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

Jie Ming, Xinwen Yu, Xiaoqiang Xu, Li Wang, Chao Ding, Zhifeng Wang, Xuan Xie, Sheli Li, Wenjuan Yang, Shu Luo, Qingzhen He, Yafang Du, Zhufang Tian, Xiling Gao, Kaiyan Ma, Yujie Fang, Chen Li, Jiajun Zhao, Xiaokai Wang, Qiuhe Ji, Jie Ming, Xinwen Yu, Xiaoqiang Xu, Li Wang, Chao Ding, Zhifeng Wang, Xuan Xie, Sheli Li, Wenjuan Yang, Shu Luo, Qingzhen He, Yafang Du, Zhufang Tian, Xiling Gao, Kaiyan Ma, Yujie Fang, Chen Li, Jiajun Zhao, Xiaokai Wang, Qiuhe Ji

Abstract

Background: Berberine and Bifidobacterium have been reported to improve glucose tolerance in people with hyperglycemia or other metabolic disorders. This study aimed to assess the hypoglycemic effect and the regulation of the gut microbiota caused by berberine and Bifidobacterium and the possible additive benefits of their combination.

Methods: This was an 18-week, multi-center, randomized, double-blind, parallel-controlled study of patients newly diagnosed with hyperglycemia. After a 2-week run-in period, 300 participants were randomly assigned to the following four groups for 16 weeks of treatment: berberine (Be), Bifidobacterium (Bi), berberine and Bifidobacterium (BB), and placebo group. The primary efficacy endpoint was the absolute value of fasting plasma glucose (FPG) compared with baseline after 16 weeks of treatment.

Results: Between October 2015 and April 2018, a total of 297 participants were included in the primary analysis. Significant reductions of FPG were observed in the Be and BB groups compared with the placebo group, with a least square (LS) mean difference of - 0.50, 95% CI [- 0.85, - 0.15] mmol/L, and - 0.55, 95% CI [- 0.91, - 0.20] mmol/L, respectively. The Be and BB groups also showed significant reductions in 2-h postprandial plasma glucose. A pronounced decrease in HbA1c occurred in the BB group compared to the placebo group. Moreover, compared with the Bi and placebo groups, the Be and BB groups had more changes in the gut microbiota from the baseline.

Conclusions: Berberine could regulate the structure and function of the human gut microbiota, and Bifidobacterium has the potential to enhance the hypoglycemic effect of berberine. These findings provide new insights into the hypoglycemic potential of berberine and Bifidobacterium.

Trial registration: ClinicalTrials.gov , NCT03330184. Retrospectively registered on 18 October 2017.

Keywords: Berberine; Bifidobacterium; Gut microbiota; Hyperglycemia.

Conflict of interest statement

The Northeast Pharmaceutical Group Shenyang First Pharmaceutical Co., Ltd. and Livzon Pharmaceutical Group Inc. provided drugs for free. XX, ZW, and XW are affiliated to Aimigene Institute, which is the research department of Shenzhen 01 Life Science and Technology Ltd. The remaining authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Trial profile. *The criteria were not mutually exclusive. The full analysis set, as the primary analysis set for this study, included participants who received at least one dose of the trial drug and had at least one post-treatment data point. The per-protocol set included participants who adhered adequately to the assigned regimen, including undergoing the trial drug treatment according to the protocol without any significant protocol deviation and completing all the evaluations of this study. The safety set included participants who received at least one dose of the trial drug and had at least one safety assessment
Fig. 2
Fig. 2
Heat map showing differentially abundant taxa of the fecal microbiota between baseline and 16 weeks of treatment in four experiments. The values of color in the heat map represent the Z-score. Only bacterial taxa that were significant in one of the experiments were included. The Wilcoxon matched-pairs signed-rank tests were used, *P < 0.05; **P < 0.01

