Metabolic insights into gut microbiota in the pharmacology of natural medicines

Abstract

Natural medicines (NMs) demonstrate distinct advantages in the clinical management of chronic diseases. Recent years have seen growing recognition of the gut microbiota’s role in the efficacy and synergy of NMs, providing new impetus for elucidating the material basis and mechanisms of NMs and their path toward modernization. A fundamental question that has emerged is how NM-microbiota interactions integrate into the multi-target holistic mechanisms of NMs, the answer to which may also illuminate new avenues for drug discovery. Metabolic regulation via small-molecule metabolites has been increasingly implicated in host-microbe interaction. This review presents an integral metabolic perspective on NMs-microbiota interaction in host health and disease. It highlights the emerging understanding of gut microbiota-related metabolic signals implicated in NM components’ local and systemic actions. Additionally, it discusses key issues and prospects related to drug development and the translational study of NMs.

Keywords

Natural medicines / Gut microbiota / Metabolic signals / Pharmacokinetics / Drug discovery

References

[1] Newman DJ, Cragg GM.Natural products as sources of new drugs over the nearly four decades from 01/ 1981 to 09/2019. J Nat Prod. 2020; 83(3):770-803. https://doi.org/10.1021/acs.jnatprod.9b01285.

[2] Luo Z, Yin F, Wang X, et al. Progress in approved drugs from natural product resources. Chin J Nat Med. 2024; 22(3):195-211. https://doi.org/10.1016/s1875-5364(24)60582-0.

[3] Chi X, Zhang H, Zhang S, et al. Chinese herbal medicine for gout: a review of the clinical evidence and pharmacological mechanisms. Chin Med. 2020;15:17. https://doi.org/10.1186/s13020-020-0297-y.

[4] Zhang S, Luo H, Tan D, et al. Holism of Chinese herbal medicine prescriptions for inflammatory bowel disease: a review based on clinical evidence and experimental research. Phytomedicine. 2022;102:154202. https://doi.org/10.1016/j.phymed.2022.154202.

[5] Chen J, Ding Z. Natural products as potential drug treatments for acute promyelocytic leukemia. Chin Med. 2024; 19(1):57. https://doi.org/10.1186/s13020-024-00928-8.

[6] Chen J, Ding Z.Advances in natural product anti-coronavirus research (2002-2022). Chin Med. 2023; 18(1):13. https://doi.org/10.1186/s13020-023-00715-x.

[7] Katz L, Baltz RH. Natural product discovery: past, present, and future. J Ind Microbiol Biotechnol. 2016; 43(2-3):155-76. https://doi.org/10.1007/s10295-015-1723-5.

[8] Zhang Y, Chen T, Hao X, et al. Mapping the regulatory effects of herbal organic compounds on gut bacteria. Pharmacol Res. 2023;193:106804. https://doi.org/10.1016/j.phrs.2023.106804.

[9] Shen J, Guo H, Jin W, et al. Aberrant branched-chain amino acid accumulation along the microbiota-gut-brain axis: crucial targets affecting the occurrence and treatment of ischaemic stroke. Br J Pharmacol. 2023; 180(3):347-368. https://doi.org/10.1111/bph.15965.

[10] Cheng P, Wu J, Zong G, et al. Capsaicin shapes gut microbiota and pre-metastatic niche to facilitate cancer metastasis to liver. Pharmacol Res. 2023;188:106643. https://doi.org/10.1016/j.phrs.2022.106643.

[11] Alexander JL, Wilson ID, Teare J, et al. Gut microbiota modulation of chemotherapy efficacy and toxicity. Nat Rev Gastroenterol Hepatol. 2017; 14(6):356-365. https://doi.org/10.1038/nrgastro.2017.20.

[12] Wang S, Ren H, Zhong H, et al. Combined berberine and probiotic treatment as an effective regimen for improving postprandial hyperlipidemia in type 2 diabetes patients: a double blinded placebo controlled randomized study. Gut Microbes. 2022; 14(1):2003176. https://doi.org/10.1080/19490976.2021.2003176.

