Modulating the gut microbiota: a multi-target mechanism of traditional Chinese medicine for type 2 diabetes management

Abstract

Type 2 diabetes mellitus (T2DM) is fundamentally linked to gut microbiota dysbiosis, a condition that triggers a cascade of pathophysiological changes including aberrant host-microbe co-metabolism, compromised intestinal barrier integrity, and chronic low-grade inflammation, which collectively drive insulin resistance. While conventional therapies have limitations, traditional Chinese medicine (TCM) presents a promising therapeutic strategy. This review comprehensively elucidates the pathophysiological link between gut dysbiosis and T2DM. It then systematically summarizes the multi-target mechanisms by which TCM exerts its therapeutic effects, including: remodeling the gut microbial ecosystem; reprogramming host-microbe co-metabolism of short-chain fatty acids (SCFAs), bile acids (BAs), and branched-chain amino acids (BCAAs); reinforcing the intestinal barrier to mitigate metabolic endotoxemia; and modulating key signaling pathways involved in inflammation and immunity, etc. Key clinical evidence is also summarized. Furthermore, the review critically evaluates the preclinical and clinical evidence supporting these mechanisms, highlighting both therapeutic potential and current challenges, such as the need for standardization. Finally, current limitations and future prospects are considered, proposing a path forward for integrating microbiota-targeted TCM therapies into the modern, evidence-based management of T2DM.

Keywords

Traditional Chinese medicine / Gut microbiota / Type 2 diabetes mellitus / Therapeutic mechanisms

Funding

This work was supported by Shandong Provincial Natural Science Foundation (No. ZR2020MH346); and the National Natural Science Foundation of China (No. 81273667).

Declaration of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

[1] The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003; 26(suppl_1):s5-s20. https://doi.org/10.2337/diacare.26.2007.S5.

[2] Gregory GA, Robinson TIG, Linklater SE, et al. Global incidence, prevalence, and mortality of type 1 diabetes in 2021 with projection to 2040: a modelling study. Lancet Diabetes Endocrinol. 2022; 10(10):741-760. https://doi.org/10.1016/S2213-8587(22)00218-2.

[3] Wang R, Tang RQ, Li B, et al. Gut microbiome, liver immunology, and liver diseases. Cell Mol Immunol. 2021; 18(1):4-17. https://doi.org/10.1038/s41423-020-00592-6.

[4] Canfora EE, Meex RCR, Venema K, et al. Gut microbial metabolites in obesity, NAFLD and T2DM. Nat Rev Endocrinol. 2019; 15(5):261-273. https://doi.org/10.1038/s41574-019-0156-z.

[5] Krishnan K, Alden N, Lee K. Pathways and functions of gut microbiota metabolism impacting host physiology. Curr Opin Biotechnol. 2015; 36:137-145. https://doi.org/10.1016/j.copbio.2015.08.015.

[6] McPhee JB, Schertzer JD. Immunometabolism of obesity and diabetes: microbiota link compartmentalized immunity in the gut to metabolic tissue inflammation. Clin Sci Lond Engl. 2015; 129(12):1083-1096. https://doi.org/10.1042/CS20150431.

[7] Liu LL, Zhang JH, Cheng Y, et al. Gut microbiota: a new target for T2DM prevention and treatment. Front Endocrinol. 2022; 13:958218. https://doi.org/10.3389/fendo.2022.958218.

[8] Zhou Z, Sun B, Yu DS, et al. Gut microbiota: an important player in type 2 diabetes mellitus. Front Cell Infect Microbiol. 2022; 12:834485. https://doi.org/10.3389/fcimb.2022.834485.

[9] Sun J, Ren JG, Hu XJ, et al. Therapeutic effects of Chinese herbal medicines and their extracts on diabetes. Biomed Pharmacother. 2021; 142:111977. https://doi.org/10.1016/j.biopha.2021.111977.

[10] Tian JX, Jin D, Bao Q, et al. Evidence and potential mechanisms of traditional Chinese medicine for the treatment of type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2019; 21(8):1801-1816. https://doi.org/10.1111/dom.13760.

[11] Tong XL, Dong L, Chen L, et al. Treatment of diabetes using traditional Chinese medicine: past, present and future. Am J Chin Med. 2012; 40(5):877-886. https://doi.org/10.1142/S0192415X12500656.

[12] Pan LL, Li ZZ, Wang YF, et al. Network pharmacology and metabolomics study on the intervention of traditional Chinese medicine Huanglian Decoction in rats with type 2 diabetes mellitus. J Ethnopharmacol. 2020; 258:112842. https://doi.org/10.1016/j.jep.2020.112842.

[13] Yang J, Miao X, Yang FJ, et al. Therapeutic potential of curcumin in diabetic retinopathy (review). Int J Mol Med. 2021; 47(5):75. https://doi.org/10.3892/ijmm.2021.4908.

[14] Ng CYJ, Zhong LD, Ng HS, et al. Managing type 2 diabetes mellitus via the regulation of gut microbiota: a Chinese medicine perspective. Nutrients. 2024; 16(22):3935. https://doi.org/10.3390/nu16223935.

[15] He QL, Wang HC, Ma YK, et al. Changes in the microbiota and their roles in patients with type 2 diabetes mellitus. Curr Microbiol. 2023; 80(4):132. https://doi.org/10.1007/s00284-023-03219-x.

[16] Zhang S, Zhang YJ, Li J, et al. Butyrate and propionate are negatively correlated with obesity and glucose levels in patients with type 2 diabetes and obesity. Diabetes Metab Syndr Obes. 2024; 17:1533-1541. https://doi.org/10.2147/DMSO.S434499.

[17] Tolhurst G, Heffron H, Lam YS, et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes. 2012; 61(2):364-371. https://doi.org/10.2337/db11-1019.

[18] Zhao LP, Zhang F, Ding XY, et al. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science. 2018; 359(6380):1151-1156. https://doi.org/10.1126/science.aao5774.

