{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T05:32:33Z","timestamp":1769059953917,"version":"3.49.0"},"reference-count":39,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science and Technology Development Program of Shanghai University of Traditional Chinese Medicine","award":["24KFL019"],"award-info":[{"award-number":["24KFL019"]}]},{"name":"Open Project of the State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine","award":["LSLSKL20240131"],"award-info":[{"award-number":["LSLSKL20240131"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Bile acids participate in several metabolic processes, and disturbances in their circulating profiles are commonly observed in type 2 diabetes. In a cohort of older adults, individuals with diabetes exhibited markedly lower concentrations of metabolites derived from lithocholic acid. These findings prompted further evaluation of the metabolic effects of lithocholic acid. Methods: We assessed the actions of lithocholic acid in a mouse model of diabetes induced by a high-fat diet and streptozotocin. Fasting glucose, insulin levels, lipid parameters, and measures of insulin resistance were evaluated. Gut microbial composition, short-chain fatty acids, fecal enzyme activities, intestinal barrier markers, and bile acid patterns were analyzed. In vitro assays examined the direct effects of lithocholic acid on A. muciniphila and bile acid metabolism. Results: Lithocholic acid supplementation lowered fasting glucose and insulin levels and improved insulin resistance. It shifted the gut microbial community toward a healthier structure, increased the abundance of A. muciniphila, and raised short-chain fatty acid concentrations. Fecal bile salt hydrolase and \u03b2-glucuronidase activity declined, and intestinal barrier markers improved. Lithocholic acid enhanced TGR5 expression and reduced FXR signaling in the ileum. In vitro, physiologically relevant concentrations promoted A. muciniphila growth and altered microbial bile acid metabolism. Conclusions: Lithocholic acid influences the interactions among gut microbes, bile acid pathways, and host metabolic regulation. These findings suggest that this compound may have value as a dietary component that supports metabolic health in type 2 diabetes.<\/jats:p>","DOI":"10.3390\/nu18020341","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T13:59:54Z","timestamp":1769003994000},"page":"341","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lithocholic Acid Restores Gut Microbiota and Bile Acid Homeostasis to Improve Type 2 Diabetes"],"prefix":"10.3390","volume":"18","author":[{"given":"Han","family":"Ge","sequence":"first","affiliation":[{"name":"Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"},{"name":"State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengxiao","family":"Guo","sequence":"additional","affiliation":[{"name":"Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"},{"name":"State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[{"name":"Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"},{"name":"State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lu","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7799-7425","authenticated-orcid":false,"given":"Xin","family":"Yang","sequence":"additional","affiliation":[{"name":"Section of Endocrinology, Internal Medicine, School of Medicine, Yale University, New Haven, CT 06510, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dingzuo","family":"Ge","sequence":"additional","affiliation":[{"name":"Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"},{"name":"State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liqiang","family":"Guo","sequence":"additional","affiliation":[{"name":"Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"},{"name":"State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Luo","sequence":"additional","affiliation":[{"name":"Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"},{"name":"State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guangbo","family":"Ge","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"},{"name":"State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruirui","family":"Wang","sequence":"additional","affiliation":[{"name":"Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"},{"name":"State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,21]]},"reference":[{"key":"ref_1","unstructured":"GBD 2021 Diabetes Collaborators (2023). Global, Regional, and National Burden of Diabetes from 1990 to 2021, with Projections of Prevalence to 2050: A Systematic Analysis for the Global Burden of Disease Study 2021. Lancet, 402, 203\u2013234."