[13] 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(1):207. https://doi.org/10.1038/s41392-022-01027-6.

[14] Zhou J, Fan Q, Cai X, et al. Ginkgo biloba extract protects against depression-like behavior in mice through regulating gut microbial bile acid metabolism. Chin J Nat Med. 2023; 21(10):745-758. https://doi.org/10.1016/s1875-5364(23)60496-0.

[15] Wang T, Wu L, Wang S, et al. Chang Wei Qing Decoction enhances the anti-tumor effect of PD-1 inhibitor therapy by regulating the immune microenvironment and gut microbiota in colorectal cancer. Chin J Nat Med. 2023; 21(5):333-345. https://doi.org/10.1016/s1875-5364(23)60451-0.

[16] Hu J, Ni J, Zheng J, et al. Tripterygium hypoglaucum extract ameliorates adjuvant-induced arthritis in mice through the gut microbiota. Chin J Nat Med. 2023; 21(10):730-744. https://doi.org/10.1016/s1875-5364(23)60466-2.

[17] Li M, Wang Y, Chen Y, et al. A comprehensive review on pharmacokinetic mechanism of herb-herb/drug interactions in Chinese herbal formula. Pharmacol Ther. 2024;264:108728. https://doi.org/10.1016/j.pharmthera.2024.108728.

[18] Perry RJ, Peng L, Barry NA, et al. Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome. Nature. 2016; 534(7606):213-7. https://doi.org/10.1038/nature18309.

[19] Board PG, Anders MW.Moonlighting in drug metabolism. Drug Metab Rev. 2021; 53(1):76-99. https://doi.org/10.1080/03602532.2020.1858857.

[20] Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, et al. Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature. 2019; 570(7762):462-467. https://doi.org/10.1038/s41586-019-1291-3.

[21] Javdan B, Lopez JG, Chankhamjon P, et al. Personalized mapping of drug metabolism by the human gut microbiome. Cell.. 2020; 181(7):1661-1679.e22. https://doi.org/10.1016/j.cell.2020.05.001.

[22] Zhang H, Xu HL, et al. 20(S)-Protopanaxadiol-induced apoptosis in MCF-7 breast cancer cell line through the inhibition of PI3K/AKT/mTOR signaling pathway. Int J Mol Sci. 2018; 19(4):1053. https://doi.org/10.3390/ijms19041053.

[23] Zhang Z, Zhang Y, Li J, et al. The neuroprotective effect of tea polyphenols on the regulation of intestinal flora. Molecules. 2021; 26(12):3692. https://doi.org/10.3390/molecules26123692.

[24] Chen Z, Zhang Z, Liu J, et al. Gut microbiota: therapeutic targets of ginseng against multiple disorders and ginsenoside transformation. Front Cell Infect Microbiol. 2022;12:853981. https://doi.org/10.3389/fcimb.2022.853981.

[25] Wang Y, Wu J, Yu H, et al. Ginsenosides retard atherogenesis via remodelling host-microbiome metabolic homeostasis. Br J Pharmacol. 2024; 181(12):1768-1792. https://doi.org/10.1111/bph.16320.

[26] Zhang ZW, Han P, Fu J, et al. Gut microbiota-based metabolites of Xiaoyao Pills (a typical traditional Chinese medicine) ameliorate depression by inhibiting fatty acid amide hydrolase levels in brain. J Ethnopharmacol. 2023;313:116555. https://doi.org/10.1016/j.jep.2023.116555.

[27] Wen HY, Pan LB, Ma SR, et al. Structural basis for the transformation of the traditional medicine berberine by bacterial nitroreductase. Acta Crystallogr D Struct Biol. 2022; 78(Pt 10):1273-1282. https://doi.org/10.1107/s2059798322008373.

