Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats

Scientific Reports - Tập 5 Số 1
Xu Zhang1, Yufeng Zhao2, Jia Xu1, Zhengsheng Xue1, Menghui Zhang1, Xiaoyan Pang1, Xiaojun Zhang1, Liping Zhao2,1
1State Key Laboratory of Microbial Metabolism and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China
2Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China

Tóm tắt

AbstractAccumulating evidence suggests that the gut microbiota is an important factor in mediating the development of obesity-related metabolic disorders, including type 2 diabetes. Metformin and berberine, two clinically effective drugs for treating diabetes, have recently been shown to exert their actions through modulating the gut microbiota. In this study, we demonstrated that metformin and berberine similarly shifted the overall structure of the gut microbiota in rats. Both drugs showed reverting effects on the high-fat diet-induced structural changes of gut microbiota. The diversity of gut microbiota was significantly reduced by both berberine- and metformin-treatments. Nearest shrunken centroids analysis identified 134 operational taxonomic units (OTUs) responding to the treatments, which showed close associations with the changes of obese phenotypes. Sixty out of the 134 OTUs were decreased by both drugs, while those belonging to putative short-chain fatty acids (SCFA)-producing bacteria, including Allobaculum, Bacteriodes, Blautia, Butyricoccus and Phascolarctobacterium, were markedly increased by both berberine and, to a lesser extent, metformin. Taken together, our findings suggest that berberine and metformin showed similarity in modulating the gut microbiota, including the enrichment of SCFA-producing bacteria and reduction of microbial diversity, which may contribute to their beneficial effects to the host.

Từ khóa


Tài liệu tham khảo

Backhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proceedings of the National Academy of Sciences of the United States of America 101, 15718–15723, 10.1073/pnas.0407076101 (2004).

Fei, N. & Zhao, L. An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice. The ISME journal 7, 880–884, 10.1038/ismej.2012.153 (2013).

Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031, 10.1038/nature05414 (2006).

Vijay-Kumar, M. et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231, 10.1126/science.1179721 (2010).

Cani, P. D. et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57, 1470–1481, 10.2337/db07-1403 (2008).

Xiao, S. et al. A gut microbiota-targeted dietary intervention for amelioration of chronic inflammation underlying metabolic syndrome. FEMS Microbiol Ecol 87, 357–367, 10.1111/1574-6941.12228 (2014).

Delzenne, N. M., Neyrinck, A. M., Backhed, F. & Cani, P. D. Targeting gut microbiota in obesity: effects of prebiotics and probiotics. Nature reviews. Endocrinology 7, 639–646, 10.1038/nrendo.2011.126 (2011).

Wang, J. et al. Modulation of gut microbiota during probiotic-mediated attenuation of metabolic syndrome in high fat diet-fed mice. The ISME journal, 10.1038/ismej.2014.99 (2014).

Cabreiro, F. et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153, 228–239, 10.1016/j.cell.2013.02.035 (2013).

Shin, N. R. et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63, 727–735, 10.1136/gutjnl-2012-303839 (2014).

Xu, J. et al. Structural modulation of gut microbiota during alleviation of type 2 diabetes with a Chinese herbal formula. The ISME journal, 10.1038/ismej.2014.177 (2014).

Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352, 854–865 (1998).

Kong, W. et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 10, 1344–1351, 10.1038/nm1135 (2004).

Xie, W., Gu, D., Li, J., Cui, K. & Zhang, Y. Effects and action mechanisms of berberine and Rhizoma coptidis on gut microbes and obesity in high-fat diet-fed C57BL/6J mice. PloS one 6, e24520, 10.1371/journal.pone.0024520 (2011).

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 7, e42529, 10.1371/journal.pone.0042529 (2012).

Tang, J. et al. Berberine and Coptidis rhizoma as novel antineoplastic agents: a review of traditional use and biomedical investigations. J Ethnopharmacol 126, 5–17, 10.1016/j.jep.2009.08.009 (2009).

Zhang, Y. et al. Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J Clin Endocrinol Metab 93, 2559–2565, 10.1210/jc.2007-2404 (2008).

Lee, Y. S. et al. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes 55, 2256–2264, 10.2337/db06-0006 (2006).

Hua, W. et al. Determination of berberine in human plasma by liquid chromatography-electrospray ionization-mass spectrometry. J Pharm Biomed Anal 44, 931–937, 10.1016/j.jpba.2007.03.022 (2007).

He, L. et al. Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 137, 635–646, 10.1016/j.cell.2009.03.016 (2009).

Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108, 1167–1174, 10.1172/JCI13505 (2001).

Napolitano, A. et al. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PloS one 9, e100778, 10.1371/journal.pone.0100778 (2014).

Bajzer, M. & Seeley, R. J. Physiology: obesity and gut flora. Nature 444, 1009–1010, 10.1038/4441009a (2006).

Maslowski, K. M. et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282–1286, 10.1038/nature08530 (2009).

De Filippo, C. et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proceedings of the National Academy of Sciences of the United States of America 107, 14691–14696, 10.1073/pnas.1005963107 (2010).

Qin, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60, 10.1038/nature11450 (2012).

Biagi, E. et al. Through ageing and beyond: gut microbiota and inflammatory status in seniors and centenarians. PloS one 5, e10667, 10.1371/journal.pone.0010667 (2010).

Wang, T. et al. Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers. The ISME journal 6, 320–329, 10.1038/ismej.2011.109 (2012).