References

    1. Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract. 2019;157:107843. doi: 10.1016/j.diabres.2019.107843.
    1. American Diabetes A Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S98–S110. doi: 10.2337/dc20-S009.
    1. Gu Y, Wang X, Li J, Zhang Y, Zhong H, Liu R, Zhang D, Feng Q, Xie X, Hong J, Ren H, Liu W, Ma J, Su Q, Zhang H, Yang J, Wang X, Zhao X, Gu W, Bi Y, Peng Y, Xu X, Xia H, Li F, Xu X, Yang H, Xu G, Madsen L, Kristiansen K, Ning G, Wang W. Analyses of gut microbiota and plasma bile acids enable stratification of patients for antidiabetic treatment. Nat Commun. 2017;8(1):1785. doi: 10.1038/s41467-017-01682-2.
    1. Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Manneras-Holm L, 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. doi: 10.1038/nm.4345.
    1. Yu M, Jin X, Liang C, Bu F, Pan D, He Q, et al. Berberine for diarrhea in children and adults: a systematic review and meta-analysis. Therap Adv Gastroenterol. 2020;13:1756284820961299.
    1. Lan J, Zhao Y, Dong F, Yan Z, Zheng W, Fan J, Sun G. Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension. J Ethnopharmacol. 2015;161:69–81. doi: 10.1016/j.jep.2014.09.049.
    1. Zhang Y, Cui YL, Gao LN, Jiang HL. Effects of beta-cyclodextrin on the intestinal absorption of berberine hydrochloride, a P-glycoprotein substrate. Int J Biol Macromol. 2013;59:363–371. doi: 10.1016/j.ijbiomac.2013.04.074.
    1. Zhang Y, Li X, Zou D, Liu W, Yang J, Zhu N, Huo L, Wang M, Hong J, Wu P, Ren G, Ning G. Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J Clin Endocrinol Metab. 2008;93(7):2559–2565. doi: 10.1210/jc.2007-2404.
    1. Zhu L, Zhang D, Zhu H, Zhu J, Weng S, Dong L, Liu T, Hu Y, Shen X. Berberine treatment increases Akkermansia in the gut and improves high-fat diet-induced atherosclerosis in Apoe(-/-) mice. Atherosclerosis. 2018;268:117–126. doi: 10.1016/j.atherosclerosis.2017.11.023.
    1. Habtemariam S. Berberine pharmacology and the gut microbiota: a hidden therapeutic link. Pharmacol Res. 2020;155:104722. doi: 10.1016/j.phrs.2020.104722.
    1. Zhang X, Zhao Y, Zhang M, Pang X, Xu J, Kang C, Li M, Zhang C, Zhang Z, Zhang Y, Li X, Ning G, Zhao L. Structural changes of gut microbiota during berberine-mediated prevention of obesity and insulin resistance in high-fat diet-fed rats. PLoS One. 2012;7(8):e42529. doi: 10.1371/journal.pone.0042529.
    1. Yue SJ, Liu J, Wang AT, Meng XT, Yang ZR, Peng C, Guan HS, Wang CY, Yan D. Berberine alleviates insulin resistance by reducing peripheral branched-chain amino acids. Am J Physiol Endocrinol Metab. 2019;316(1):E73–E85. doi: 10.1152/ajpendo.00256.2018.
    1. Sun R, Yang N, Kong B, Cao B, Feng D, Yu X, Ge C, Huang J, Shen J, Wang P, Feng S, Fei F, Guo J, He J, Aa N, Chen Q, Pan Y, Schumacher JD, Yang CS, Guo GL, Aa J, Wang G. Orally administered berberine modulates hepatic lipid metabolism by altering microbial bile acid metabolism and the intestinal FXR signaling pathway. Mol Pharmacol. 2017;91(2):110–122. doi: 10.1124/mol.116.106617.
    1. Liu D, Zhang Y, Liu Y, Hou L, Li S, Tian H, Zhao T. Berberine modulates gut microbiota and reduces insulin resistance via the TLR4 signaling pathway. Exp Clin Endocrinol Diabetes. 2018;126(8):513–520. doi: 10.1055/s-0043-125066.
    1. Cui HX, Hu YN, Li JW, Yuan K. Hypoglycemic mechanism of the berberine organic acid salt under the synergistic effect of intestinal flora and oxidative stress. Oxid Med Cell Longev. 2018;2018:8930374. doi: 10.1155/2018/8930374.