[19] Kumar KK, Aburawi EH, Ljubisavljevic M, et al. Exploring histone deacetylases in type 2 diabetes mellitus: pathophysiological insights and therapeutic avenues. Clin Epigenetics. 2024; 16(1):78. https://doi.org/10.1186/s13148-024-01692-0.

[20] Khan S, Jena GB. Protective role of sodium butyrate, a HDAC inhibitor on beta-cell proliferation, function and glucose homeostasis through modulation of p38/ERK MAPK and apoptotic pathways:study in juvenile diabetic rat. Chem Biol Interact. 2014; 213:1-12. https://doi.org/10.1016/j.cbi.2014.02.001.

[21] Pedersen SS, Ingerslev LR, Olsen M, et al. Butyrate functions as a histone deacetylase inhibitor to protect pancreatic beta cells from IL-1β-induced dysfunction. FEBS J. 2024; 291(3):566-583. https://doi.org/10.1111/febs.17005.

[22] Sonthalia M, Roy BS, Chandrawanshi D, et al. Histone deacetylase inhibitors as antidiabetic agents: advances and opportunities. Eur J Pharmacol. 2022; 935:175328. https://doi.org/10.1016/j.ejphar.2022.175328.

[23] Pingitore A, Chambers ES, Hill T, et al. The diet-derived short chain fatty acid propionate improves beta-cell function in humans and stimulates insulin secretion from human islets in vitro. Diabetes Obes Metab. 2017; 19(2):257-265. https://doi.org/10.1111/dom.12811.

[24] Kondo T, Kishi M, Fushimi T, et al. Acetic acid upregulates the expression of genes for fatty acid oxidation enzymes in liver to suppress body fat accumulation. J Agric Food Chem. 2009; 57(13):5982-5986. https://doi.org/10.1021/jf900470c.

[25] Pedersen HK, Gudmundsdottir V, Nielsen HB, et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature. 2016; 535(7612):376-381. https://doi.org/10.1038/nature18646.

[26] Nie CX, He T, Zhang WJ, et al. Branched chain amino acids: beyond nutrition metabolism. Int J Mol Sci. 2018; 19(4):954. https://doi.org/10.3390/ijms19040954.

[27] Zheng Y, Li YP, Qi QB, et al. Cumulative consumption of branched-chain amino acids and incidence of type 2 diabetes. Int J Epidemiol. 2016; 45(5):1482-1492. https://doi.org/10.1093/ije/dyw143.

[28] Lynch CJ, Adams SH. Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol. 2014; 10(12):723-736. https://doi.org/10.1038/nrendo.2014.171.

[29] Gojda J, Cahova M. Gut microbiota as the link between elevated BCAA serum levels and insulin resistance. Biomolecules. 2021; 11(10):1414. https://doi.org/10.3390/biom11101414.

[30] Vanweert F, Schrauwen P, Phielix E. Role of branched-chain amino acid metabolism in the pathogenesis of obesity and type 2 diabetes-related metabolic disturbances BCAA metabolism in type 2 diabetes. Nutr Diabetes. 2022; 12:35. https://doi.org/10.1038/s41387-022-00213-3.

[31] Hou YS, Zhai XZ, Wang XT, et al. Research progress on the relationship between bile acid metabolism and type 2 diabetes mellitus. Diabetol Metab Syndr. 2023; 15:235. https://doi.org/10.1186/s13098-023-01207-6.

[32] Shapiro H, Kolodziejczyk AA, Halstuch D, et al. Bile acids in glucose metabolism in health and disease. J Exp Med. 2018; 215(2):383-396. https://doi.org/10.1084/jem.20171965.

[33] Kong XC, Yang CX, Li BF, et al. FXR/Menin-mediated epigenetic regulation of E2F3 expression controls β-cell proliferation and is increased in islets from diabetic GK rats after RYGB. Biochim Biophys Acta Mol Basis Dis. 2024; 1870(5):167136. https://doi.org/10.1016/j.bbadis.2024.167136.

[34] Kong XC, Li BF, Deng YS, et al. FXR mediates adenylyl cyclase 8 expression in pancreatic β-cells. J Diabetes Res. 2019; 2019:8915818. https://doi.org/10.1155/2019/8915818.

[35] Zheng XJ, Chen TL, Jiang RQ, et al. Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism. Cell Metab. 2021; 33(4):791-803.e7. https://doi.org/10.1016/j.cmet.2020.11.017.

[36] Katsuma S, Hirasawa A, Tsujimoto G. Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem Biophys Res Commun. 2005; 329(1):386-390. https://doi.org/10.1016/j.bbrc.2005.01.139.

[37] Maghsoodi N, Shaw N, Cross GF, et al. Bile acid metabolism is altered in those with insulin resistance after gestational diabetes mellitus. Clin Biochem. 2019; 64:12-17. https://doi.org/10.1016/j.clinbiochem.2018.11.016.

[38] Zhang F, Yuan WZ, Wei YH, et al. The alterations of bile acids in rats with high-fat diet/streptozotocin-induced type 2 diabetes and their negative effects on glucose metabolism. Life Sci. 2019; 229:80-92. https://doi.org/10.1016/j.lfs.2019.05.031.

[39] Sayin SI, Wahlstrom A, Felin J, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 2013; 17(2):225-235. https://doi.org/10.1016/j.cmet.2013.01.003.

[40] Tian Y, Gui W, Koo I, et al. The microbiome modulating activity of bile acids. Gut Microbes. 2020; 11(4):979-996. https://doi.org/10.1080/19490976.2020.1732268.

[41] Yoshida N, Emoto T, Yamashita T, et al. Bacteroides vulgatus and bacteroides dorei reduce gut microbial lipopolysaccharide production and inhibit atherosclerosis. Circulation. 2018; 138(22):2486-2498. https://doi.org/10.1161/CIRCULATIONAHA.118.033714.

[42] Plovier H, Everard A, Druart C, et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med. 2017; 23(1):107-113. https://doi.org/10.1038/nm.4236.

