Honokiol attenuates diabetes by enriching Akkermansia muciniphila andregulating tryptophan metabolism in mice

Abstract

Diabetes mellitus (DM) is a chronic disease influenced by gut microbiome disturbances. Honokiol (HON), a low oral bioavailability compound from Magnolia officinalis bark, has demonstrated potential as a treatment for DM. This research investigates the effects of HON on gut microbiota and host metabolism to elucidate its mechanism of action in DM. After 8 weeks of intervention through fecal microbiota transplantation (FMT) or antibiotic treatment, HON improved glucose tolerance and lipid metabolism in a gut microbiota-dependent manner. Specifically, HON administration significantly increased Akkermansia muciniphila (AKK) abundance and modulated tryptophan (TRP) metabolism, as evidenced by 16S ribosomal ribonucleic acid (rRNA) gene sequencing and untargeted/targeted metabolomics analysis. Notably, research revealed that AKK metabolized TRP into tryptamine (TA) and other metabolites in vitro. Both AKK and TA activated the aryl hydrocarbon receptor (AHR) pathway, increasing circulating glucagon-like peptide-1 (GLP-1) levels and ameliorating diabetes-related symptoms in DM mice. These findings indicate that HON’s hypoglycemic effect primarily stems from AHR-GLP-1 pathway activation through targeted modulation of AKK and microbial TRP metabolite TA, potentially enhancing HON’s clinical applications.

Keywords

Honokiol / Diabetes mellitus / Akkermansia muciniphila / Tryptamine / Aryl hydrocarbon receptor

References

[1] Li X, Watanabe K, Kimura I. Gut microbiota dysbiosis drives and implies novel therapeutic strategies for diabetes mellitus and related metabolic diseases. Front Immunol. 2017;8:1882. https://doi.org/10.3389/fimmu.2017.01882.

[2] Jia W, Panagiotou G. Recent advances in diabetes and microbiota. Sci Bull. 2022; 67(17):1720-1723. https://doi.org/10.1016/j.scib.2022.07.027.

[3] Zhou W, Yang T, Xu W, et al. The polysaccharides from the fruits of Lycium barbarum L. confer anti-diabetic effect by regulating gut microbiota and intestinal barrier. Carbohydr Polym. 2022;291:119626. https://doi.org/10.1016/j.carbpol.2022.119626.

[4] Amiel SA, Frier BM, Heller SR, et al. Hypoglycaemia, cardiovascular disease, and mortality in diabetes: epidemiology, pathogenesis, and management. Lancet Diabetes Endocrinol. 2019; 7(5):385-396. https://doi.org/10.1016/S2213-8587(18)30315-2.

[5] 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.

[6] Huang S, Shao L, Chen M, et al. Biotransformation differences of ginsenoside compound K mediated by the gut microbiota from diabetic patients and healthy subjects. Chin J Nat Med. 2023; 21(10):723-729. https://doi.org/10.1016/S1875-5364(23)60402-9.

[7] Crudele L, Gadaleta RM, Cariello M, et al. Gut microbiota in the pathogenesis and therapeutic approaches of diabetes. EBioMedicine. 2023;97:104821. https://doi.org/10.1016/j.ebiom.2023.104821.

[8] Zhang Y, Liu L, Wei C, et al. Vitamin K2 supplementation improves impaired glycemic homeostasis and insulin sensitivity for type 2 diabetes through gut microbiome and fecal metabolites. BMC Med. 2023; 21(1):174. https://doi.org/10.1186/s12916-023-02880-0.

[9] Vallianou NG, Stratigou T, Tsagarakis S. Microbiome and diabetes: where are we now? Diabetes Res Clin Pract. 2018; 146:111-118. https://doi.org/10.1016/j.diabres.2018.10.008.

[10] Yang X, Wang Z, Niu J, et al. Pathobionts from chemically disrupted gut microbiota induce insulin-dependent diabetes in mice. Microbiome. 2023;11:62. https://doi.org/10.1186/s40168-023-01507-z.

[11] Wu H, Esteve E, Tremaroli V, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. 2017; 23(7):850-858. https://doi.org/10.1038/nm.4345.

