Stenman Lotta K, Waget Aurélie, Garret Céline, Briand François, Burcelin Rémy, Sulpice Thierry, Lahtinen Sampo
DuPont Nutrition and Health, Active Nutrition, Sokeritehtaantie 20, 02460 Kantvik, Finland.
Institut des Maladies Métaboliques et Cardiovasculaires de Rangueil, Rangueil Hospital, INSERM1048, 31432 Toulouse, France.
Diabetol Metab Syndr. 2015 Sep 12;7:75. doi: 10.1186/s13098-015-0075-7. eCollection 2015.
Gut microbiota is now known to control glucose metabolism. Previous studies have shown that probiotics and prebiotics may improve glucose metabolism, but their effects have not been studied in combination with drug therapy. The aim of this study was to investigate whether probiotics and prebiotics combined with drug therapy affect diabetic outcomes.
Two different study designs were used to test gut microbiota modulating treatments with metformin (MET) or sitagliptin (SITA) in male C57Bl/6J mice. In Design 1, diabetes was induced with four-week feeding with a ketogenic, 72 kcal% fat diet with virtually no carbohydrates. Mice were then randomly divided into four groups (n = 10 in each group): (1) vehicle, (2) Bifidobacterium animalis ssp. lactis 420 (B420) (10(9) CFU/day), (3) MET (2 mg/mL in drinking water), or (4) MET + B420 (same doses as in the MET and B420 groups). After another 4 weeks, glucose metabolism was assessed with a glucose tolerance test. Fasting glucose, fasting insulin and HOMA-IR were also assessed. In Design 2, mice were fed the same 72 kcal% fat diet to induce diabetes, but they were simultaneously treated within their respective groups (n = 8 in each group): (1) non-diabetic healthy control, (2) vehicle, (3) SITA [3 mg/(kg*day)] (4) SITA with prebiotic polydextrose (PDX) (0.25 g/day), (5) SITA with B420 (10(9) CFU/day), and (6) SITA + PDX + B420. Glucose metabolism was assessed at 4 weeks, and weight development was monitored for 6 weeks.
In Design 1, with low-dose metformin, mice treated with B420 had a significantly lower glycemic response (area under the curve) (factorial experiment, P = 0.002) and plasma glucose concentration (P = 0.02) compared to mice not treated with B420. In Design 2, SITA + PDX reduced glycaemia in the oral glucose tolerance test significantly more than SITA only (area under the curve reduced 28 %, P < 0.0001). In addition, B420, PDX or B420+PDX, together with SITA, further decreased fasting glucose concentrations compared to SITA only (-19.5, -40 and -49 %, respectively, P < 0.01 for each comparison). The effect of PDX may be due to its ability to increase portal vein GLP-1 concentrations together with SITA (P = 0.0001 compared to vehicle) whereas SITA alone had no statistically significant effect compared to vehicle (P = 0.14).
This study proposes that combining probiotics and/or prebiotics with antidiabetic drugs improves glycemic control and insulin sensitivity in mice. Mechanisms could be related to incretin secretion.
现已明确肠道微生物群可控制葡萄糖代谢。既往研究表明，益生菌和益生元可能改善葡萄糖代谢，但尚未对它们与药物治疗联合使用的效果进行研究。本研究旨在调查益生菌和益生元联合药物治疗是否会影响糖尿病结局。
采用两种不同的研究设计，在雄性C57Bl/6J小鼠中测试用二甲双胍（MET）或西他列汀（SITA）调节肠道微生物群的治疗方法。在设计1中，通过喂食四周生酮、72千卡%脂肪且几乎不含碳水化合物的饮食诱导糖尿病。然后将小鼠随机分为四组（每组n = 10）：（1）赋形剂组，（2）动物双歧杆菌乳酸亚种420（B420）（10⁹CFU/天），（3）MET（饮用水中2mg/mL），或（4）MET + B420（剂量与MET组和B420组相同）。再过4周后，通过葡萄糖耐量试验评估葡萄糖代谢。还评估了空腹血糖、空腹胰岛素和HOMA-IR。在设计2中，给小鼠喂食相同的72千卡%脂肪饮食以诱导糖尿病，但在各自组内同时进行治疗（每组n = 8）：（1）非糖尿病健康对照，（2）赋形剂组，（3）SITA [3mg/（kg·天）]，（4）SITA与益生元聚葡萄糖（PDX）（0.25g/天），（5）SITA与B420（10⁹CFU/天），以及（6）SITA + PDX + B420。在4周时评估葡萄糖代谢，并监测6周的体重增长情况。
在设计1中，使用低剂量二甲双胍时，与未用B42处理的小鼠相比，用B420处理的小鼠血糖反应（曲线下面积）显著更低（析因实验，P = 0.002），血浆葡萄糖浓度也更低（P = 0.02）。在设计2中，SITA + PDX在口服葡萄糖耐量试验中降低血糖水平明显超过单独使用SITA（曲线下面积减少28%，P < 0.0001）。此外，与单独使用SITA相比，B420、PDX或B420 + PDX与SITA联合使用进一步降低了空腹血糖浓度（分别降低19.5%、40%和49%，每次比较P < 0.01）。PDX的作用可能归因于其与SITA一起增加门静脉GLP-1浓度的能力（与赋形剂组相比，P = 0.0001），而单独使用SITA与赋形剂组相比无统计学显著差异（P = 0.14）。
本研究表明，将益生菌和/或益生元与抗糖尿病药物联合使用可改善小鼠的血糖控制和胰岛素敏感性。作用机制可能与肠促胰岛素分泌有关。