[43] Chelakkot C, Choi Y, Kim DK, et al. Akkermansia muciniphila-derived extracellular vesicles influence gut permeability through the regulation of tight junctions. Exp Mol Med. 2018; 50(2):e450. https://doi.org/10.1038/emm.2017.282.

[44] Patterson AM, Mulder IE, Travis AJ, et al. Human gut symbiont Roseburia hominis promotes and regulates innate immunity. Front Immunol. 2017; 8:1166. https://doi.org/10.3389/fimmu.2017.01166.

[45] Liu PY, Wang YB, Yang G, et al. The role of short-chain fatty acids in intestinal barrier function, inflammation, oxidative stress, and colonic carcinogenesis. Pharmacol Res. 2021; 165:105420. https://doi.org/10.1016/j.phrs.2021.105420.

[46] Chen KY, Gao ZZ, Ding QY, et al. Effect of natural polyphenols in Chinese herbal medicine on obesity and diabetes: interactions among gut microbiota, metabolism, and immunity. Front Nutr. 2022; 9:962720. https://doi.org/10.3389/fnut.2022.962720.

[47] Hotamisligil GS, Peraldi P, Budavari A, et al. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α- and obesity-induced insulin resistance. Science. 1996; 271(5249):665-670. https://doi.org/10.1126/science.271.5249.665.

[48] Rui LY, Aguirre V, Kim JK, et al. Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser 307 via distinct pathways. J Clin Invest. 2001; 107(2):181-189. https://doi.org/10.1172/JCI10934.

[49] Chaurasia B, Talbot CL, Summers SA. Adipocyte ceramides—the nexus of inflammation and metabolic disease. Front Immunol. 2020; 11:576347. https://doi.org/10.3389/fimmu.2020.576347.

[50] Zhang HH, Halbleib M, Ahmad F, et al. Tumor necrosis factor-alpha stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP. Diabetes. 2002; 51(10):2929-2935. https://doi.org/10.2337/diabetes.51.10.2929.

[51] Ye J. Regulation of PPARgamma function by TNF-alpha. Biochem Biophys Res Commun. 2008; 374(3):405-408. https://doi.org/10.1016/j.bbrc.2008.07.068.

[52] Rehman K, Akash MSH, Liaqat A, et al. Role of interleukin-6 in development of insulin resistance and type 2 diabetes mellitus. Crit Rev Eukaryot Gene Expr. 2017; 27(3):229-236. https://doi.org/10.1615/CritRevEukaryotGeneExpr.2017019712.

[53] Rohm TV, Meier DT, Olefsky JM, et al. Inflammation in obesity, diabetes and related disorders. Immunity. 2022; 55(1):31-55. https://doi.org/10.1016/j.immuni.2021.12.013.

[54] Kim KA, Gu W, Lee IA, et al. High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One. 2012; 7(10):e47713. https://doi.org/10.1371/journal.pone.0047713.

[55] Tsuruta M, Iwashita M, Shinjo T, et al. Metabolic endotoxemia-activated macrophages promote pancreatic β cell death via IFNβ-Xaf1 pathway. Horm Metab Res. 2018; 50(2):160-167. https://doi.org/10.1055/s-0043-121467.

[56] Segain JP, Raingeard de La BD, Bourreille A, et al. Butyrate inhibits inflammatory responses through NFκB inhibition: implications for Crohn’s disease. Gut. 2000; 47(3):397-403. https://doi.org/10.1136/gut.47.3.397.

[57] Lee C, Kim BG, Kim JH, et al. Sodium butyrate inhibits the NF-kappa B signaling pathway and histone deacetylation, and attenuates experimental colitis in an IL-10 independent manner. Int Immunopharmacol. 2017; 51:47-56. https://doi.org/10.1016/j.intimp.2017.07.023.

[58] Zhang SW, Gang XK, Yang S, et al. The alterations in and the role of the Th17/Treg balance in metabolic diseases. Front Immunol. 2021; 12:678355. https://doi.org/10.3389/fimmu.2021.678355.

[59] Tangvarasittichai S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes. 2015; 6(3):456-480. https://doi.org/10.4239/wjd.v6.i3.456.

[60] Murphy B, Bhattacharya R, Mukherjee P. Hydrogen sulfide signaling in mitochondria and disease. FASEB J. 2019; 33(12):13098-13125. https://doi.org/10.1096/fj.201901304R.

[61] Ma LL, Zhang L, Li J, et al. The potential mechanism of gut microbiota-microbial metabolites-mitochondrial axis in progression of diabetic kidney disease. Mol Med. 2023; 29:148. https://doi.org/10.1186/s10020-023-00745-z.

[62] Longo S, Rizza S, Federici M. Microbiota-gut-brain axis: relationships among the vagus nerve, gut microbiota, obesity, and diabetes. Acta Diabetol. 2023; 60(8):1007-1017. https://doi.org/10.1007/s00592-023-02088-x.

[63] Gribble FM, Reimann F. Enteroendocrine cells: chemosensors in the intestinal epithelium. Annu Rev Physiol. 2016; 78(1):277-299. https://doi.org/10.1146/annurev-physiol-021115-105439.

[64] Krieger JP, Arnold M, Pettersen KG, et al. Knockdown of GLP-1 receptors in vagal afferents affects normal food intake and glycemia. Diabetes. 2016; 65(1):34-43. https://doi.org/10.2337/db15-0973.

[65] Zhang Q, Delessa CT, Augustin R, et al. The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling. Cell Metab. 2021; 33(4):833-844.e5. https://doi.org/10.1016/j.cmet.2021.01.015.

[66] Cheung GWC, Kokorovic A, Lam CKL, et al. Intestinal cholecystokinin controls glucose production through a neuronal network. Cell Metab. 2009; 10(2):99-109. https://doi.org/10.1016/j.cmet.2009.07.005.

[67] Karra E, Chandarana K, Batterham RL. The role of peptide YY in appetite regulation and obesity. J Physiol. 2009; 587(1):19-25. https://doi.org/10.1113/jphysiol.2008.164269.