[28] Koppel N, Bisanz JE, Pandelia ME, et al. Discovery and characterization of a prevalent human gut bacterial enzyme sufficient for the inactivation of a family of plant toxins. Elife. 2018;7:e33953. https://doi.org/10.7554/eLife.33953.

[29] Zeng SL, Li SZ, Xiao PT, et al. Citrus polymethoxyflavones attenuate metabolic syndrome by regulating gut microbiome and amino acid metabolism. Sci Adv. 2020; 6(1):eaax6208. https://doi.org/10.1126/sciadv.aax6208.

[30] Irrazábal T, Belcheva A, Girardin SE, et al. The multifaceted role of the intestinal microbiota in colon cancer. Mol Cell. 2014; 54(2):309-320. https://doi.org/10.1016/j.molcel.2014.03.039.

[31] Wei J, Zheng Z, Hou X, et al. Echinacoside inhibits colorectal cancer metastasis via modulating the gut microbiota and suppressing the PI3K/AKT signaling pathway. J Ethnopharmacol. 2024;318(Pt A):116866. https://doi.org/10.1016/j.jep.2023.116866.

[32] Gou H, Su H, Liu D, et al. Traditional medicine Pien Tze Huang suppresses colorectal tumorigenesis through restoring gut microbiota and metabolites. Gastroenterology. 2023; 165(6):1404-1419. https://doi.org/10.1053/j.gastro.2023.08.052.

[33] Ford AC, Sperber AD, Corsetti M, et al.Irritable bowel syndrome. Lancet. 2020; 396(10263):1675-1688. https://doi.org/10.1016/s0140-6736(20)31548-8.

[34] Zhang MM, Dang M, Wu X, et al. Da-Jian-Zhong Decoction alleviates diarrhea-predominant irritable bowel syndrome via modulation of gut microbiota and Th17/Treg balance. J Ethnopharmacol. 2024;331:118275. https://doi.org/10.1016/j.jep.2024.118275.

[35] Dai H, Han J, Wang T, et al. Recent advances in gut microbiota-associated natural products: structures, bioactivities, and mechanisms. Nat Prod Rep. 2023; 40(6):1078-1093. https://doi.org/10.1039/d2np00075j.

[36] Li SZ, Zhang NN, Yang X, et al. Nobiletin ameliorates nonalcoholic fatty liver disease by regulating gut microbiota and myristoleic acid metabolism. J Agric Food Chem. 2023; 71(19):7312-7323. https://doi.org/10.1021/acs.jafc.2c08637.

[37] Jensen SN, Cady NM, Shahi SK, et al. Isoflavone diet ameliorates experimental autoimmune encephalomyelitis through modulation of gut bacteria depleted in patients with multiple sclerosis. Sci Adv. 2021; 7(28):eabd4595. https://doi.org/10.1126/sciadv.abd4595.

[38] Han ND, Cheng J, Delannoy-Bruno O, et al. Microbial liberation of N-methylserotonin from orange fiber in gnotobiotic mice and humans. Cell. 2022; 185(14):2495-2509.e11. https://doi.org/10.1016/j.cell.2022.06.004.

[39] Jia B, Han X, Kim KH, et al. Discovery and mining of enzymes from the human gut microbiome. Trends Biotechnol. 2022; 40(2):240-254. https://doi.org/10.1016/j.tibtech.2021.06.008.

[40] Zheng X, Cai X, Hao HP. Emerging targetome and signalome landscape of gut microbial metabolites. Cell Metab. 2022; 34(1):35-58. https://doi.org/10.1016/j.cmet.2021.12.011.

[41] Schoeler M, Caesar R. Dietary lipids, gut microbiota and lipid metabolism. Rev Endocr Metab Disord. 2019; 20(4):461-472. https://doi.org/10.1007/s11154-019-09512-0.

