Gut microbiome-related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study)
Yifei Zhang, Yanyun Gu, Huahui Ren, Shujie Wang, Huanzi Zhong, Xinjie Zhao, Jing Ma, Xuejiang Gu, Yaoming Xue, Shan Huang, Jialin Yang, Li Chen, Gang Chen, Shen Qu, Jun Liang, Li Qin, Qin Huang, Yongde Peng, Qi Li, Xiaolin Wang, Ping Kong, Guixue Hou, Mengyu Gao, Zhun Shi, Xuelin Li, Yixuan Qiu, Yuanqiang Zou, Huanming Yang, Jian Wang, Guowang Xu, Shenghan Lai, Junhua Li, Guang Ning, Weiqing Wang, Yifei Zhang, Yanyun Gu, Huahui Ren, Shujie Wang, Huanzi Zhong, Xinjie Zhao, Jing Ma, Xuejiang Gu, Yaoming Xue, Shan Huang, Jialin Yang, Li Chen, Gang Chen, Shen Qu, Jun Liang, Li Qin, Qin Huang, Yongde Peng, Qi Li, Xiaolin Wang, Ping Kong, Guixue Hou, Mengyu Gao, Zhun Shi, Xuelin Li, Yixuan Qiu, Yuanqiang Zou, Huanming Yang, Jian Wang, Guowang Xu, Shenghan Lai, Junhua Li, Guang Ning, Weiqing Wang
Abstract
Human gut microbiome is a promising target for managing type 2 diabetes (T2D). Measures altering gut microbiota like oral intake of probiotics or berberine (BBR), a bacteriostatic agent, merit metabolic homoeostasis. We hence conducted a randomized, double-blind, placebo-controlled trial with newly diagnosed T2D patients from 20 centres in China. Four-hundred-nine eligible participants were enroled, randomly assigned (1:1:1:1) and completed a 12-week treatment of either BBR-alone, probiotics+BBR, probiotics-alone, or placebo, after a one-week run-in of gentamycin pretreatment. The changes in glycated haemoglobin, as the primary outcome, in the probiotics+BBR (least-squares mean [95% CI], -1.04[-1.19, -0.89]%) and BBR-alone group (-0.99[-1.16, -0.83]%) were significantly greater than that in the placebo and probiotics-alone groups (-0.59[-0.75, -0.44]%, -0.53[-0.68, -0.37]%, P < 0.001). BBR treatment induced more gastrointestinal side effects. Further metagenomics and metabolomic studies found that the hypoglycaemic effect of BBR is mediated by the inhibition of DCA biotransformation by Ruminococcus bromii. Therefore, our study reports a human microbial related mechanism underlying the antidiabetic effect of BBR on T2D. (Clinicaltrial.gov Identifier: NCT02861261).
Conflict of interest statement
The authors declare no competing interests.
Figures
References
- Xu Y, et al. Prevalence and control of diabetes in Chinese adults. JAMA. 2013;310:948–959. doi: 10.1001/jama.2013.168118.
- Weng J, et al. Standards of care for type 2 diabetes in China. Diabetes Metab. Res. Rev. 2016;32:442–458. doi: 10.1002/dmrr.2827.
- Qi J, et al. Cancer risk among patients with type 2 diabetes: a real-world study in Shanghai, China. J. Diabetes. 2019;11:878–883. doi: 10.1111/1753-0407.12926.
- Liu R, et al. Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention. Nat. Med. 2017;23:859–868. doi: 10.1038/nm.4358.
- Ridaura VK, et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. 2013;341:1241214. doi: 10.1126/science.1241214.
- Ning G. Decade in review-type 2 diabetes mellitus: at the centre of things. Nat. Rev. Endocrinol. 2015;11:636–638. doi: 10.1038/nrendo.2015.147.
- Turnbaugh PJ, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–1031. doi: 10.1038/nature05414.
- Qin J, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490:55–60. doi: 10.1038/nature11450.
- Karlsson FH, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013;498:99–103. doi: 10.1038/nature12198.
- Cani PD, et al. Microbial regulation of organismal energy homeostasis. Nat. Metab. 2019;1:34–46. doi: 10.1038/s42255-018-0017-4.
- Wu, H. 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. 23, 850–858 (2017).
- Forslund, K. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature528, 262–266 (2015).
- Wan, Y. et al. Effects of dietary fat on gut microbiota and faecal metabolites, and their relationship with cardiometabolic risk factors: a 6-month randomised controlled-feeding trial. Gut68, 1417 (2019).
- Gu, Y. et al. Analyses of gut microbiota and plasma bile acids enable stratification of patients for antidiabetic treatment. Nat. Commun.8, 1785 (2017).