[68] Wachsmuth HR, Weninger SN, Duca FA. Role of the gut-brain axis in energy and glucose metabolism. Exp Mol Med. 2022; 54:377-392. https://doi.org/10.1038/s12276-021-00677-w.

[69] Zhang ML, Zhou CY, Li XG, et al. Interactions between gut microbiota, host circadian rhythms, and metabolic diseases. Adv Nutr. 2025; 16(6):100416. https://doi.org/10.1016/j.advnut.2025.100416.

[70] Reitmeier S, Kiessling S, Clavel T, et al. Arrhythmic gut microbiome signatures predict risk of type 2 diabetes. Cell Host Microbe. 2020; 28(2):258-272.e6. https://doi.org/10.1016/j.chom.2020.06.004.

[71] Leone V, Gibbons SM, Martinez K, et al. Effects of diurnal variation of gut microbes and high-fat feeding on host circadian clock function and metabolism. Cell Host Microbe. 2015; 17(5):681-689. https://doi.org/10.1016/j.chom.2015.03.006.

[72] Zhao E, Tait C, Minacapelli CD, et al. Circadian rhythms, the gut microbiome, and metabolic disorders. Gastro Hep Adv. 2022; 1(1):93-105. https://doi.org/10.1016/j.gastha.2021.10.008.

[73] Heddes M, Altaha B, Niu YH, et al. The intestinal clock drives the microbiome to maintain gastrointestinal homeostasis. Nat Commun. 2022; 13(1):6068. https://doi.org/10.1038/s41467-022-33609-x.

[74] Fawad JA, Luzader DH, Hanson GF, et al. Histone deacetylase inhibition by gut microbe-generated short-chain fatty acids entrains intestinal epithelial circadian rhythms. Gastroenterology. 2022; 163(5):1377-1390.e11. https://doi.org/10.1053/j.gastro.2022.07.051.

[75] Govindarajan K, MacSharry J, Casey PG, et al. Unconjugated bile acids influence expression of circadian genes: a potential mechanism for microbe-host crosstalk. PLoS One. 2016; 11(12):e0167319. https://doi.org/10.1371/journal.pone.0167319.

[76] Tang WHW, Hazen SL. Microbiome, trimethylamine N-oxide (TMAO), and cardiometabolic disease. Transl Res. 2017; 179:45-56. https://doi.org/10.1016/j.trsl.2016.07.007.

[77] Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011; 472(7341):57-63. https://doi.org/10.1038/nature09922.

[78] Geng J, Yang CC, Wang BJ, et al. Trimethylamine N-oxide promotes atherosclerosis via CD36-dependent MAPK/JNK pathway. Biomed Pharmacother. 2018; 97:941-947. https://doi.org/10.1016/j.biopha.2017.11.016.

[79] Mohammadi A, Najar AG, Yaghoobi MM, et al. Trimethylamine-N-oxide treatment induces changes in the ATP-binding cassette transporter A1 and scavenger receptor A1 in murine macrophage J774A.1 cells. Inflammation. 2016; 39(1):393-404. https://doi.org/10.1007/s10753-015-0261-7.

[80] Janeiro MH, Ramírez MJ, Milagro FI, et al. Implication of trimethylamine N-oxide (TMAO) in disease: potential biomarker or new therapeutic target. Nutrients. 2018; 10(10):1398. https://doi.org/10.3390/nu10101398.

[81] Ahmad F, Boulaftali Y, Greene TK, et al. Relative contribution of STIM1 and CalDAG-GEFI to calcium-dependent platelet activation and thrombosis. J Thromb Haemost. 2011; 9(10):2077-2086. https://doi.org/10.1111/j.1538-7836.2011.04474.x.

[82] Zhu W, Gregory JC, Org E, et al.Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell. 2016; 165(1):111-124. https://doi.org/10.1016/j.cell.2016.02.011.

[83] Münzer P, Borst O. CRACking the molecular regulatory mechanism of SOCE during platelet activation in thrombo-occlusive diseases. Cells. 2022; 11(4):619. https://doi.org/10.3390/cells11040619.

[84] Chen ML, Zhu XH, Ran L, et al. Trimethylamine-N-oxide induces vascular inflammation by activating the NLRP3 inflammasome through the SIRT3-SOD2-mtROS signaling pathway. J Am Heart Assoc. 2017; 6(9):e006347. https://doi.org/10.1161/JAHA.117.006347.

[85] Lei DY, Yu WB, Liu Y, et al. Trimethylamine N-oxide (TMAO) inducing endothelial injury: UPLC-MS/MS-based quantification and the activation of cathepsin B-mediated NLRP 3 inflammasome. Molecules. 2023; 28(9):3817. https://doi.org/10.3390/molecules28093817.

[86] Penna C, Pagliaro P. Endothelial dysfunction: redox imbalance, NLRP3 inflammasome, and inflammatory responses in cardiovascular diseases. Antioxidants. 2025; 14(3):256. https://doi.org/10.3390/antiox14030256.

[87] Ding L, Chang MR, Guo Y, et al. Trimethylamine-N-oxide (TMAO)-induced atherosclerosis is associated with bile acid metabolism. Lipids Health Dis. 2018; 17:286. https://doi.org/10.1186/s12944-018-0939-6.

[88] Pathak P, Helsley RN, Brown AL, et al. Small molecule inhibition of gut microbial choline trimethylamine lyase activity alters host cholesterol and bile acid metabolism. Am J Physiol Heart Circ Physiol. 2020; 318(6):H1474-H1486. https://doi.org/10.1152/ajpheart.00584.2019.

[89] Bartolomaeus H, Balogh A, Yakoub M, et al. Short-chain fatty acid propionate protects from hypertensive cardiovascular damage. Circulation. 2019; 139(11):1407-1421. https://doi.org/10.1161/CIRCULATIONAHA.118.036652.

[90] Muralitharan RR, Zheng TH, Dinakis E, et al. Gut microbiota metabolites sensed by host GPR41/43 protect against hypertension. Circ Res. 2025; 136(4):e20-e33. https://doi.org/10.1161/CIRCRESAHA.124.325770.