[42] Zhang JD, Liu J, Zhu SW, et al. Berberine alleviates visceral hypersensitivity in rats by altering gut microbiome and suppressing spinal microglial activation. Acta Pharmacol Sin. 2021; 42(11):1821-1833. https://doi.org/10.1038/s41401-020-00601-4.

[43] Yue M, Tao Y, Fang Y, et al. The gut microbiota modulator berberine ameliorates collagen-induced arthritis in rats by facilitating the generation of butyrate and adjusting the intestinal hypoxia and nitrate supply. FASEB J. 2019; 33(11):12311-12323 https://doi.org/10.1096/fj.201900425RR.

[44] Li Y, Peng Y, Yang H, et al. Antidepressant-like effects of Cistanche tubulosa extract on chronic unpredictable stress rats through restoration of gut microbiota homeostasis. Front Pharmacol. 2018;9:967. https://doi.org/10.3389/fphar.2018.00967.

[45] Schlegel N, Boerner K, Waschke J. Targeting desmosomal adhesion and signalling for intestinal barrier stabilization in inflammatory bowel diseases-lessons from experimental models and patients. Acta Physiol (Oxf). 2021; 231(1):e13492. https://doi.org/10.1111/apha.13492.

[46] Jiang ZM, Zeng SL, Huang TQ, et al. Sinomenine ameliorates rheumatoid arthritis by modulating tryptophan metabolism and activating aryl hydrocarbon receptor via gut microbiota regulation. Sci Bull. 2023; 68(14):1540-1555. https://doi.org/10.1016/j.scib.2023.06.027.

[47] Wang X, Sun G, Feng T, et al. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res. 2019; 29(10):787-803. https://doi.org/10.1038/s41422-019-0216-x.

[48] Cheng L, Wu H, Cai X, et al. A Gpr35-tuned gut microbe-brain metabolic axis regulates depressive-like behavior. Cell Host Microbe. 2024; 32(2):227-243.e6. https://doi.org/10.1016/j.chom.2023.12.009.

[49] Liu H, Hu C, Zhang X, et al. Role of gut microbiota, bile acids and their cross-talk in the effects of bariatric surgery on obesity and type 2 diabetes. J Diabetes Investig. 2018; 9(1):13-20. https://doi.org/10.1111/jdi.12687.

[50] Zhang YL, Li ZJ, Gou HZ, et al. The gut microbiota-bile acid axis: a potential therapeutic target for liver fibrosis. Front Cell Infect Microbiol. 2022;12:945368. https://doi.org/10.3389/fcimb.2022.945368.

[51] Zhang L, Shi J, Shen Q, et al. Astragalus saponins protect against extrahepatic and intrahepatic cholestatic liver fibrosis models by activation of farnesoid X receptor. J Ethnopharmacol. 2024;318(Pt A): 116833. https://doi.org/10.1016/j.jep.2023.116833.

[52] Bourgin M, Kriaa A, Mkaouar H, et al. Bile salt hydrolases: at the crossroads of microbiota and human health. Microorganisms. 2021; 9(6):1122. https://doi.org/10.3390/microorganisms9061122.

[53] Zhai Y, Zhou W, Yan X, et al. Astragaloside IV ameliorates diet-induced hepatic steatosis in obese mice by inhibiting intestinal FXR via intestinal flora remodeling. Phytomedicine. 2022;107:154444. https://doi.org/10.1016/j.phymed.2022.154444.

[54] Qiao S, Bao L, Wang K, et al. Activation of a specific gut bacteroides-folate-liver axis benefits for the alleviation of nonalcoholic hepatic steatosis. Cell Rep. 2020; 32(6):108005. https://doi.org/10.1016/j.celrep.2020.108005.

[55] Li HY, Huang SY, Zhou DD, et al. Theabrownin inhibits obesity and non-alcoholic fatty liver disease in mice via serotonin-related signaling pathways and gut-liver axis. J Adv Res. 2023; 52:59-72. https://doi.org/10.1016/j.jare.2023.01.008.

