactobacillus plantarum 23-1 improves intestinal inflammation and barrier function through the TLR4\/NF-\u03baB signaling pathway in obese mice","volume":"13","author":"Liu","year":"2022","journal-title":"Food Funct."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Lu, Y., Sun, W., Zhang, Z., Yu, J., Zhang, J., and Guo, Q. (2025). Lactiplantibacillus plantarum A5 alleviates high-fat diet-induced hyperlipidemia via regulating gut microbiota to promote short-chain fatty acids production. Food Biosci., 64.","DOI":"10.1016\/j.fbio.2025.105848"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1002\/ptr.5541","article-title":"Gastrodin Ameliorates Oxidative Stress and Proinflammatory Response in Nonalcoholic Fatty Liver Disease through the AMPK\/Nrf2 Pathway","volume":"30","author":"Qu","year":"2016","journal-title":"Phytother. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"341","DOI":"10.2478\/jvetres-2018-0048","article-title":"Effects of Repeated Lipopolysaccharide Treatment on Growth Performance, Immune Organ Index, and Blood Parameters of Sprague-Dawley Rats","volume":"62","author":"Zhong","year":"2018","journal-title":"J. Vet. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"103665","DOI":"10.1016\/j.jff.2019.103665","article-title":"Lactobacillus plantarum LP104 ameliorates hyperlipidemia induced by AMPK pathways in C57BL\/6N mice fed high-fat diet","volume":"64","author":"Teng","year":"2020","journal-title":"J. Funct. Foods"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1038\/s41467-023-37450-8","article-title":"Neuraminidase 1 promotes renal fibrosis development in male mice","volume":"14","author":"Chen","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e146775","DOI":"10.1172\/JCI146775","article-title":"TRIB1 regulates LDL metabolism through CEBP\u03b1-mediated effects on the LDL receptor in hepatocytes","volume":"131","author":"Vitali","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1053\/j.gastro.2009.08.042","article-title":"High-fat diet determines the composition of the murine gut microbiome independently of obesity","volume":"137","author":"Hildebrandt","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/s41467-025-55917-8","article-title":"Moderate-intensity interval exercise exacerbates cardiac lipotoxicity in high-fat, high-calories diet-fed mice","volume":"16","author":"Geng","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1194\/jlr.M069807","article-title":"Cholesterol 7\u03b1-hydroxylase protects the liver from inflammation and fibrosis by maintaining cholesterol homeostasis","volume":"57","author":"Liu","year":"2016","journal-title":"J. Lipid Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/s41574-018-0037-x","article-title":"Liver X receptors in lipid signalling and membrane homeostasis","volume":"14","author":"Wang","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"155774","DOI":"10.1016\/j.metabol.2023.155774","article-title":"Inhibition of PCSK9 prevents and alleviates cholesterol gallstones through PPAR\u03b1-mediated CYP7A1 activation","volume":"152","author":"Chen","year":"2024","journal-title":"Metabolism"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Jiang, B., Yuan, G., Wu, J., Wu, Q., Li, L., and Jiang, P. (2022). Prevotella copri ameliorates cholestasis and liver fibrosis in primary sclerosing cholangitis by enhancing the FXR signalling pathway. Biochim. Biophys. Acta Mol. Basis Dis., 1868.","DOI":"10.1016\/j.bbadis.2021.166320"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Jin, M., Shen, Y., Pan, T., Zhu, T., Li, X., Xu, F., Betancor, M.B., Jiao, L., Tocher, D.R., and Zhou, Q. (2021). Dietary Betaine Mitigates Hepatic Steatosis and Inflammation Induced by a High-Fat-Diet by Modulating the Sirt1\/Srebp-1\/Ppar\u0251 Pathway in Juvenile Black Seabream (Acanthopagrus schlegelii). Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.694720"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1172\/JCI0215593","article-title":"SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver","volume":"109","author":"Horton","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.dsx.2014.09.015","article-title":"PPAR gamma gene\u2014A review","volume":"9","author":"Janani","year":"2015","journal-title":"Diabetes Metab. Syndr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.fitote.2014.08.006","article-title":"Coptis chinensis alkaloids exert anti-adipogenic activity on 3T3-L1 adipocytes by downregulating C\/EBP-\u03b1 and PPAR-\u03b3","volume":"98","author":"Choi","year":"2014","journal-title":"Fitoterapia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1210\/endo.137.1.8536636","article-title":"Differential expression of peroxisome proliferator-activated receptors (PPARs): Tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat","volume":"137","author":"Braissant","year":"1996","journal-title":"Endocrinology"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Janssen, A.W., Betzel, B., Stoopen, G., Berends, F.J., Janssen, I.M., Peijnenburg, A.A., and Kersten, S. (2015). The impact of PPAR\u03b1 activation on whole genome gene expression in human precision cut liver slices. BMC Genom., 16.","DOI":"10.1186\/s12864-015-1969-3"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1126\/science.1093131","article-title":"Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption","volume":"303","author":"Altmann","year":"2004","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1146\/annurev-physiol-012110-142233","article-title":"Niemann-pick C1-like 1 (NPC1L1) protein in intestinal and hepatic cholesterol transport","volume":"73","author":"Jia","year":"2011","journal-title":"Annu. Rev. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1172\/JCI22186","article-title":"Disruption of cholesterol homeostasis by plant sterols","volume":"114","author":"Yang","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"765","DOI":"10.18433\/J3M029","article-title":"Pravastatin Modulate Niemann-Pick C1-Like 1 and ATP-Binding Cassette G5 and G8 to Influence Intestinal Cholesterol Absorption","volume":"18","author":"Kawase","year":"2015","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.jhep.2015.04.030","article-title":"Gut microbiota inhibit Asbt-dependent intestinal bile acid reabsorption via Gata4","volume":"63","author":"Out","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6798","DOI":"10.1021\/jf200681n","article-title":"Barley intake induces bile acid excretion by reduced expression of intestinal ASBT and NPC1L1 in C57BL\/6J mice","volume":"59","author":"Hoang","year":"2011","journal-title":"J. Agric. Food Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1172\/JCI0216001","article-title":"Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol","volume":"110","author":"Yu","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1177\/0884533615609899","article-title":"Gut Microbiome: What We Do and Don\u2019t Know","volume":"30","author":"Cresci","year":"2015","journal-title":"Nutr. Clin. Pract."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1136\/gut.2010.215665","article-title":"Composition and energy harvesting capacity of the gut microbiota: Relationship to diet, obesity and time in mouse models","volume":"59","author":"Murphy","year":"2010","journal-title":"Gut"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1242\/dmm.017400","article-title":"How informative is the mouse for human gut microbiota research?","volume":"8","author":"Nguyen","year":"2015","journal-title":"Dis. Model. Mech."}],"container-title":["Foods"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2304-8158\/14\/5\/867\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:46:13Z","timestamp":1760028373000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2304-8158\/14\/5\/867"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,3]]},"references-count":41,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["foods14050867"],"URL":"https:\/\/doi.org\/10.3390\/foods14050867","relation":{},"ISSN":["2304-8158"],"issn-type":[{"value":"2304-8158","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,3]]}}}