[91] Mehta NN, McGillicuddy FC, Anderson PD, et al. Experimental endotoxemia induces adipose inflammation and insulin resistance in humans. Diabetes. 2010; 59(1):172-181. https://doi.org/10.2337/db09-0367.

[92] Kim F, Pham M, Luttrell I, et al. Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ Res. 2007; 100(11):1589-1596. https://doi.org/10.1161/CIRCRESAHA.106.142851.

[93] Lu ZY, Li YC, Brinson CW, et al. Cooperative stimulation of atherogenesis by lipopolysaccharide and palmitic acid-rich high fat diet in low-density lipoprotein receptor-deficient mice. Atherosclerosis. 2017; 265:231-241. https://doi.org/10.1016/j.atherosclerosis.2017.09.008.

[94] Nemet I, Saha PP, Gupta N, et al. A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell. 2020; 180(5):862-877.e22. https://doi.org/10.1016/j.cell.2020.02.016.

[95] Krishnamoorthy NK, Kalyan M, Hediyal TA, et al. Role of the gut bacteria-derived metabolite phenylacetylglutamine in health and diseases. ACS Omega. 2024; 9(3):3164-3172. https://doi.org/10.1021/acsomega.3c08184.

[96] Zhang GD, Liu XX, Liang JL, et al. The distribution pattern of traditional Chinese medicine syndromes in 549 patients with type 2 diabetes. Diabetes Metab Syndr Obes. 2021; 14:2209-2216. https://doi.org/10.2147/DMSO.S295351.

[97] Wang JK, Ma QT, Li YQ, et al. Research progress on traditional Chinese medicine syndromes of diabetes mellitus. Biomed Pharmacother. 2020; 121:109565. https://doi.org/10.1016/j.biopha.2019.109565.

[98] Dou ZL, Xia Y, Zhang JW, et al. Syndrome differentiation and treatment regularity in traditional Chinese medicine for type 2 diabetes: a text mining analysis. Front Endocrinol (Lausanne). 2021; 12:728032. https://doi.org/10.3389/fendo.2021.728032.

[99] Meng XL, Liu XQ, Tan JY, et al. From Xiaoke to diabetes mellitus: a review of the research progress in traditional Chinese medicine for diabetes mellitus treatment. Chin Med. 2023; 18:75. https://doi.org/10.1186/s13020-023-00783-z.

[100] Lian FM, Ni Q, Shen YD, et al. International traditional Chinese medicine guideline for diagnostic and treatment principles of diabetes. Ann Palliat Med. 2020; 9(4):2237-2250. https://doi.org/10.21037/apm-19-271.

[101] Chen Y, Li Q, Zhao SW, et al. Berberine protects mice against type 2 diabetes by promoting PPARγ-FGF21-GLUT2-regulated insulin sensitivity and glucose/lipid homeostasis. Biochem Pharmacol. 2023; 218:115928. https://doi.org/10.1016/j.bcp.2023.115928.

[102] Yang WL, Zhang CY, Ji WY, et al. Berberine metabolites stimulate GLP-1 secretion by alleviating oxidative stress and mitochondrial dysfunction. Am J Chin Med. 2024; 52(1):253-274. https://doi.org/10.1142/S0192415X24500113.

[103] Liu SY, Wang LY, Zhang ZH, et al. The potential of Astragalus polysaccharide for treating diabetes and its action mechanism. Front Pharmacol. 2024; 15:1339406. https://doi.org/10.3389/fphar.2024.1339406.

[104] Yuan HS, Xu GQ, Liu JR, et al. Astragalus mongholicus polysaccharides alleviate insulin resistance through modulation of PI3K/AKT, TLR4/NF-κB signaling pathway and microbiota in rats with type 2 diabetes mellitus. J Tradit Complement Med. 2025; 15(3):274-285. https://doi.org/10.1016/j.jtcme.2024.05.007.

[105] Shao JW, Jiang JL, Zou JJ, et al. Therapeutic potential of ginsenosides on diabetes: from hypoglycemic mechanism to clinical trials. J Funct Foods. 2020; 64:103630. https://doi.org/10.1016/j.jff.2019.103630.

[106] Silva ML, Bernardo MA, Singh J, et al. Cinnamon as a complementary therapeutic approach for dysglycemia and dyslipidemia control in type 2 diabetes mellitus and its molecular mechanism of action: a review. Nutrients. 2022; 14(13):2773. https://doi.org/10.3390/nu14132773.

[107] Liu SW, Yu JC, Fu MF, et al. Regulatory effects of hawthorn polyphenols on hyperglycemic, inflammatory, insulin resistance responses, and alleviation of aortic injury in type 2 diabetic rats. Food Res Int. 2021; 142:110239. https://doi.org/10.1016/j.foodres.2021.110239.

[108] Chen SK, Xi MM, Gao F, et al. Evaluation of mulberry leaves’ hypoglycemic properties and hypoglycemic mechanisms. Front Pharmacol. 2023; 14:1045309. https://doi.org/10.3389/fphar.2023.1045309.

[109] Li JS, Ji T, Su SL, et al. Mulberry leaves ameliorate diabetes via regulating metabolic profiling and AGEs/RAGE and p38 MAPK/NF-κB pathway. J Ethnopharmacol. 2022; 283:114713. https://doi.org/10.1016/j.jep.2021.114713.

[110] Liu H, Cui B, Zhang Z. Mechanism of glycometabolism regulation by bioactive compounds from the fruits of Lycium barbarum: a review. Food Res Int. 2022; 159:111408. https://doi.org/10.1016/j.foodres.2022.111408.

[111] Bhattamisra SK, Koh HM, Lim SY, et al. Molecular and biochemical pathways of catalpol in alleviating diabetes mellitus and its complications. Biomolecules. 2021; 11(2):323. https://doi.org/10.3390/biom11020323.

[112] Yan JT, Wang CY, Jin Y, et al. Catalpol ameliorates hepatic insulin resistance in type 2 diabetes through acting on AMPK/NOX4/PI3K/AKT pathway. Pharmacol Res. 2018; 130:466-480. https://doi.org/10.1016/j.phrs.2017.12.026.