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"102590","DOI":"10.1016\/j.ebiom.2019.11.051","article-title":"Role of Gut Microbiota in Type 2 Diabetes Pathophysiology","volume":"51","author":"Gurung","year":"2020","journal-title":"EBioMedicine"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"101805","DOI":"10.1016\/j.molmet.2023.101805","article-title":"Effects of Metformin on the Gut Microbiota: A Systematic Review","volume":"77","author":"Petakh","year":"2023","journal-title":"Mol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.cmet.2013.01.003","article-title":"Gut Microbiota Regulates Bile Acid Metabolism by Reducing the Levels of Tauro-Beta-Muricholic Acid, a Naturally Occurring FXR Antagonist","volume":"17","author":"Sayin","year":"2013","journal-title":"Cell Metab."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Gao, R., Meng, X., Xue, Y., Mao, M., Liu, Y., Tian, X., Sui, B., Li, X., and Zhang, P. (2022). Bile Acids-Gut Microbiota Crosstalk Contributes to the Improvement of Type 2 Diabetes Mellitus. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1027212"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1172\/JCI76738","article-title":"Intestinal Farnesoid X Receptor Signaling Promotes Nonalcoholic Fatty Liver Disease","volume":"125","author":"Jiang","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.cmet.2011.11.006","article-title":"TGR5 Activation Inhibits Atherosclerosis by Reducing Macrophage Inflammation and Lipid Loading","volume":"14","author":"Pols","year":"2011","journal-title":"Cell Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2384","DOI":"10.1038\/ncomms3384","article-title":"Microbiome Remodelling Leads to Inhibition of Intestinal Farnesoid X Receptor Signalling and Decreased Obesity","volume":"4","author":"Li","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/nature04330","article-title":"Bile Acids Induce Energy Expenditure by Promoting Intracellular Thyroid Hormone Activation","volume":"439","author":"Watanabe","year":"2006","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/j.jhep.2010.12.004","article-title":"The Bile Acid Membrane Receptor TGR5 as an Emerging Target in Metabolism and Inflammation","volume":"54","author":"Pols","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"102130","DOI":"10.1016\/j.xcrm.2025.102130","article-title":"Restoration of Intestinal Secondary Bile Acid Synthesis: A Potential Approach to Improve Pancreatic \u03b2 Cell Function in Type 1 Diabetes","volume":"6","author":"Liu","year":"2025","journal-title":"Cell Rep. Med."},{"key":"ref_12","first-page":"e14456","article-title":"The Secondary Bile Acids, Ursodeoxycholic Acid and Lithocholic Acid, Protect against Intestinal Inflammation by Inhibition of Epithelial Apoptosis","volume":"8","author":"Porru","year":"2020","journal-title":"Physiol. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.2147\/DMSO.S495623","article-title":"Profile of Serum Bile Acids in Elderly Type 2 Diabetic Patients with Various Obesity Types: A Cross-Sectional Study","volume":"18","author":"Guo","year":"2025","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s12967-024-05873-6","article-title":"Gut Bacteria Prevotellaceae Related Lithocholic Acid Metabolism Promotes Colonic Inflammation","volume":"23","author":"Chen","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/s41586-024-08329-5","article-title":"Lithocholic Acid Phenocopies Anti-Ageing Effects of Calorie Restriction","volume":"643","author":"Qu","year":"2025","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Yue, B., Gao, R., Lv, C., Yu, Z., Wang, H., Geng, X., Wang, Z., and Dou, W. (2021). Berberine Improves Irinotecan-Induced Intestinal Mucositis Without Impairing the Anti-Colorectal Cancer Efficacy of Irinotecan by Inhibiting Bacterial \u03b2-Glucuronidase. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.774560"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"111320","DOI":"10.1016\/j.cclet.2025.111320","article-title":"Rationally Engineered a Universal Far-Red Fluorogenic Substrate of Bile Salt Hydrolase for Functional Imaging and Inhibitor Screening","volume":"37","author":"Chen","year":"2025","journal-title":"Chin. Chem. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"122304","DOI":"10.1016\/j.lfs.2023.122304","article-title":"Review on Chronic Metabolic Diseases Surrounding Bile Acids and Gut Microbiota: What We Have Explored so Far","volume":"336","author":"Zhu","year":"2024","journal-title":"Life Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/s41586-019-1785-z","article-title":"Bile Acid Metabolites Control TH17 and Treg Cell Differentiation","volume":"576","author":"Hang","year":"2019","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"He, Y., Shaoyong, W., Chen, Y., Li, M., Gan, Y., Sun, L., Liu, Y., Wang, Y., and Jin, M. (J. Adv. Res., 2025). The Functions of Gut Microbiota-Mediated Bile Acid Metabolism in Intestinal Immunity, J. Adv. Res., in press.","DOI":"10.1016\/j.jare.2025.05.015"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Zheng, Z., Pang, Q., Luo, X., Tao, F., Duan, J., and Cao, J. (2022). The Role of Bile Acid in Improving Glucose Tolerance of Non-Obese Diabetic Rats After Proximal Small Bowel Bypass. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.878505"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Li, J., Yang, G., Zhang, Q., Liu, Z., Jiang, X., and Xin, Y. (2023). Function of Akkermansia Muciniphila in Type 2 Diabetes and Related Diseases. Front. Microbiol., 14.","DOI":"10.3389\/fmicb.2023.1172400"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1186\/s12967-022-03631-0","article-title":"The Potential Impact of a Probiotic: Akkermansia Muciniphila in the Regulation of Blood Pressure-the Current Facts and Evidence","volume":"20","author":"Lakshmanan","year":"2022","journal-title":"J. Transl. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"115276","DOI":"10.1016\/j.biopha.2023.115276","article-title":"The Impact of Microbiota-Derived Short-Chain Fatty Acids on Macrophage Activities in Disease: Mechanisms and Therapeutic Potentials","volume":"165","author":"Duan","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/s41577-024-01014-8","article-title":"Short-Chain Fatty Acids: Linking Diet, the Microbiome and Immunity","volume":"24","author":"Mann","year":"2024","journal-title":"Nat. Rev. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1186\/s12964-023-01219-9","article-title":"Short-Chain Fatty Acids in Diseases","volume":"21","author":"Zhang","year":"2023","journal-title":"Cell Commun. Signal."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Mohammad, S., and Thiemermann, C. (2020). Role of Metabolic Endotoxemia in Systemic Inflammation and Potential Interventions. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.594150"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.metabol.2016.12.009","article-title":"Metabolic Endotoxemia and Diabetes Mellitus: A Systematic Review","volume":"68","author":"Gomes","year":"2017","journal-title":"Metabolism"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1186\/s40168-021-01101-1","article-title":"Review: Microbial Transformations of Human Bile Acids","volume":"9","author":"Guzior","year":"2021","journal-title":"Microbiome"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Gallucci, G.M., Hayes, C.M., Boyer, J.L., Barbier, O., Assis, D.N., and Ghonem, N.S. (2024). PPAR-Mediated Bile Acid Glucuronidation: Therapeutic Targets for the Treatment of Cholestatic Liver Diseases. Cells, 13.","DOI":"10.3390\/cells13151296"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e42866","DOI":"10.7554\/eLife.42866","article-title":"The Human Gut Chemical Landscape Predicts Microbe-Mediated Biotransformation of Foods and Drugs","volume":"8","author":"Guthrie","year":"2019","journal-title":"eLife"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Bourgin, M., Kriaa, A., Mkaouar, H., Mariaule, V., Jablaoui, A., Maguin, E., and Rhimi, M. (2021). Bile Salt Hydrolases: At the Crossroads of Microbiota and Human Health. Microorganisms, 9.","DOI":"10.3390\/microorganisms9061122"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1080\/19490976.2015.1127483","article-title":"Consequences of Bile Salt Biotransformations by Intestinal Bacteria","volume":"7","author":"Ridlon","year":"2016","journal-title":"Gut Microbes"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.2337\/db23-0676","article-title":"Comprehensive Clinical and Genetic Analyses of Circulating Bile Acids and Their Associations with Diabetes and Its Indices","volume":"73","author":"Choucair","year":"2024","journal-title":"Diabetes"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/s41586-022-04480-z","article-title":"Human Gut Bacteria Produce \u03a4H17-Modulating Bile Acid Metabolites","volume":"603","author":"Paik","year":"2022","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2398","DOI":"10.1016\/j.neuropharm.2012.02.002","article-title":"Neuritic Growth Impairment and Cell Death by Unconjugated Bilirubin Is Mediated by NO and Glutamate, Modulated by Microglia, and Prevented by Glycoursodeoxycholic Acid and Interleukin-10","volume":"62","author":"Silva","year":"2012","journal-title":"Neuropharmacology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1038\/s41591-018-0222-4","article-title":"Gut Microbiota and Intestinal FXR Mediate the Clinical Benefits of Metformin","volume":"24","author":"Sun","year":"2018","journal-title":"Nat. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1042\/CS20210198","article-title":"Glycoursodeoxycholic Acid Ameliorates Diet-Induced Metabolic Disorders with Inhibiting Endoplasmic Reticulum Stress","volume":"135","author":"Cheng","year":"2021","journal-title":"Clin. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Sheng, W., Ji, G., and Zhang, L. (2022). The Effect of Lithocholic Acid on the Gut-Liver Axis. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.910493"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/2\/341\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T14:11:47Z","timestamp":1769004707000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/2\/341"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,21]]},"references-count":39,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["nu18020341"],"URL":"https:\/\/doi.org\/10.3390\/nu18020341","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,21]]}}}