    1. Wang Y, Shou JW, Li XY, Zhao ZX, Fu J, He CY, Feng R, Ma C, Wen BY, Guo F, Yang XY, Han YX, Wang LL, Tong Q, You XF, Lin Y, Kong WJ, Si SY, Jiang JD. Berberine-induced bioactive metabolites of the gut microbiota improve energy metabolism. Metabolism. 2017;70:72–84. doi: 10.1016/j.metabol.2017.02.003.
    1. Imenshahidi M, Hosseinzadeh H. Berberine and barberry (Berberis vulgaris): a clinical review. Phytother Res. 2019;33(3):504–523. doi: 10.1002/ptr.6252.
    1. Chen Y-X, Gao Q-Y, Zou T-H, Wang B-M, Liu S-D, Sheng J-Q, Ren JL, Zou XP, Liu ZJ, Song YY, Xiao B, Sun XM, Dou XT, Cao HL, Yang XN, Li N, Kang Q, Zhu W, Xu HZ, Chen HM, Cao XC, Fang JY. Berberine versus placebo for the prevention of recurrence of colorectal adenoma: a multicentre, double-blinded, randomised controlled study. The Lancet Gastroenterology & Hepatology. 2020;5(3):267–275. doi: 10.1016/S2468-1253(19)30409-1.
    1. Zhang LS, Zhang JH, Feng R, Jin XY, Yang FW, Ji ZC, Zhao MY, Zhang MY, Zhang BL, Li XM. Efficacy and safety of berberine alone or combined with statins for the treatment of hyperlipidemia: a systematic review and meta-analysis of randomized controlled clinical trials. Am J Chin Med. 2019;47(4):751–767. doi: 10.1142/S0192415X19500393.
    1. Feng R, Shou JW, Zhao ZX, He CY, Ma C, Huang M, Fu J, Tan XS, Li XY, Wen BY, Chen X, Yang XY, Ren G, Lin Y, Chen Y, You XF, Wang Y, Jiang JD. Transforming berberine into its intestine-absorbable form by the gut microbiota. Sci Rep. 2015;5(1):12155. doi: 10.1038/srep12155.
    1. Ebrahimi ZS, Nasli-Esfahani E, Nadjarzade A, Mozaffari-Khosravi H. Effect of symbiotic supplementation on glycemic control, lipid profiles and microalbuminuria in patients with non-obese type 2 diabetes: a randomized, double-blind, clinical trial. J Diabetes Metab Disord. 2017;16(1):23. doi: 10.1186/s40200-017-0304-8.
    1. Kijmanawat A, Panburana P, Reutrakul S, Tangshewinsirikul C. Effects of probiotic supplements on insulin resistance in gestational diabetes mellitus: a double-blind randomized controlled trial. J Diabetes Investig. 2019;10(1):163–170. doi: 10.1111/jdi.12863.
    1. Gomes AC, de Sousa RG, Botelho PB, Gomes TL, Prada PO, Mota JF. The additional effects of a probiotic mix on abdominal adiposity and antioxidant status: a double-blind, randomized trial. Obesity (Silver Spring). 2017;25(1):30–38. doi: 10.1002/oby.21671.
    1. Kouchaki E, Tamtaji OR, Salami M, Bahmani F, Daneshvar Kakhaki R, Akbari E, Tajabadi-Ebrahimi M, Jafari P, Asemi Z. Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial. Clin Nutr. 2017;36(5):1245–1249. doi: 10.1016/j.clnu.2016.08.015.
    1. Famouri F, Shariat Z, Hashemipour M, Keikha M, Kelishadi R. Effects of probiotics on nonalcoholic fatty liver disease in obese children and adolescents. J Pediatr Gastroenterol Nutr. 2017;64(3):413–417. doi: 10.1097/MPG.0000000000001422.
    1. Ming J, Xu S, Liu C, Liu X, Jia A, Ji Q. Effectiveness and safety of bifidobacteria and berberine in people with hyperglycemia: study protocol for a randomized controlled trial. Trials. 2018;19(1):72. doi: 10.1186/s13063-018-2438-5.
    1. Truong DT, Franzosa EA, Tickle TL, Scholz M, Weingart G, Pasolli E, Tett A, Huttenhower C, Segata N. MetaPhlAn2 for enhanced metagenomic taxonomic profiling. Nat Methods. 2015;12(10):902–903. doi: 10.1038/nmeth.3589.
    1. Li J, Jia H, Cai X, Zhong H, Feng Q, Sunagawa S, et al. An integrated catalog of reference genes in the human gut microbiome. Nat Biotechnol. 2014;32(8):834–841. doi: 10.1038/nbt.2942.
    1. Patil KR, Nielsen J. Uncovering transcriptional regulation of metabolism by using metabolic network topology. Proc Natl Acad Sci U S A. 2005;102(8):2685–2689. doi: 10.1073/pnas.0406811102.