[113] Wang ZJ, Du H, Peng WQ, et al. Efficacy and mechanism of Pueraria lobata and Pueraria thomsonii polysaccharides in the treatment of type 2 diabetes. Nutrients. 2022; 14(19):3926. https://doi.org/10.3390/nu14193926.

[114] Zou JJ, Song QB, Shaw PC, et al. Dendrobium officinale regulate lipid metabolism in diabetic mouse liver via PPAR-RXR signaling pathway: evidence from an integrated multi-omics analysis. Biomed Pharmacother. 2024; 173:116395. https://doi.org/10.1016/j.biopha.2024.116395.

[115] Zhao JD, Li Y, Sun M, et al. Effect of berberine on hyperglycaemia and gut microbiota composition in type 2 diabetic Goto-Kakizaki rats. World J Gastroenterol. 2021; 27(8):708-724. https://doi.org/10.3748/wjg.v27.i8.708.

[116] Zhang W, Xu JH, Yu T, et al. Effects of berberine and metformin on intestinal inflammation and gut microbiome composition in db/db mice. Biomed Pharmacother. 2019; 118:109131. https://doi.org/10.1016/j.biopha.2019.109131.

[117] Song QB, Cheng SW, Li D, et al. Gut microbiota mediated hypoglycemic effect of Astragalus membranaceus polysaccharides in db/db mice. Front Pharmacol. 2022; 13:1043527. https://doi.org/10.3389/fphar.2022.1043527.

[118] Ke M, Shen Z, Ma N, et al. Astragalus polysaccharides alleviates lipopolysaccharides-induced inflammatory lung injury by altering intestinal microbiota in mice. Front Microbiol. 2022; 13:1033875. https://doi.org/10.3389/fmicb.2022.1033875.

[119] Zhang X, Jia LN, Ma Q, et al. Astragalus polysaccharide modulates the gut microbiota and metabolites of patients with type 2 diabetes in an in vitro fermentation model. Nutrients. 2024; 16(11):1698. https://doi.org/10.3390/nu16111698.

[120] Gong P, Long H, Yang Q, et al. Astragaloside IV alleviates diabetic nephropathy by modulating the gut-kidney axis and AMPK/PI3K/AKT pathway. Food Biosci. 2024; 62:105448. https://doi.org/10.1016/j.fbio.2024.105448.

[121] Gong P, Xiao XY, Wang S, et al. Hypoglycemic effect of astragaloside IV via modulating gut microbiota and regulating AMPK/SIRT1 and PI3K/AKT pathway. J Ethnopharmacol. 2021; 281:114558. https://doi.org/10.1016/j.jep.2021.114558.

[122] Yue SJ, Liu J, Wang AT, et al. Berberine alleviates insulin resistance by reducing peripheral branched-chain amino acids. Am J Physiol Endocrinol Metab. 2019; 316(1):E73-E85. https://doi.org/10.1152/ajpendo.00256.2018.

[123] Chen HH, Nie QX, Hu JL, et al. Multiomics approach to explore the amelioration mechanisms of glucomannans on the metabolic disorder of type 2 diabetic rats. J Agric Food Chem. 2021; 69(8):2632-2645. https://doi.org/10.1021/acs.jafc.0c07871.

[124] Liu J, Wu S, Cheng Y, et al. Sargassum fusiforme alginate relieves hyperglycemia and modulates intestinal microbiota and metabolites in type 2 diabetic mice. Nutrients. 2021; 13(8):2887. https://doi.org/10.3390/nu13082887.

[125] Zhao LJ, Ma P, Peng Y, et al. Amelioration of hyperglycaemia and hyperlipidaemia by adjusting the interplay between gut microbiota and bile acid metabolism: Radix Scutellariae as a case. Phytomedicine. 2021; 83:153477. https://doi.org/10.1016/j.phymed.2021.153477.

[126] Yan XM, Zhang YL, Peng Y, et al. The water extract of Radix Scutellariae, its total flavonoids and baicalin inhibited CYP7A1 expression, improved bile acid, and glycolipid metabolism in T2DM mice. J Ethnopharmacol. 2022; 293:115238. https://doi.org/10.1016/j.jep.2022.115238.

[127] Liu R, Wang JH, Zhao YK, et al. Study on the mechanism of modified Gegen Qinlian Decoction in regulating the intestinal flora-bile acid-TGR5 axis for the treatment of type 2 diabetes mellitus based on macro genome sequencing and targeted metabonomics integration. Phytomedicine. 2024; 132:155329. https://doi.org/10.1016/j.phymed.2023.155329.

[128] Tawulie D, Jin LL, Shang X, et al. Jiang-Tang-San-Huang Pill alleviates type 2 diabetes mellitus through modulating the gut microbiota and bile acids metabolism. Phytomedicine. 2023; 113:154733. https://doi.org/10.1016/j.phymed.2023.154733.

[129] Chen M, Gao MJ, Wang H, et al. Jingangteng Capsules ameliorate liver lipid disorders in diabetic rats by regulating microflora imbalances, metabolic disorders, and farnesoid X receptor. Phytomedicine. 2024; 132:155806. https://doi.org/10.1016/j.phymed.2024.155806.

[130] Tao Q, Zhang JH, Liang Q, et al. Puerarin alleviates sleep disorders in aged mice related to repairing intestinal mucosal barrier. Nat Prod Bioprospect. 2023; 13:29. https://doi.org/10.1007/s13659-023-00390-3.

[131] Kim MR, Cho SY, Lee HJ, et al. Schisandrin C improves leaky gut conditions in intestinal cell monolayer, organoid, and nematode models by increasing tight junction protein expression. Phytomedicine. 2022; 103:154209. https://doi.org/10.1016/j.phymed.2022.154209.

[132] Wang CX, Su J, Tian YJ, et al. The rhizomes of Atractylodes macrocephala Koidz improve gastrointestinal health and pregnancy outcomes in pregnant mice via modulating intestinal barrier and water-fluid metabolism. J Ethnopharmacol. 2024; 326:117971. https://doi.org/10.1016/j.jep.2024.117971.