[56] Chi L, Khan I, Lin Z, et al. Fructo-oligosaccharides from Morinda officinalis remodeled gut microbiota and alleviated depression features in a stress rat model. Phytomedicine. 2020;67:153157. https://doi.org/10.1016/j.phymed.2019.153157.

[57] Quan LH, Zhang C, Dong M, et al. Myristoleic acid produced by enterococci reduces obesity through brown adipose tissue activation. Gut. 2020; 69(7):1239-1247. https://doi.org/10.1136/gutjnl-2019-319114.

[58] Yang F, Zhu W, Sun S, et al. Isolation and structural characterization of specific bacterial β-glucuronidase inhibitors from Noni (Morinda citrifolia) fruits. J Nat Prod. 2020; 83(4):825-833. https://doi.org/10.1021/acs.jnatprod.9b00279.

[59] Ning L, Hong J. Gut microbial β-glucuronidase: a key regulator of endobiotic homeostasis. Cell Host Microbe. 2024; 32(6):783-785. https://doi.org/10.1016/j.chom.2024.05.007.

[60] Wang K, Zhang Z, Hang J, et al. Microbial-host-isozyme analyses reveal microbial DPP4 as a potential antidiabetic target. Science. 2023; 381(6657):eadd5787. https://doi.org/10.1126/science.add5787.

[61] Li M, Li H. Microbial-host-isozyme: a new territory for understanding personalized responses towards drug therapy. Chin J Nat Med. 2023; 21(8):561-562. https://doi.org/10.1016/S1875-5364(23)60493-5.

[62] Liu L, Wu Q, Chen Y, et al. Gut microbiota in chronic pain: novel insights into mechanisms and promising therapeutic strategies. Int Immunopharmacol. 2023;115:109685. https://doi.org/10.1016/j.intimp.2023.109685.

[63] Aa LX, Fei F, Qi Q, et al. Rebalancing of the gut flora and microbial metabolism is responsible for the anti-arthritis effect of kaempferol. Acta Pharmacol Sin. 2020; 41(1):73-81. https://doi.org/10.1038/s41401-019-0279-8.

[64] Zhang Y, Geng J, Hong Y, et al. Orally administered crocin protects against cerebral ischemia/reperfusion injury through the metabolic transformation of crocetin by gut microbiota. Front Pharmacol. 2019;10:440. https://doi.org/10.3389/fphar.2019.00440.

[65] Fan L, Xia Y, Wang Y, et al. Gut microbiota bridges dietary nutrients and host immunity. Sci China Life Sci. 2023; 66(11):2466-2514. https://doi.org/10.1007/s11427-023-2346-1.

[66] Fadlallah J, Sterlin D, Fieschi C, et al. Synergistic convergence of microbiota-specific systemic IgG and secretory IgA. J Allergy Clin Immunol. 2019; 143(4):1575-1585.e4. https://doi.org/10.1016/j.jaci.2018.09.036.

[67] Sun MF, Shen YQ. Dysbiosis of gut microbiota and microbial metabolites in Parkinson’s Disease. Ageing Res Rev. 2018; 45:53-61. https://doi.org/10.1016/j.arr.2018.04.004.

[68] Hao H, Zheng X, Wang G, et al. Insights into drug discovery from natural medicines using reverse pharmacokinetics. Trends Pharmacol Sci. 2014; 35(4):168-177. https://doi.org/10.1016/j.tips.2014.02.001.

[69] Belkaid Y, Harrison OJ.Homeostatic immunity and the microbiota. Immunity. 2017; 46(4):562-576. https://doi.org/10.1016/j.immuni.2017.04.008.

[70] Gao J, Xu K, Liu H, et al. Impact of the gut microbiota on intestinal immunity mediated by tryptophan metabolism. Front Cell Infect Microbiol. 2018;8:13. https://doi.org/10.3389/fcimb.2018.00013.