[12] Zhang Y, Hu J, Tan H, et al. Akkermansia muciniphila, an important link between dietary fiber and host health. Curr Opin Food Sci. 2022;47:100905. https://doi.org/10.1016/j.cofs.2022.100905.

[13] Zhang Y, Yang Y, Ding L, et al. Emerging applications of metabolomics to assess the efficacy of traditional Chinese medicines for treating type 2 diabetes mellitus. Front Pharmacol. 2021;12:735410. https://doi.org/10.3389/fphar.2021.735410.

[14] 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.

[15] Liu Z, Dai X, Zhang H, et al. Gut microbiota mediates intermittent-fasting alleviation of diabetes-induced cognitive impairment. Nat Commun. 2020; 11(1):855. https://doi.org/10.1038/s41467-020-14676-4.

[16] Giannoudaki E, Hernandez-Santana YE, Mulfaul K, et al. Interleukin-36 cytokines alter the intestinal microbiome and can protect against obesity and metabolic dysfunction. Nat Commun. 2019; 10(1):4003. https://doi.org/10.1038/s41467-019-11944-w.

[17] Bui D, Li L, Yin T, et al. Pharmacokinetic and metabolic profiling of key active components of dietary supplement Magnolia officinalis extract for prevention against oral carcinoma. J Agric Food Chem. 2020; 68(24):6576-6587. https://doi.org/10.1021/acs.jafc.0c01475.

[18] Pillai VB, Samant S, Sundaresan NR, et al.Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3. Nat Commun. 2015;6:6656. https://doi.org/10.1038/ncomms7656.

[19] Cho JH, Jeon YJ, Park SM, et al. Multifunctional effects of honokiol as an anti-inflammatory and anti-cancer drug in human oral squamous cancer cells and xenograft. Biomaterials. 2015; 53:274-284. https://doi.org/10.1016/j.biomaterials.2015.02.091.

[20] Sun J, Wang Y, Fu X, et al. Magnolia officinalis extract contains potent inhibitors against PTP1B and attenuates hyperglycemia in db/db mice. Biomed Res Int. 2015;2015:139451. https://doi.org/10.1155/2015/139451.

[21] Kerr M, Miller JJ, Thapa D, et al. Rescue of myocardial energetic dysfunction in diabetes through the correction of mitochondrial hyperacetylation by honokiol. JCI Insight. 2020; 5(17):e140326. https://doi.org/10.1172/jci.insight.140326.

[22] Li CG, Ni CL, Yang M, et al. Honokiol protects pancreatic beta cell against high glucose and intermittent hypoxia-induced injury by activating Nrf2/ARE pathway in vitro and in vivo. Biomed Pharmacother. 2018; 97:1229-1237. https://doi.org/10.1016/j.biopha.2017.11.063.

[23] Yang J, Shang J, Yang L, et al. Nanotechnology-based drug delivery systems for honokiol: enhancing therapeutic potential and overcoming limitations. Int J Nanomed. 2023; 18:6639-6665. https://doi.org/10.2147/IJN.S431409.

[24] Peng D, Tian W, An M, et al. Characterization of antidiabetic effects of Dendrobium officinale derivatives in a mouse model of type 2 diabetes mellitus. Food Chem. 2023;399:133974. https://doi.org/10.1016/j.foodchem.2022.133974.

[25] Hosomi K, Saito M, Park J, et al. Oral administration of Blautia wexlerae ameliorates obesity and type 2 diabetes via metabolic remodeling of the gut microbiota. Nat Commun. 2022; 13(1):4477. https://doi.org/10.1038/s41467-022-32015-7.

[26] Lin Y, Wang ZY, Wang MJ, et al. Baicalin attenuate diet-induced metabolic syndrome by improving abnormal metabolism and gut microbiota. Eur J Pharmacol. 2022;925:174996. https://doi.org/10.1016/j.ejphar.2022.174996.

[27] 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.

[28] Huang TQ, Chen YX, Zeng SL, et al. Bergenin alleviates ulcerative colitis by decreasing gut commensal Bacteroides vulgatus-mediated elevated branched-chain amino acids. J Agric Food Chem. 2024; 72(7):3606-3621. https://doi.org/10.1021/acs.jafc.3c09448.