- Sun, L. et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat. Med.24, 1919–1929 (2018).
- Bloomgarden Z. Diabetes and branched-chain amino acids: what is the link? J. Diabetes. 2018;10:350–352. doi: 10.1111/1753-0407.12645.
- Koh, A. et al. Microbially produced imidazole propionate impairs insulin signaling through mTORC1. Cell175, 947–961.e17 (2018).
- Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat. Rev. Endocrinol. 2015;11:577–591. doi: 10.1038/nrendo.2015.128.
- Priyadarshini M, Wicksteed B, Schiltz GE, Gilchrist A, Layden BT. SCFA receptors in pancreatic beta cells: novel diabetes targets? Trends Endocrinol. Metab. 2016;27:653–664. doi: 10.1016/j.tem.2016.03.011.
- Sonnenburg ED, Sonnenburg JL. Starving our microbial self: the deleterious consequences of a diet deficient in microbiota-accessible carbohydrates. Cell Metab. 2014;20:779–786. doi: 10.1016/j.cmet.2014.07.003.
- Sayin SI, 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;17:225–235. doi: 10.1016/j.cmet.2013.01.003.
- Parseus, A. et al. Microbiota-induced obesity requires farnesoid X receptor. Gut66, 429–437 (2016).
- McGavigan AK, et al. TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice. Gut. 2017;66:226–234. doi: 10.1136/gutjnl-2015-309871.
- Ryan KK, et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature. 2014;509:183–188. doi: 10.1038/nature13135.
- Kong W, et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat. Med. 2004;10:1344–1351. doi: 10.1038/nm1135.
- Zhang Z, et al. Berberine activates thermogenesis in white and brown adipose tissue. Nat. Commun. 2014;5:5493. doi: 10.1038/ncomms6493.
- Zhang Y, et al. Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J. Clin. Endocrinol. Metab. 2008;93:2559–2565. doi: 10.1210/jc.2007-2404.
- Han J, Lin H, Huang W. Modulating gut microbiota as an anti-diabetic mechanism of berberine. Med. Sci. Monit. 2011;17:RA164–RA167. doi: 10.12659/MSM.881842.
- Kumar A, et al. Current knowledge and pharmacological profile of berberine: an update. Eur. J. Pharm. 2015;761:288–297. doi: 10.1016/j.ejphar.2015.05.068.
- Yang Y, et al. Gut microbiota drives the attenuation of dextran sulphate sodium-induced colitis by Huangqin decoction. Oncotarget. 2017;8:48863–48874. doi: 10.18632/oncotarget.16458.
- Zhang X, et al. Structural changes of gut microbiota during berberine-mediated prevention of obesity and insulin resistance in high-fat diet-fed rats. PLoS ONE. 2012;7:e42529. doi: 10.1371/journal.pone.0042529.
- Suez J, Zmora N, Segal E, Elinav E. The pros, cons, and many unknowns of probiotics. Nat. Med. 2019;25:716–729. doi: 10.1038/s41591-019-0439-x.
- Firouzi S, Majid HA, Ismail A, Kamaruddin NA, Barakatun-Nisak MY. Effect of multi-strain probiotics (multi-strain microbial cell preparation) on glycemic control and other diabetes-related outcomes in people with type 2 diabetes: a randomized controlled trial. Eur. J. Nutr. 2017;56:1535–1550. doi: 10.1007/s00394-016-1199-8.
- Zmora N, et al. Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features. Cell. 2018;174:1388–1405. doi: 10.1016/j.cell.2018.08.041.
- Fang C, et al. Assessment of the cPAS-based BGISEQ-500 platform for metagenomic sequencing. Gigascience. 2018;7:1–8. doi: 10.1093/gigascience/gix133.
- Falony G, Vlachou A, Verbrugghe K, De Vuyst L. Cross-feeding between Bifidobacterium longum BB536 and acetate-converting, butyrate-producing colon bacteria during growth on oligofructose. Appl. Environ. Microbiol. 2006;72:7835–7841. doi: 10.1128/AEM.01296-06.
- Rios-Covian, D., Gueimonde, M., Duncan, S. H., Flint, H. J. & de los Reyes-Gavilan, C.G. Enhanced butyrate formation by cross-feeding between Faecalibacterium prausnitzii and Bifidobacterium adolescentis. FEMS Microbiol Lett362, fnv176 (2015).
- Belenguer A, et al. Two routes of metabolic cross-feeding between Bifidobacterium adolescentis and butyrate-producing anaerobes from the human gut. Appl. Environ. Microbiol. 2006;72:3593–3599. doi: 10.1128/AEM.72.5.3593-3599.2006.