[71] Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol. 2021; 19(1):55-71. https://doi.org/10.1038/s41579-020-0433-9.

[72] Shandilya S, Kumar S, Jha NK, et al. Interplay of gut microbiota and oxidative stress: perspective on neurodegeneration and neuroprotection. J Adv Res. 2022; 38:223-244. https://doi.org/10.1016/j.jare.2021.09.005.

[73] Liu Y, Li H, Wang X, et al. Anti-Alzheimers molecular mechanism of icariin: insights from gut microbiota, metabolomics, and network pharmacology. J Transl Med. 2023; 21(1):277. https://doi.org/10.1186/s12967-023-04137-z.

[74] Hu H, Yao Y, Liu F, et al. Integrated microbiome and metabolomics revealed the protective effect of baicalin on alveolar bone inflammatory resorption in aging. Phytomedicine. 2024;124:155233. https://doi.org/10.1016/j.phymed.2023.155233.

[75] Han S, Treuren WV, Fischer CR, et al. A metabolomics pipeline for the mechanistic interrogation of the gut microbiome. Nature. 2021; 595(7867):415-420. https://doi.org/10.1038/s41586-021-03707-9.

[76] Zhang X, Wang H, Xie C, et al. Shenqi compound ameliorates type-2 diabetes mellitus by modulating the gut microbiota and metabolites. J Chromatogr B Analyt Technol Biomed Life Sci. 2022;1194:123189. https://doi.org/10.1016/j.jchromb.2022.123189.

[77] Zhang B, Luo X, Han C, et al. Terminalia bellirica ethanol extract ameliorates nonalcoholic fatty liver disease in mice by amending the intestinal microbiota and faecal metabolites. J Ethnopharmacol. 2023;305:116082. https://doi.org/10.1016/j.jep.2022.116082.

[78] Zhao W, Xiao M, Yang J, et al. The combination of ilexhainanoside D and ilexsaponin A1 reduces liver inflammation and improves intestinal barrier function in mice with high-fat diet-induced non-alcoholic fatty liver disease. Phytomedicine. 2019;63:153039. https://doi.org/10.1016/j.phymed.2019.153039.

[79] Chen Y, Zhu L, Hu W, et al. Simiao Wan modulates the gut microbiota and bile acid metabolism during improving type 2 diabetes mellitus in mice. Phytomedicine. 2022;104:154264. https://doi.org/10.1016/j.phymed.2022.154264.

[80] Luo Z, Xu W, Yuan T, et al. Platycodon grandiflorus root extract activates hepatic PI3K/PIP3/Akt insulin signaling by enriching gut Akkermansia muciniphila in high fat diet fed mice. Phytomedicine. 2023;109:154595. https://doi.org/10.1016/j.phymed.2022.154595.

[81] Meng Q, Guo J, Lv K, et al. 5S-Heudelotinone alleviates experimental colitis by shaping the immune system and enhancing the intestinal barrier in a gut microbiota-dependent manner. Acta Pharm Sin B. 2024; 14(5):2153-2176. https://doi.org/10.1016/j.apsb.2024.02.020.

[82] Rekdal VM, Bess EN, Bisanz JE, et al. Discovery and inhibition of an interspecies gut bacterial pathway for levodopa metabolism. Science. 2019; 364(6445):eaau6323. https://doi.org/10.1126/science.aau6323.

[83] Wang Y, Tong Q, Ma SR, et al. Oral berberine improves brain dopa/dopamine levels to ameliorate Parkinson’s disease by regulating gut microbiota. Signal Transduct Target Ther. 2021; 6(1):77. https://doi.org/10.1038/s41392-020-00456-5.

[84] Cheng L, Wu H, Chen Z, et al. Gut microbiome at the crossroad of genetic variants and behavior disorders. Gut Microbes. 2023; 15(1):2201156. https://doi.org/10.1080/19490976.2023.2201156.