Zhao, G., Nyman, M. & Jonsson, J. A. Rapid determination of short-chain fatty acids in colonic contents and faeces of humans and rats by acidified water-extraction and direct-injection gas chromatography. Biomedical chromatography: BMC 20, 674–682, 10.1002/bmc.580 (2006).

Lee, H. & Ko, G. Effect of metformin on metabolic improvement and gut microbiota. Applied and environmental microbiology 80, 5935–5943, 10.1128/AEM.01357-14 (2014).

Everard, A. et al. Microbiome of prebiotic-treated mice reveals novel targets involved in host response during obesity. The ISME journal 8, 2116–2130, 10.1038/ismej.2014.45 (2014).

Zhang, C. et al. Interactions between gut microbiota, host genetics and diet relevant to development of metabolic syndromes in mice. The ISME journal 4, 232–241, 10.1038/ismej.2009.112 (2010).

Choi, Y. H., Kim, S. G. & Lee, M. G. Dose-independent pharmacokinetics of metformin in rats: Hepatic and gastrointestinal first-pass effects. J Pharm Sci 95, 2543–2552, 10.1002/jps.20744 (2006).

Scheen, A. J. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 30, 359–371 (1996).

Marchesini, G. et al. Metformin in non-alcoholic steatohepatitis. Lancet 358, 893–894 (2001).

Moghetti, P. et al. Metformin effects on clinical features, endocrine and metabolic profiles and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 85, 139–146, 10.1210/jcem.85.1.6293 (2000).

Ratner, R. et al. Impact of intensive lifestyle and metformin therapy on cardiovascular disease risk factors in the diabetes prevention program. Diabetes Care 28, 888–894 (2005).

Evans, J. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R. & Morris, A. D. Metformin and reduced risk of cancer in diabetic patients. BMJ 330, 1304–1305, 10.1136/bmj.38415.708634.F7 (2005).

Flint, H. J., Scott, K. P., Louis, P. & Duncan, S. H. The role of the gut microbiota in nutrition and health. Nature reviews. Gastroenterology & hepatology 9, 577–589, 10.1038/nrgastro.2012.156 (2012).

Tang, W. H. & Hazen, S. L. The contributory role of gut microbiota in cardiovascular disease. J Clin Invest 124, 4204–4211, 10.1172/JCI72331 (2014).

Derosa, G., Maffioli, P. & Cicero, A. F. Berberine on metabolic and cardiovascular risk factors: an analysis from preclinical evidences to clinical trials. Expert Opin Biol Ther 12, 1113–1124, 10.1517/14712598.2012.704014 (2012).

Zhang, C. et al. Structural modulation of gut microbiota in life-long calorie-restricted mice. Nature communications 4, 2163, 10.1038/ncomms3163 (2013).

Faith, J. J. et al. The long-term stability of the human gut microbiota. Science 341, 1237439, 10.1126/science.1237439 (2013).

Santacruz, A. et al. Interplay between weight loss and gut microbiota composition in overweight adolescents. Obesity 17, 1906–1915, 10.1038/oby.2009.112 (2009).

Ravussin, Y. et al. Responses of gut microbiota to diet composition and weight loss in lean and obese mice. Obesity 20, 738–747, 10.1038/oby.2011.111 (2012).

Sedova, L., Seda, O., Krenova, D., Kren, V. & Kazdova, L. Isotretinoin and fenofibrate induce adiposity with distinct effect on metabolic profile in a rat model of the insulin resistance syndrome. Int J Obes Relat Metab Disord 28, 719–725, 10.1038/sj.ijo.0802613 (2004).

DeSantis, T. Z., Jr. et al. NAST: a multiple sequence alignment server for comparative analysis of 16S rRNA genes. Nucleic acids research 34, W394–399, 10.1093/nar/gkl244 (2006).

Ovreas, L., Forney, L., Daae, F. L. & Torsvik, V. Distribution of bacterioplankton in meromictic Lake Saelenvannet, as determined by denaturing gradient gel electrophoresis of PCR-amplified gene fragments coding for 16S rRNA. Applied and environmental microbiology 63, 3367–3373 (1997).

Reeder, J. & Knight, R. Rapid denoising of pyrosequencing amplicon data: exploiting the rank-abundance distribution. Nature methods 7, 668–669, 10.1038/nmeth0910-668b (2010).

Pinto, A. J. & Raskin, L. PCR biases distort bacterial and archaeal community structure in pyrosequencing datasets. PloS one 7, e43093, 10.1371/journal.pone.0043093 (2012).

Schloss, P. D. & Handelsman, J. Introducing DOTUR, a computer program for defining operational taxonomic units and estimating species richness. Applied and environmental microbiology 71, 1501–1506, 10.1128/AEM.71.3.1501-1506.2005 (2005).

Caporaso, J. G. et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods 7, 335–336, 10.1038/nmeth.f.303 (2010).

Wang, Q., Garrity, G. M., Tiedje, J. M. & Cole, J. R. Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Applied and environmental microbiology 73, 5261–5267, 10.1128/AEM.00062-07 (2007).

Lozupone, C. & Knight, R. UniFrac: a new phylogenetic method for comparing microbial communities. Applied and environmental microbiology 71, 8228–8235, 10.1128/AEM.71.12.8228-8235.2005 (2005).

Tibshirani, R., Hastie, T., Narasimhan, B. & Chu, G. Diagnosis of multiple cancer types by shrunken centroids of gene expression. Proceedings of the National Academy of Sciences of the United States of America 99, 6567–6572, 10.1073/pnas.082099299 (2002).

Thông tin
Thông tin xuất bản

Scientific Reports

Tập 5 Số 1

Thông tin tác giả