小柯机器人

德国基尔大学Christoph Kaleta研究小组与伦敦医学科学研究院Filipe Cabreiro研究小组合作取得一项新突破。他们采用宿主-微生物-药物-营养筛选的方式鉴定二甲双胍治疗的细菌效应因子。 2019年8月29日出版的《细胞》发表了这项成果。

科学家们着手解决了这样一个基本问题，即肠道微生物和营养物质（宿主生理学的关键调节因子）如何影响二甲双胍的作用。结合大肠杆菌和秀丽隐杆线虫这两种易于处理的遗传模型，研究团队开发了一个高通量的四向筛选，以确定潜在的宿主-微生物-药物-营养之间的相互作用。研究结果发现，微生物通过磷酸转移酶信号通路整合二甲双胍和饮食中的线索，该信号通路收敛于转录调节因子Crp。进一步表征二甲双胍对Crp下游的影响，结合对二甲双胍治疗的2型糖尿病患者体内微生物群的代谢模型，预测了微生物胍基丁胺的产生，胍基丁胺是二甲双胍对宿主脂质代谢和寿命影响的调节因子。这一高通量筛选平台为识别可利用的药物-营养-微生物组相互作用铺平了道路，并通过靶向微生物组治疗改善宿主健康和寿命。

据悉，二甲双胍是治疗II型糖尿病的一线药物，是一种很有前景的抗衰老药物。

附：英文原文

Title: Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy

Author: Rosina Pryor, Povilas Norvaisas, Georgios Marinos, Lena Best, Louise B. Thingholm, Leonor M. Quintaneiro, Wouter De Haes, Daniela Esser, Silvio Waschina, Celia Lujan, Reuben L. Smith, Timothy A. Scott, Daniel Martinez-Martinez, Orla Woodward, Kevin Bryson, Matthias Laudes, Wolfgang Lieb, Riekelt H. Houtkooper, Andre Franke, Liesbet Temmerman, Ivana Bjedov, Helena M. Cochemé, Christoph Kaleta, Filipe Cabreiro

Issue&Volume: 29 August 2019

Abstract: Metformin is the first-line therapy for treating type 2 diabetes and a promising anti-aging drug. We set out to address the fundamental question of how gut microbes and nutrition, key regulators of host physiology, affect the effects of metformin. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we developed a high-throughput four-way screen to define the underlying host-microbe-drug-nutrient interactions. We show that microbes integrate cues from metformin and the diet through the phosphotransferase signaling pathway that converges on the transcriptional regulator Crp. A detailed experimental characterization of metformin effects downstream of Crp in combination with metabolic modeling of the microbiota in metformin-treated type 2 diabetic patients predicts the production of microbial agmatine, a regulator of metformin effects on host lipid metabolism and lifespan. Our high-throughput screening platform paves the way for identifying exploitable drug-nutrient-microbiome interactions to improve host health and longevity through targeted microbiome therapies.

DOI: https://doi.org/10.1016/j.cell.2019.08.003

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30891-8#