[85] Yan Q, Li S, Yan Q, et al. A genomic compendium of cultivated human gut fungi characterizes the gut mycobiome and its relevance to common diseases. Cell.. 2024; 187(12):2969-2989.e24. https://doi.org/10.1016/j.cell.2024.04.043.

[86] Soehnlein O, Libby P. Targeting inflammation in atherosclerosis-from experimental insights to the clinic. Nat Rev Drug Discov. 2021; 20(8):589-610. https://doi.org/10.1038/s41573-021-00198-1.

[87] Zhang Z, Geng J, Tang X, et al. Spatial heterogeneity and co-occurrence patterns of human mucosal-associated intestinal microbiota. ISME J. 2014; 8(4):881-893. https://doi.org/10.1038/ismej.2013.185.

[88] Su Q, Tun HM, Liu Q, et al. Gut microbiome signatures reflect different subtypes of irritable bowel syndrome. Gut Microbes. 2023; 15(1):2157697. https://doi.org/10.1080/19490976.2022.2157697.

[89] Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001; 69(3):89-95. https://doi.org/10.1067/mcp.2001.113989.

[90] Lin TL, Lu CC, Lai WF, et al. Role of gut microbiota in identification of novel TCM-derived active metabolites. Protein Cell. 2021; 12(5):394-410. https://doi.org/10.1007/s13238-020-00784-w.

[91] Jin X, Zhou J, Zhang Z, et al. The combined administration of parthenolide and ginsenoside CK in long circulation liposomes with targeted tLyp-1 ligand induce mitochondria-mediated lung cancer apoptosis. Artif Cells Nanomed Biotechnol. 2018; 46(sup3):931-942. https://doi.org/10.1080/21691401.2018.1518913.

[92] Zhou L, Zheng Y, Li Z, et al. Compound K attenuates the development of atherosclerosis in ApoE^-/- mice via LXRα activation. Int J Mol Sci. 2016; 17(7):1054. https://doi.org/10.3390/ijms17071054.

[93] Lee YS, Cha BY, Saito K, et al. Nobiletin improves hyperglycemia and insulin resistance in obese diabetic ob/ob mice. Biochem Pharmacol. 2010; 79(11):1674-1683. https://doi.org/10.1016/j.bcp.2010.01.034.

[94] Li S, Li X, Chen F, et al. Nobiletin mitigates hepatocytes death, liver inflammation, and fibrosis in a murine model of NASH through modulating hepatic oxidative stress and mitochondrial dysfunction. J Nutr Biochem. 2022;100:108888. https://doi.org/10.1016/j.jnutbio.2021.108888.

[95] Zhao ZX, Fu J, Ma SR, et al. Gut-brain axis metabolic pathway regulates antidepressant efficacy of albiflorin. Theranostics. 2018; 8(21):5945. https://doi.org/10.7150/thno.28068.

[96] He JX, Goto E, Akao T, et al. Interaction between Shaoyao-Gancao-Tang and a laxative with respect to alteration of paeoniflorin metabolism by intestinal bacteria in rats. Phytomedicine. 2007; 14(7-8):452-459. https://doi.org/10.1016/j.phymed.2006.09.014.

[97] Han DH, Lee Y, Ahn JH. Biological synthesis of baicalein derivatives using Escherichia coli. J Microbiol Biotechnol. 2016; 26(11):1918-1923. https://doi.org/10.4014/jmb.1605.05050.

[98] Agunloye OM, Oboh G, Ademiluyi AO, et al. Cardio-protective and antioxidant properties of caffeic acid and chlorogenic acid: mechanistic role of angiotensin converting enzyme, cholinesterase and arginase activities in cyclosporine induced hypertensive rats. Biomed Pharmacother. 2019; 109:450-458. https://doi.org/10.1016/j.biopha.2018.10.044.