    1. Liang Y, Xu X, Yin M, Zhang Y, Huang L, Chen R, Ni J. Effects of berberine on blood glucose in patients with type 2 diabetes mellitus: a systematic literature review and a meta-analysis. Endocr J. 2019;66(1):51–63. doi: 10.1507/endocrj.EJ18-0109.
    1. Zhang Y, Gu Y, Ren H, Wang S, Zhong H, Zhao X, Ma J, Gu X, Xue Y, Huang S, Yang J, Chen L, Chen G, Qu S, Liang J, Qin L, Huang Q, Peng Y, Li Q, Wang X, Kong P, Hou G, Gao M, Shi Z, Li X, Qiu Y, Zou Y, Yang H, Wang J, Xu G, Lai S, Li J, Ning G, Wang W. Gut microbiome-related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study) Nat Commun. 2020;11(1):5015. doi: 10.1038/s41467-020-18414-8.
    1. Chen J, Wang R, Li XF, Wang RL. Bifidobacterium adolescentis supplementation ameliorates visceral fat accumulation and insulin sensitivity in an experimental model of the metabolic syndrome. Br J Nutr. 2012;107(10):1429–1434. doi: 10.1017/S0007114511004491.
    1. Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, Liang S, Zhang W, Guan Y, Shen D, Peng Y, Zhang D, Jie Z, Wu W, Qin Y, Xue W, Li J, Han L, Lu D, Wu P, Dai Y, Sun X, Li Z, Tang A, Zhong S, Li X, Chen W, Xu R, Wang M, Feng Q, Gong M, Yu J, Zhang Y, Zhang M, Hansen T, Sanchez G, Raes J, Falony G, Okuda S, Almeida M, LeChatelier E, Renault P, Pons N, Batto JM, Zhang Z, Chen H, Yang R, Zheng W, Li S, Yang H, Wang J, Ehrlich SD, Nielsen R, Pedersen O, Kristiansen K, Wang J. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490(7418):55–60. doi: 10.1038/nature11450.
    1. Zhang X, Zhao Y, Xu J, Xue Z, Zhang M, Pang X, Zhang X, Zhao L. Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats. Sci Rep. 2015;5(1):14405. doi: 10.1038/srep14405.
    1. Tiderencel KA, Hutcheon DA, Ziegler J. Probiotics for the treatment of type 2 diabetes: a review of randomized controlled trials. Diabetes Metab Res Rev. 2020;36(1):e3213. doi: 10.1002/dmrr.3213.
    1. Kong WJ, Vernieri C, Foiani M, Jiang JD. Berberine in the treatment of metabolism-related chronic diseases: a drug cloud (dCloud) effect to target multifactorial disorders. Pharmacol Ther. 2020;209:107496. doi: 10.1016/j.pharmthera.2020.107496.
    1. Zmora N, Zilberman-Schapira G, Suez J, Mor U, Dori-Bachash M, Bashiardes S, Kotler E, Zur M, Regev-Lehavi D, Brik RBZ, Federici S, Cohen Y, Linevsky R, Rothschild D, Moor AE, Ben-Moshe S, Harmelin A, Itzkovitz S, Maharshak N, Shibolet O, Shapiro H, Pevsner-Fischer M, Sharon I, Halpern Z, Segal E, Elinav E. Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features. Cell. 2018;174(6):1388–1405. doi: 10.1016/j.cell.2018.08.041.
    1. Liu Y, Wang Y, Ni Y, Cheung CKY, Lam KSL, Wang Y, Xia Z, Ye D, Guo J, Tse MA, Panagiotou G, Xu A. Gut microbiome fermentation determines the efficacy of exercise for diabetes prevention. Cell Metab. 2020;31(1):77–91. doi: 10.1016/j.cmet.2019.11.001.
    1. Tanaka M, Sanefuji M, Morokuma S, Yoden M, Momoda R, Sonomoto K, Ogawa M, Kato K, Nakayama J. The association between gut microbiota development and maturation of intestinal bile acid metabolism in the first 3 y of healthy Japanese infants. Gut Microbes. 2020;11(2):205–216. doi: 10.1080/19490976.2019.1650997.
    1. Tanaka M, Sanefuji M, Morokuma S, Yoden M, Momoda R, Sonomoto K, et al. The association between gut microbiota development and maturation of intestinal bile acid metabolism in the first 3 y of healthy Japanese infants. Gut Microbes. 2019:1–12.