[29] Jiang L, Hong Y, Xiao P, et al. The role of fecal microbiota in liver toxicity induced by perfluorooctane sulfonate in male and female mice. Environ Health Perspect. 2022; 130(6):67009. https://doi.org/10.1289/EHP10281.

[30] Gao B, Chi L, Tu P, et al. The carbamate aldicarb altered the gut microbiome, metabolome, and lipidome of C57BL/6J mice. Chem Res Toxicol. 2019; 32(1):67-79. https://doi.org/10.1021/acs.chemrestox.8b00179.

[31] Wang J, Zhou L, Lei H, et al. Simultaneous quantification of amino metabolites in multiple metabolic pathways using ultra-high performance liquid chromatography with tandem-mass spectrometry. Sci Rep. 2017;7:1423. https://doi.org/10.1038/s41598-017-01435-7.

[32] Fang Z, Pan T, Li L, et al. Bifidobacterium longum mediated tryptophan metabolism to improve atopic dermatitis via the gut-skin axis. Gut Microbes. 2022; 14(1):2044723. https://doi.org/10.1080/19490976.2022.2044723.

[33] Yin J, Song Y, Hu Y, et al. Dose-dependent beneficial effects of tryptophan and its derived metabolites on Akkermansia in vitro: a preliminary prospective study. Microorganisms. 2021; 9(7):1511. https://doi.org/10.3390/microorganisms9071511.

[34] Dopkins N, Becker W, Miranda K, et al. Tryptamine attenuates experimental multiple sclerosis through activation of Aryl hydrocarbon receptor. Front Pharmacol. 2021;11:619265. https://doi.org/10.3389/fphar.2020.619265.

[35] Zhuang P, Li H, Jia W, et al. Eicosapentaenoic and docosahexaenoic acids attenuate hyperglycemia through the microbiome-gut-organs axis in db/db mice. Microbiome. 2021;9:185. https://doi.org/10.1186/s40168-021-01126-6.

[36] Trabelsi MS, Daoudi M, Prawitt J, et al. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nat Commun. 2015;6:7629. https://doi.org/10.1038/ncomms8629.

[37] Zhang Y, Huang S, Li P, et al.Pancreatic cancer-derived exosomes suppress the production of GIP and GLP-1 from STC-1 cells in vitro by down-regulating the PCSK1/3. Cancer Lett. 2018; 431:190-200. https://doi.org/10.1016/j.canlet.2018.05.027.

[38] Liu J, Zhang D, Yang Z, et al. Wheat alkylresorcinols modulate glucose homeostasis through improving GLP-1 secretion in high-fat-diet-induced obese mice. J Agric Food Chem. 2023; 71(43):16125-16136. https://doi.org/10.1021/acs.jafc.3c04664.

[39] Everard A, Belzer C, Geurts L, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013; 110(22):9066-9071. https://doi.org/10.1073/pnas.1219451110.

[40] Dong C, Yu J, Yang Y, et al. Berberine, a potential prebiotic to indirectly promote Akkermansia growth through stimulating gut mucin secretion. Biomed Pharmacother. 2021;139:111595. https://doi.org/10.1016/j.biopha.2021.111595.

[41] Liu MJ, Yang JY, Yan ZH, et al. Recent findings in Akkermansia muciniphila-regulated metabolism and its role in intestinal diseases. Clin Nutr. 2022; 41(10):2333-2344. https://doi.org/10.1016/j.clnu.2022.08.029.

[42] Gu Z, Pei W, Shen Y, et al. Akkermansia muciniphila and its outer protein Amuc_1100 regulates tryptophan metabolism in colitis. Food Funct. 2021; 12(20):10184-10195. https://doi.org/10.1039/D1FO02172A.

[43] Rao Y, Kuang Z, Li C, et al. Gut Akkermansia muciniphila ameliorates metabolic dysfunction-associated fatty liver disease by regulating the metabolism of L-aspartate via gut-liver axis. Gut Microbes. 2021; 13(1):1-19. https://doi.org/10.1080/19490976.2021.1927633.

[44] Agus A, Planchais J, Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe. 2018; 23(6):716-724. https://doi.org/10.1016/j.chom.2018.05.003.