- Ze X, Duncan SH, Louis P, Flint HJ. Ruminococcus bromii is a keystone species for the degradation of resistant starch in the human colon. ISME J. 2012;6:1535–1543. doi: 10.1038/ismej.2012.4.
- Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J. Lipid Res. 2006;47:241–259. doi: 10.1194/jlr.R500013-JLR200.
- Harris SC, et al. Bile acid oxidation by Eggerthella lenta strains C592 and DSM 2243(T) Gut Microbes. 2018;9:523–539. doi: 10.1080/19490976.2017.1376162.
- Sagar NM, Cree IA, Covington JA, Arasaradnam RP. The interplay of the gut microbiome, bile acids, and volatile organic compounds. Gastroenterol. Res. Pr. 2015;2015:398585.
- Staley C, Weingarden AR, Khoruts A, Sadowsky MJ. Interaction of gut microbiota with bile acid metabolism and its influence on disease states. Appl. Microbiol. Biotechnol. 2017;101:47–64. doi: 10.1007/s00253-016-8006-6.
- Zou Y, et al. 1,520 reference genomes from cultivated human gut bacteria enable functional microbiome analyses. Nat. Biotechnol. 2019;37:179–185. doi: 10.1038/s41587-018-0008-8.
- Suez J, et al. Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell. 2018;174:1406–1423. doi: 10.1016/j.cell.2018.08.047.
- Dong Y, Xu M, Chen L, Bhochhibhoya A. Probiotic foods and supplements interventions for metabolic syndromes: a systematic review and meta-analysis of recent clinical trials. Ann. Nutr. Metab. 2019;74:224–241. doi: 10.1159/000499028.
- Ruan Y, et al. Effect of probiotics on glycemic control: a systematic review and meta-analysis of randomized, controlled trials. PLoS ONE. 2015;10:e0132121. doi: 10.1371/journal.pone.0132121.
- Barengolts, E., Smith, E. D., Reutrakul, S., Tonucci, L. & Anothaisintawee, T. The effect of probiotic yogurt on glycemic control in type 2 diabetes or obesity: a meta-analysis of nine randomized controlled trials. Nutrients11, 671 (2019).
- Crost EH, et al. Mechanistic insights into the cross-feeding of Ruminococcus gnavus and Ruminococcus bromii on host and dietary carbohydrates. Front. Microbiol. 2018;9:2558. doi: 10.3389/fmicb.2018.02558.
- Xu, H. et al. Oral administration of compound probiotics improved canine feed intake, weight gain, immunity and intestinal microbiota. Front. Immunol.10, 666 (2019).
- Moroti C, Souza Magri LF, de Rezende Costa M, Cavallini DC, Sivieri K. Effect of the consumption of a new symbiotic shake on glycemia and cholesterol levels in elderly people with type 2 diabetes mellitus. Lipids Health Dis. 2012;11:29. doi: 10.1186/1476-511X-11-29.
- Gomes AC, Bueno AA, de Souza RG, Mota JF. Gut microbiota, probiotics and diabetes. Nutr. J. 2014;13:60. doi: 10.1186/1475-2891-13-60.
- Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 2018;14:576–590. doi: 10.1038/s41574-018-0059-4.
- Sun R, et al. Orally administered berberine modulates hepatic lipid metabolism by altering microbial bile acid metabolism and the intestinal FXR signaling pathway. Mol. Pharm. 2017;91:110–122. doi: 10.1124/mol.116.106617.
- Gabir MM, et al. The 1997 American Diabetes Association and 1999 World Health Organization criteria for hyperglycemia in the diagnosis and prediction of diabetes. Diabetes Care. 2000;23:1108–1112. doi: 10.2337/diacare.23.8.1108.
- Li J, et al. An integrated catalog of reference genes in the human gut microbiome. Nat. Biotechnol. 2014;32:834–841. doi: 10.1038/nbt.2942.
- Backhed F, et al. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe. 2015;17:690–703. doi: 10.1016/j.chom.2015.04.004.
- Han J, et al. Metabolic profiling of bile acids in human and mouse blood by LC-MS/MS in combination with phospholipid-depletion solid-phase extraction. Anal. Chem. 2015;87:1127–1136. doi: 10.1021/ac503816u.
- Mac Lean B, et al. Skyline: an open source document editor for creating and analyzing targeted proteomics experiments. Bioinformatics. 2010;26:966–968. doi: 10.1093/bioinformatics/btq054.
- Tonucci LB, Olbrich Dos Santos KM, Licursi de Oliveira L, Rocha Ribeiro SM, Duarte Martino HS. Clinical application of probiotics in type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled study. Clin. Nutr. 2017;36:85–92. doi: 10.1016/j.clnu.2015.11.011.
Source: PubMed