益生菌Probio-Fit~?联合二甲双胍对Ⅱ型糖尿病患者疗效及肠道菌群结构的影响
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摘要
目的:评估益生菌Probio-Fit~?联合二甲双胍对Ⅱ型糖尿病患者治疗效果及肠道菌群结构的影响。方法:招募10名志愿者,以其中6名服用益生菌Probio-Fit~?联合二甲双胍的患者作为益生菌组,其余4名服用安慰剂联合二甲双胍作为安慰剂组,为期90 d的干预。通过测定治疗前、后血液各项指标,判断两组患者的治疗效果。采集治疗前、后志愿者粪便样品,采用宏基因组测序及生物信息学方法评估益生菌Probio-Fit~?联合二甲双胍对患者肠道菌群结构及代谢通路的影响。结果:补充益生菌Probio-Fit~?可有效增强二甲双胍的降血糖作用,使肠道中双歧杆菌、霍氏真杆菌等有益菌显著增加(P<0.05),另支菌属等有害菌显著降低(P<0.05);益生菌组在治疗后肠道菌群中参与脂多糖合成、鞭毛组装和香叶醇降解的基因丰度降低,这些基因常与代谢性疾病正相关。结论:益生菌Probio-Fit~?联合二甲双胍比单独使用二甲双胍对Ⅱ型糖尿病具有更好的治疗效果,可用于Ⅱ型糖尿病的辅助治疗。
Objective: To evaluate the effect of combination treatment with metformin and probiotics Probio-Fit~? on clinical symptoms and gut microbiota in type 2 diabetes. Methods: 10 type 2 diabetic subjects were randomly assigned to double-blind treatment with metformin in combination with placebo(the placebo group, n=4) or metformin in combination with probiotics Probio-Fit~? (the probiotics group, n =6) for 90 days. We assessed the treatment effects based on blood indicators, and their effects on gut microbiota and metabolisms using high throughput sequencing technology. Results: In probiotics group, for 6 subjects receiving combination treatment with metformin and probiotics Probio-Fit~?, the hypoglycemic effect of metformin was enhanced, the abundance of beneficial bacteria, such as Bifidobacterium, Eubacterium hallii, increased, and the abundance of harmful bacteria, such as Alistipes decreased; In addition, the function gene of lipopolysaccharide biosynthesis, flagellar assembly and geraniol degradation decreased after treatment in the probiotic group, and these genes were associated with metabolic disease. Conclusion: Combination treatment with metformin and probiotics Probio-Fit~? has better therapeutic effects than metformin alone in T2 D.
Objective: To evaluate the effect of combination treatment with metformin and probiotics Probio-Fit~? on clinical symptoms and gut microbiota in type 2 diabetes. Methods: 10 type 2 diabetic subjects were randomly assigned to double-blind treatment with metformin in combination with placebo(the placebo group, n=4) or metformin in combination with probiotics Probio-Fit~? (the probiotics group, n =6) for 90 days. We assessed the treatment effects based on blood indicators, and their effects on gut microbiota and metabolisms using high throughput sequencing technology. Results: In probiotics group, for 6 subjects receiving combination treatment with metformin and probiotics Probio-Fit~?, the hypoglycemic effect of metformin was enhanced, the abundance of beneficial bacteria, such as Bifidobacterium, Eubacterium hallii, increased, and the abundance of harmful bacteria, such as Alistipes decreased; In addition, the function gene of lipopolysaccharide biosynthesis, flagellar assembly and geraniol degradation decreased after treatment in the probiotic group, and these genes were associated with metabolic disease. Conclusion: Combination treatment with metformin and probiotics Probio-Fit~? has better therapeutic effects than metformin alone in T2 D.
引文
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[36]FERREIRA R M,PEREIRA-MARQUES P,PIN-TO-RIBEIRO I,et al.Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota[J].Gut,2018,67(2):226-236.
[2]GIACCO F,BROWNLEE M.Oxidative stress and diabetic complications[J].Circulation Research,2010,107(9):1058-1070.
[3]DELZENNE N M,CANI P D.Gut microbiota and the pathogenesis of insulin resistance[J].Current Diabetes Reports,2011,11(3):154-159.
[4]NADJA L,KVIST V F,FRANCISCUS WINFRIEDJ,et al.Gut microbiota in human adults with type2 diabetes differs from non-diabetic adults[J].Plos One,2010,5(2):e9085.
[5]QIN J J,LI Y R,CAI I M,et al.Ametagenomewide association study of gut microbiota in type 2diabetes[J].Nature,2012,490(7418):55-60.
[6]FERRUCCI L,FABBRI E.Inflammageing:Chronic inflammation in ageing,cardiovascular disease,and frailty[J].Nature Reviews Cardiology,2018,15(9):505-522.
[7]NAITO E,YOSHIDA Y,KOUNOSHI Y,et al Beneficial effect of oral administration of Lactobacillus casei strain Shirota on insulin resistance in dietinduced obesity mice[J].Journal of Applied Microbiology,2011,110(3):650-657.
[8]KIKUCHI K,OTHMAN M B,SAKAMOTO KSterilized Bifidobacteria suppressed fat accumulation and blood glucose level[J].Biochemical&Biophysical Research Communications,2018,501(4):1041-1047.
[9]EJTAHED H S,EJTAHED M,JAVAD M N,et al Probiotic yogurt improves antioxidant status in type2 diabetic patients[J].Nutrition,2012,28(5):539-543.
[10]FRANZOSA E A,MCIVER L J,RAHNAVARD G,et al.Species-level functional profiling of metagenomes and metatranscriptomes[J].Nature Methods,2018,15(11):962-974.
[11]SU X Q,PAN W H,SONG B X,et al.ParallelMETA 2.0:Enhanced metagenomic data analysis with functional annotation,high performance computing and advanced visualization[J].Plos One,2014,9(3):e89323.
[12]PASOLLI E,ASNICAR F,MANARA S,et al.Extensive unexplored human microbiome diversity revealed by over 150,000 genomes from metagenomes spanning age,geography,and lifestyle[J].Cell,2019,176(3):649-652.
[13]BENJAMINI Y,HOCHBERG Y.Controlling the false discovery rate:A practical and powerful approach to multiple testing[J].Journal of the Royal Statistical Society.Series B(Methodological),1995:289-300.
[14]PATIL K R,NIELSEN J.Uncovering transcriptional regulation of metabolism by using metabolic network topology[J].Proceedings of the National Academy of Sciences of the United States of America,2005,102(8):2685-2689.
[15]SEINO Y,NANJO K,TAJIMA N,et al.Report of the committee on the classification and diagnostic criteria of diabetes mellitus[J].Journal of Diabetes Investigation,2010,1(5):212-228.
[16]LI C,LI X,HAN H,et al.Effect of probiotics on metabolic profiles in type 2 diabetes mellitus:Ameta-analysis of randomized,controlled trials[J].Medicine,2016,95(26):e4088.
[17]LI G X,JIAO X H,CHENG X B.Correlations between blood uric acid and the incidence and progression of type 2 diabetes nephropathy[J].European Review for Medical and Pharmacological Sciences,2018,22(2):506-511.
[18]DE LA CUESTA-ZULUAGA J,MUELLER N T,CORRALES-AGUDELO V,et al.Metformin is associated with higher relative abundance of mucindegrading Akkermansia muciniphila and several short-chain fatty acid-producing microbiota in the gut[J].Diabetes Care,2017.40(1):54-62.
[19]BONORA E,CIGOLINI M,BOSELLO O,et al Lack of effect of intravenous metformin on plasma concentrations of glucose,insulin,C-peptide,glucagon and growth hormone in non-diabetic subjects[J].Current Medical Research and Opinion,1984,9(1):47-51.
[20]SHIN N R,LEE J C,LEE H Y,et al.An increase in the Akkermansia spp.population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice[J].Gut,2014,63(5):727-735.
[21]WHANG A,NAGPAL R,YADAV H,et al.Bidirectional drug-microbiome interactions of anti-diabetics[J].E Bio Medicine,2018,39(1):591-600.
[22]ZHANG X,ZHAO Y F,XU J,et al.Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats[J].Scientific Reports,2015,5(6):e14405.
[23]SUAREZ-ZAMORANO N,FABBIANO S,CHEVA-LIER C,et al.Microbiota depletion promotes browning of white adipose tissue and reduces obesity[J].Nature Medicine,2015,21(12):1497-1501.
[24]WAN Y,WANG F L,YUAN J H,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[J].Gut Published Online First:19 February2019.DOI:10.1136/gutjnl-2018-317609.
[25]CHRISTINA E,HANS-JOACHIM R,NIKO B,et al.The common gut microbe Eubacterium hallii also contributes to intestinal propionate formation[J].Frontiers in Microbiology,2016,7:713-725.
[26]HERBERT T,MOSCHEN A R.Microbiota and diabetes:An evolving relationship[J].Gut,2014,63(9):1513-1521.
[27]BESTEN G D,EUNEN K V,GROEN A K,et al The role of short-chain fatty acids in the interplay between diet,gut microbiota,and host energy metabolism[J].Journal of Lipid Research,2013,54(9):2325-2340.
[28]SARKAR A,PITCHUMONI C S.Chapter 4-identification of the microbiota in the aging process[J].Microbiota in Gastrointestinal Pathophysiology,2017:37-56.
[29]KAMEYAMA K and ITOII K.Intestinal colonization by a lachnospiraceae bacterium contributes to the development of diabetes in obese mice[J].Microbes and Environments,2014,29(4):427-430.
[30]WANG J J,TANG H,ZHANG C H,et al.Modulation of gut microbiota during probiotic-mediated attenuation of metabolic syndrome in high fat dietfed mice[J].Isme Journal,2015,9(1):1-15.
[31]WU X K,MA C F,HAN L,et al.Molecular characterisation of the faecal microbiota in patients with type II diabetes[J].Current Microbiology,2010,61(1):69-78.
[32]GU Y Y,WANG X K,LI J H,et al.Analyses of gut microbiota and plasma bile acids enable stratification of patients for antidiabetic treatment[J].Nature Communications,2017,8(1):1785-1796.
[33]CANI P D,AMAR J,IGLESIAS M A,et al Metabolic endotoxemia initiates obesity and insulin resistance[J].Diabetes,2007,56(7):1761-1772.
[34]HOU Q C,KWOK L Y,ZHENG Y,et al.Differential fecal microbiota are retained in broiler chicken lines divergently selected for fatness traits[J].Scientific Reports,2016,6:e37376.
[35]MARMULLA R,HARDER J.Microbial monoterpene transformations-a review[J].Frontiers in Microbiology,2014,5:346-360.
[36]FERREIRA R M,PEREIRA-MARQUES P,PIN-TO-RIBEIRO I,et al.Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota[J].Gut,2018,67(2):226-236.