[45] Wrzosek L, Ciocan D, Hugot C, et al. Microbiota tryptophan metabolism induces aryl hydrocarbon receptor activation and improves alcohol-induced liver injury. Gut. 2021; 70(7):1299-1308. https://doi.org/10.1136/gutjnl-2020-321565.

[46] Yoon HS, Cho CH, Yun MS, et al. Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice. Nat Microbiol. 2021; 6(5):563-573. https://doi.org/10.1038/s41564-021-00880-5.

[47] Natividad JM, Agus A, Planchais J, et al. Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome. Cell Metab. 2018; 28(5):737-49.e4. https://doi.org/10.1016/j.cmet.2018.07.001.

[48] Chen M, Hou P, Zhou M, et al. Resveratrol attenuates high-fat diet-induced non-alcoholic steatohepatitis by maintaining gut barrier integrity and inhibiting gut inflammation through regulation of the endocannabinoid system. Clin Nutr. 2020; 39(4):1264-1275. https://doi.org/10.1016/j.clnu.2019.05.020.

[49] Li S, You J, Wang Z, et al. Curcumin alleviates high-fat diet-induced hepatic steatosis and obesity in association with modulation of gut microbiota in mice. Food Res Int. 2021;143:110270. https://doi.org/10.1016/j.foodres.2021.110270.

[50] Zhao L, Zhang F, Ding X, 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.

[51] Chen B, Bai Y, Tong F, et al. Glycoursodeoxycholic acid regulates bile acids level and alters gut microbiota and glycolipid metabolism to attenuate diabetes. Gut Microbes. 2023; 15(1):2192155. https://doi.org/10.1080/19490976.2023.2192155.

[52] Wang X, Yang Z, Xu X, et al. Odd-numbered agaro-oligosaccharides alleviate type 2 diabetes mellitus and related colonic microbiota dysbiosis in mice. Carbohydr Polym. 2020;240:116261. https://doi.org/10.1016/j.carbpol.2020.116261.

[53] Wu TR, Lin CS, Chang CJ, et al. Gut commensal Parabacteroides goldsteinii plays a predominant role in the anti-obesity effects of polysaccharides isolated from Hirsutella sinensis. Gut. 2019; 68(2):248-262. https://doi.org/10.1136/gutjnl-2017-315458.

[54] Gao X, Yue C, Tian R, et al. The regulatory effects of specific polyphenols on Akkermansia are dependent on uridine. Food Chem. 2023;410:135367. https://doi.org/10.1016/j.foodchem.2022.135367.

[55] Han JX, Tao ZH, Wang JL, et al. Microbiota-derived tryptophan catabolites mediate the chemopreventive effects of statins on colorectal cancer. Nat Microbiol. 2023; 8(5):919-933. https://doi.org/10.1038/s41564-023-01363-5.

[56] Williams BB, et al.Van Benschoten AH, Cimermancic P, Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe. 2014; 16(4):495-503. https://doi.org/10.1016/j.chom.2014.09.001.

[57] Krishnan S, Ding Y, Saedi N, et al. Gut microbiota-derived tryptophan metabolites modulate inflammatory response in hepatocytes and macrophages. Cell Rep. 2018; 23(4):1099-1111. https://doi.org/10.1016/j.celrep.2018.03.109.

[58] Sugimoto Y, Kimura I, Yamada J, et al. The involvement of insulin in tryptamine-induced hypoglycemia in mice. Life Sci. 1991; 48(17):1679-1683. https://doi.org/10.1016/0024-3205(91)90128-X.

[59] Zhai L, Xiao H, Lin C, et al. Gut microbiota-derived tryptamine and phenethylamine impair insulin sensitivity in metabolic syndrome and irritable bowel syndrome. Nat Commun. 2023; 14(1):4986. https://doi.org/10.1038/s41467-023-40552-y.

[60] Kristensen SL, Rorth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019; 7(10):776-785. https://doi.org/10.1016/S2213-8587(19)30249-9.

[61] Tao X, Huang W, Pan L, et al. Optimizing ex vivo culture conditions to study human gut microbiome. ISME Commun. 2023; 3(1):38. https://doi.org/10.1038/s43705-023-00245-5.