[133] Guo CY, Li QJ, Chen RH, et al. Baicalein alleviates non-alcoholic fatty liver disease in mice by ameliorating intestinal barrier dysfunction. Food Funct. 2023; 14(4):2138-2148. https://doi.org/10.1039/D2FO03015B.

[134] Yin S, Sun C, Ji Y, et al. Herbal medicine WangShiBaoChiWan improves gastrointestinal health in mice via modulation of intestinal tight junctions and gut microbiota and inhibition of inflammation. Biomed Pharmacother. 2021; 138:111426. https://doi.org/10.1016/j.biopha.2021.111426.

[135] Lan T, Tang T, Li Y, et al. FTZ polysaccharides ameliorate kidney injury in diabetic mice by regulating gut-kidney axis. Phytomedicine. 2023; 118:154935. https://doi.org/10.1016/j.phymed.2023.154935.

[136] Zhang YL, Xu YN, Zhang L, et al. Licorice extract ameliorates hyperglycemia through reshaping gut microbiota structure and inhibiting TLR4/NF-κB signaling pathway in type 2 diabetic mice. Food Res Int. 2022; 153:110945. https://doi.org/10.1016/j.foodres.2022.110945.

[137] Chen XX, Wu JL, Fu X, et al. Fructus Mori polysaccharide alleviates diabetic symptoms by regulating intestinal microbiota and intestinal barrier against TLR4/NF-κB pathway. Int J Biol Macromol. 2023; 249:126038. https://doi.org/10.1016/j.ijbiomac.2023.126038.

[138] Chen XX, Chen C, Fu X. Dendrobium officinale polysaccharide alleviates type 2 diabetes mellitus by restoring gut microbiota and repairing intestinal barrier via the LPS/TLR4/TRIF/NF-κB axis. J Agric Food Chem. 2023; 71(31):11929-11940. https://doi.org/10.1021/acs.jafc.3c02429.

[139] Zhao HJ, Li M, Liu L, et al. Cordyceps militaris polysaccharide alleviates diabetic symptoms by regulating gut microbiota against TLR4/NF-κB pathway. Int J Biol Macromol. 2023; 230:123241. https://doi.org/10.1016/j.ijbiomac.2023.123241.

[140] Yao B, Pan BC, Tian T, et al. Baihu Renshen Decoction ameliorates type 2 diabetes mellitus in rats through affecting gut microbiota enhancing gut permeability and inhibiting TLR4/NF-κB-mediated inflammatory response. Front Cell Infect Microbiol. 2022; 12:1051962. https://doi.org/10.3389/fcimb.2022.1051962.

[141] Zhong YB, Xiao QP, Huang JQ, et al. Ginsenoside Rg1 alleviates ulcerative colitis in obese mice by regulating the gut microbiota-lipid metabolism-Th1/Th2/Th17 cells axis. J Agric Food Chem. 2023; 71(50):20073-20091. https://doi.org/10.1021/acs.jafc.3c04811.

[142] Liu G, Wang J, Liu J, et al. Total glucosides of paeony alleviates Sjogren’s syndrome by inhibiting Th1 and Th 17 responses. Phytomedicine. 2025; 139:156525. https://doi.org/10.1016/j.phymed.2025.156525.

[143] Cheng BB, Hu ZQ, Li B, et al. Beneficial effects of hawthorn extract on metabolic hypertensive rats by regulating Treg/Th 17 immune balance. J Funct Foods. 2023; 108:105750. https://doi.org/10.1016/j.jff.2023.105750.

[144] Li N, Han XY, Ruan M, et al. Prebiotic inulin controls Th17 cells mediated central nervous system autoimmunity through modulating the gut microbiota and short chain fatty acids. Gut Microbes. 2024; 16(1):2402547. https://doi.org/10.1080/19490976.2024.2402547.

[145] Dong YJ, Zhang YP, Jiang XF, et al. Beneficial effects of Dendrobium officinale National Herbal Drink on metabolic immune crosstalk via regulate SCFAs-Th17/Treg. Phytomedicine. 2024; 132:155816. https://doi.org/10.1016/j.phymed.2024.155816.

[146] Ding XQ, Chen Y, Du LL, et al. Benefits of inulin and fructo-oligosaccharides on high fat diet-induced type 2 diabetes mellitus by regulating the gut microbiota in mice. J Nutr Biochem. 2025; 141:109908. https://doi.org/10.1016/j.jnutbio.2025.109908.

[147] Xu GQ, Yuan HS, Liu JR, et al. Astragalus mongholicus polysaccharides alleviate kidney injury in rats with type 2 diabetes through modulation of oxidation, inflammation, and gut microbiota. Int J Mol Sci. 2025; 26(4):1470. https://doi.org/10.3390/ijms26041470.

[148] Chen C, You LJ, Huang Q, et al. Modulation of gut microbiota by mulberry fruit polysaccharide treatment of obese diabetic db/db mice. Food Funct. 2018; 9(7):3732-3742. https://doi.org/10.1039/C7FO01346A.

[149] Liu XJ, Yang KM, Jia YB, et al. Chaihushugan Powder regulates the gut microbiota to alleviate mitochondrial oxidative stress in the gastric tissues of rats with functional dyspepsia. Front Immunol. 2025; 16:1549554. https://doi.org/10.3389/fimmu.2025.1549554.

[150] Li XL, Zhao TT, Gu JL, et al. Intake of flavonoids from Astragalus membranaceus ameliorated brain impairment in diabetic mice via modulating brain-gut axis. Chin Med. 2022; 17(1):22. https://doi.org/10.1186/s13020-022-00578-8.

[151] Li JR, Zhang H, Ouyang H, et al. Pueraria Thomsonii Radix water extract alleviate type 2 diabetes mellitus in db/db mice through comprehensive regulation of metabolism and gut microbiota. Molecules. 2023; 28(22):7471. https://doi.org/10.3390/molecules28227471.