[99] Burapan S, Kim M, Han J. Curcuminoid demethylation as an alternative metabolism by human intestinal microbiota. J Agric Food Chem. 2017; 65(16):3305-3310. https://doi.org/10.1021/acs.jafc.7b00943.

[100] Chen XQ, Lv XY, Liu SJ. Baitouweng Decoction alleviates dextran sulfate sodium-induced ulcerative colitis by regulating intestinal microbiota and the IL-6/STAT3 signaling pathway. J Ethnopharmacol. 2021;265:113357. https://doi.org/10.1016/j.jep.2020.113357.

[101] Tang S, Liu W, Zhao Q, et al. Combination of polysaccharides from Astragalus membranaceus and Codonopsis pilosula ameliorated mice colitis and underlying mechanisms. J Ethnopharmacol. 2021;264:113280. https://doi.org/10.1016/j.jep.2020.113280.

[102] Hu J, Huang H, Chen Y, et al. Qingchang Huashi Formula attenuates DSS-induced colitis in mice by restoring gut microbiota-metabolism homeostasis and goblet cell function. J Ethnopharmacol. 2021;266:113394. https://doi.org/10.1016/j.jep.2020.113394.

[103] Li L, Zhu HM, Yan Q, et al. The antibacterial activity of Berberis heteropoda Schrenk and its effect on irritable bowel syndrome in rats. Chin J Nat Med. 2020; 18(5):356-368. https://doi.org/10.1016/S1875-5364(20)30042-X.

[104] Li XM, Yuan DY, Liu YH, et al. Panax notoginseng saponins prevent colitis-associated colorectal cancer via inhibition IDO1 mediated immune regulation. Chin J Nat Med. 2022; 20(4):258-269. https://doi.org/10.1016/S1875-5364(22)60179-1.

[105] Han X, Liu J, Hang A, et al. An iridoid glycoside from Cornus officinalis balances intestinal microbiome disorder and alleviates alcohol-induced liver injury. J Funct Foods. 2021;82:104488. https://doi.org/10.1016/j.jff.2021.104488.

[106] Chang CJ, Lin CS, Lu CC, et al. Ganoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota. Nat Commun. 2015;6:7489. https://doi.org/10.1038/ncomms8489.

[107] Zong X, Zhang H, Zhu L, et al. Auricularia auricula polysaccharides attenuate obesity in mice through gut commensal Papillibacter cinnamivorans. J Adv Res. 2023; 52:203-218. https://doi.org/10.1016/j.jare.2023.08.003.

[108] Liu Q, Xie T, Xi Y, et al. Sesamol attenuates amyloid peptide accumulation and cognitive deficits in APP/PS1 mice: the mediating role of the gut-brain axis. J Agric Food Chem. 2021; 69(43):12717-12729. https://doi.org/10.1021/acs.jafc.1c04687.

[109] Chen H, Shen J, Li H, et al. Ginsenoside Rb 1 exerts neuroprotective effects through regulation of Lactobacillus helveticus abundance and GABAA receptor expression. J Ginseng Res. 2020; 44(1):86-95. https://doi.org/10.1016/j.jgr.2018.09.002.

[110] Song Y, Shan B, Zeng S, et al. Raw and wine processed Schisandra chinensis attenuate anxiety like behavior via modulating gut microbiota and lipid metabolism pathway. J Ethnopharmacol. 2021;266:113426. https://doi.org/10.1016/j.jep.2020.113426.

[111] Wang Y, Xu Y, Xu X, et al. Ginkgo biloba extract ameliorates atherosclerosis via rebalancing gut flora and microbial metabolism. Phytother Res. 2022; 36(6):2463-2480. https://doi.org/10.1002/ptr.7439.

[112] Guo LX, Wang HY, Liu XD, et al. Saponins from Clematis mandshurica Rupr. regulates gut microbiota and its metabolites during alleviation of collagen-induced arthritis in rats. Pharmacolo Res. 2019;149:104459. https://doi.org/10.1016/j.phrs.2019.104459.