    1. Ethanic M, Stanimirov B, Pavlovic N, Golocorbin-Kon S, Al-Salami H, Stankov K, et al. Pharmacological applications of bile acids and their derivatives in the treatment of metabolic syndrome. Front Pharmacol. 2018;9:1382. doi: 10.3389/fphar.2018.01382.
    1. Hoffmann TW, Pham HP, Bridonneau C, Aubry C, Lamas B, Martin-Gallausiaux C, Moroldo M, Rainteau D, Lapaque N, Six A, Richard ML, Fargier E, le Guern ME, Langella P, Sokol H. Microorganisms linked to inflammatory bowel disease-associated dysbiosis differentially impact host physiology in gnotobiotic mice. ISME J. 2016;10(2):460–477. doi: 10.1038/ismej.2015.127.
    1. Williams Brianna B, Van Benschoten AH, Cimermancic P, Donia Mohamed S, Zimmermann M, Taketani M, et al. Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe. 2014;16(4):495–503. doi: 10.1016/j.chom.2014.09.001.
    1. Cervera-Tison M, Tailford LE, Fuell C, Bruel L, Sulzenbacher G, Henrissat B, Berrin JG, Fons M, Giardina T, Juge N. Functional analysis of family GH36 alpha-galactosidases from Ruminococcus gnavus E1: insights into the metabolism of a plant oligosaccharide by a human gut symbiont. Appl Environ Microbiol. 2012;78(21):7720–7732. doi: 10.1128/AEM.01350-12.
    1. Li CN, Wang X, Lei L, Liu MZ, Li RC, Sun SJ, Liu SN, Huan Y, Zhou T, Liu Q, Cao H, Bai GL, Han YW, Shen ZF. Berberine combined with stachyose induces better glycometabolism than berberine alone through modulating gut microbiota and fecal metabolomics in diabetic mice. Phytother Res. 2020;34(5):1166–1174. doi: 10.1002/ptr.6588.
    1. Wu DN, Guan L, Jiang YX, Ma SH, Sun YN, Lei HT, Yang WF, Wang QF. Microbiome and metabonomics study of quercetin for the treatment of atherosclerosis. Cardiovasc Diagn Ther. 2019;9(6):545–560. doi: 10.21037/cdt.2019.12.04.
    1. Zhang W, Xu JH, Yu T, Chen QK. Effects of berberine and metformin on intestinal inflammation and gut microbiome composition in db/db mice. Biomed Pharmacother. 2019;118:109131. doi: 10.1016/j.biopha.2019.109131.
    1. Yu Y, Liu L, Wang X, Liu X, Liu X, Xie L, Wang G. Modulation of glucagon-like peptide-1 release by berberine: in vivo and in vitro studies. Biochem Pharmacol. 2010;79(7):1000–1006. doi: 10.1016/j.bcp.2009.11.017.
    1. Yu Y, Hao G, Zhang Q, Hua W, Wang M, Zhou W, Zong S, Huang M, Wen X. Berberine induces GLP-1 secretion through activation of bitter taste receptor pathways. Biochem Pharmacol. 2015;97(2):173–177. doi: 10.1016/j.bcp.2015.07.012.
    1. Holst JJ, Deacon CF. Glucagon-like peptide 1 and inhibitors of dipeptidyl peptidase IV in the treatment of type 2 diabetes mellitus. Curr Opin Pharmacol. 2004;4(6):589–596. doi: 10.1016/j.coph.2004.08.005.
    1. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3(3):153–165. doi: 10.1016/j.cmet.2006.01.004.
    1. Houghton D, Stewart CJ, Day CP, Trenell M. Gut microbiota and lifestyle interventions in NAFLD. Int J Mol Sci. 2016;17(4):447. doi: 10.3390/ijms17040447.
    1. Guevara-Cruz M, Flores-Lopez AG, Aguilar-Lopez M, Sanchez-Tapia M, Medina-Vera I, Diaz D, et al. Improvement of lipoprotein profile and metabolic endotoxemia by a lifestyle intervention that modifies the gut microbiota in subjects with metabolic syndrome. J Am Heart Assoc. 2019;8(17):e012401. doi: 10.1161/JAHA.119.012401.
    1. Fernandez-Murga ML, Olivares M, Sanz Y. Bifidobacterium pseudocatenulatum CECT 7765 reverses the adverse effects of diet-induced obesity through the gut-bone axis. Bone. 2020;141:115580. doi: 10.1016/j.bone.2020.115580.
    1. Ming J, Yu X, Xu X, Wang L, Ding C, Wang Z, 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. Eur Nucleotide Arch. 2021; .

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj