Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.
American University of Beirut Medical Center, Department of Internal Medicine, Beirut, Lebanon.
J Mol Endocrinol. 2020 Jan;64(1):29-42. doi: 10.1530/JME-19-0132.
Diabetic dysbiosis has been described as a novel key player in diabetes and diabetic complications. However, the cellular/molecular alterations associated with dysbiosis remain poorly characterized. For that, control, non-obese type 2 diabetic MKR mice and MKR mice treated with butyrate were used to delineate the epigenetic, cellular and molecular mechanisms by which dysbiosis associated with diabetes induces colon shortening and inflammation attesting to gastrointestinal disturbance. Our results show that dysbiosis is associated with T2DM and characterized by reduced Bacteroid fragilis population and butyrate-forming bacteria. The reduction of butyrate-forming bacteria and inadequate butyrate secretion result in alleviating HDAC3 inhibition and altering colon permeability. The observed changes are also associated with an increase in ROS production, a rise in NOX4 proteins, and a shift in the inflammatory markers, where IL-1β is increased and IL-10 and IL-17α are reduced. Treatment with butyrate restores the homeostatic levels of NOX4 and IL-1β. In summary, our data suggest that in T2DM, dysbiosis is associated with a reduction in butyrate content leading to increased HDAC3 activity. Butyrate treatment restores the homeostatic levels of the inflammatory markers and reduces ROS production known to mediate diabetes-induced colon disturbance. Taken together, our results suggest that butyrate could be a potential treatment to attenuate diabetic complications.
糖尿病肠道菌群失调已被描述为糖尿病及其并发症的一个新的关键因素。然而，与肠道菌群失调相关的细胞/分子变化仍未得到很好的描述。为此，我们使用对照、非肥胖型 2 型糖尿病 MKR 小鼠和用丁酸盐治疗的 MKR 小鼠，来描绘与糖尿病相关的肠道菌群失调诱导结肠缩短和炎症的表观遗传、细胞和分子机制，这表明存在胃肠道紊乱。我们的结果表明，肠道菌群失调与 T2DM 有关，其特征是脆弱拟杆菌种群减少和产生丁酸盐的细菌减少。产生丁酸盐的细菌减少和丁酸盐分泌不足导致 HDAC3 抑制缓解和结肠通透性改变。观察到的变化还与 ROS 产生增加、NOX4 蛋白升高以及炎症标志物的变化有关，其中 IL-1β 增加，IL-10 和 IL-17α 减少。丁酸盐治疗恢复了 NOX4 和 IL-1β 的稳态水平。总之，我们的数据表明，在 T2DM 中，肠道菌群失调与丁酸盐含量减少有关，导致 HDAC3 活性增加。丁酸盐治疗恢复了炎症标志物的稳态水平，并减少了已知介导糖尿病引起的结肠紊乱的 ROS 产生。综上所述，我们的研究结果表明，丁酸盐可能是一种潜在的治疗方法，可以减轻糖尿病的并发症。