[152] Chen SM, Zeng FS, Fu WW, et al. White hyacinth bean polysaccharide ameliorates diabetes via microbiota-gut-brain axis in type 2 diabetes mellitus rats. Int J Biol Macromol. 2023; 253(Pt 6):127307. https://doi.org/10.1016/j.ijbiomac.2024.136489.

[153] Qi YZ, Li J, Tang Y, et al. Total alkaloids of Rhizoma Corydalis regulates gut microbiota and restores gut immune barrier to ameliorate cognitive dysfunction in diabetic rats. Front Microbiol. 2024; 15:1456406. https://doi.org/10.3389/fmicb.2024.1456406.

[154] Bai Y, Zhao Y, Jin JL, et al. Jiang Tang San Hao Formula exerts its anti-diabetic effect by affecting the gut-microbiota-brain axis. Phytomedicine. 2024; 135:156100. https://doi.org/10.1016/j.phymed.2024.156100.

[155] Zhao R, Gao X, Zhang T, et al. Effects of Lycium barbarum polysaccharide on type 2 diabetes mellitus rats by regulating biological rhythms. Iran J Basic Med Sci. 2016; 19(9):1024-1030. https://doi.org/10.22038/ijbms.2016.7604.

[156] Dong YJ, Jiang NH, Zhan LH, et al. Soporific effect of modified Suanzaoren Decoction on mice models of insomnia by regulating orexin-A and HPA axis homeostasis. Biomed Pharmacother. 2021; 143:112141. https://doi.org/10.1016/j.biopha.2021.112141.

[157] Mao JQ, Cheng L, Zhang YD, et al. Chinese formula Guben-Jiannao Ye alleviates the dysfunction of circadian and sleep rhythms in APP/PS1 mice implicated in activation of the PI3K/AKT/mTOR signaling pathway. J Ethnopharmacol. 2024; 335:118696. https://doi.org/10.1016/j.jep.2024.118696.

[158] Ma SR, Tong Q, Lin Y, et al. Berberine treats atherosclerosis via a vitamine-like effect down-regulating choline-TMA-TMAO production pathway in gut microbiota. Signal Transduct Target Ther. 2022; 7:207. https://doi.org/10.1038/s41392-022-01027-6.

[159] Panyod S, Wu WK, Peng SY, et al. Ginger essential oil and citral ameliorates atherosclerosis in ApoE^-/- mice by modulating trimethylamine-N-oxide and gut microbiota. NPJ Sci Food. 2023; 7:19. https://doi.org/10.1038/s41538-023-00196-0.

[160] Panyod S, Wu WK, Chen PC, et al. Atherosclerosis amelioration by allicin in raw garlic through gut microbiota and trimethylamine-N-oxide modulation. NPJ Biofilms Microbiomes. 2022; 8:4. https://doi.org/10.1038/s41522-022-00266-3.

[161] Wang XF, Sun XJ, Abulizi A, et al. Effects of salvianolic acid A on intestinal microbiota and lipid metabolism disorders in Zucker diabetic fatty rats. Diabetol Metab Syndr. 2022; 14:135. https://doi.org/10.1186/s13098-022-00868-z.

[162] Wang AL, Guan BY, Shao C, et al. Qing-Xin-Jie-Yu Granule alleviates atherosclerosis by reshaping gut microbiota and metabolic homeostasis of ApoE^-/- mice. Phytomedicine. 2022; 103:154220. https://doi.org/10.1016/j.phymed.2022.154220.

[163] Zheng JP, Chen M, Ye C, et al. BuZangTongLuo Decoction improved hindlimb ischemia by activating angiogenesis and regulating gut microbiota in diabetic mice. J Ethnopharmacol. 2020; 248:112330. https://doi.org/10.1016/j.jep.2019.112330.

[164] Zheng YJ, Ding QY, Wei Y, et al. Effect of traditional Chinese medicine on gut microbiota in adults with type 2 diabetes: a systematic review and meta-analysis. Phytomedicine. 2021; 88:153455. https://doi.org/10.1016/j.phymed.2020.153455.

[165] Xu YX, Zheng SY, Jiang S, et al. The effect of Chinese herbal formulas combined with metformin on modulating the gut microbiota in the amelioration of type 2 diabetes mellitus: a systematic review and meta-analysis. Front Endocrinol (Lausanne). 2022; 13:927959. https://doi.org/10.3389/fendo.2022.927959.

[166] Ming J, Yu XW, Xu XQ, et al. Effectiveness and safety of Bifidobacterium and berberine in human hyperglycemia and their regulatory effect on the gut microbiota: a multi-center, double-blind, randomized, parallel-controlled study. Genome Med. 2021; 13(1):125. https://doi.org/10.1186/s13073-021-00942-7.

[167] Gao ZZ, Zhang WH, He LS, et al. Double-blinded, randomized clinical trial of Gegen Qinlian Decoction pinpoints Faecalibacterium as key gut bacteria in alleviating hyperglycemia. Precis Clin Med. 2024; 7(1):pbae003. https://doi.org/10.1093/pcmedi/pbae003.

[168] Xu J, Lian FM, Zhao LH, et al. Structural modulation of gut microbiota during alleviation of type 2 diabetes with a Chinese herbal formula. ISME J. 2015; 9(3):552-562. https://doi.org/10.1038/ismej.2014.177.

[169] Peng XJ, Chen SS, Zhong L, et al. Cyclocarya paliurus leaves extracts alleviate metabolic phenotypes in Chinese T2DM patients by modulating gut microbiota and metabolites: a clinical randomized controlled trial. Front Endocrinol (Lausanne). 2023; 14:1176256. https://doi.org/10.3389/fendo.2023.1176256.

[170] Ma KL, Zhou LJ, Zhang YJ, et al. Efficacy and safety of traditional Chinese medicines combined with conventional Western medicines in the treatment of type 2 diabetes mellitus: a network meta-analysis of randomized controlled trials. Front Endocrinol (Lausanne). 2023; 14:1134297. https://doi.org/10.3389/fendo.2023.1134297.