Gut microbes impact stroke severity

Here we show that gut microbiota directly impact host susceptibility for stroke, and adverse outcomes following stroke, through the dietary choline, gut microbiota, TMAO pathway. In initial gnotobiotic mouse stroke model studies, fecal microbial transplantation into germ-free recipient mice from low versus high TMAO-producing human donors was shown to transmit both capacity for TMAO generation and stroke severity. Next, employing independent murine stroke models with conventionally-reared mice, we showed that dietary supplementation with either choline or TMAO enhanced both cerebral infarct size and motor functional deficits. Finally, in additional gnotobiotic transplantation studies employing a synthetic microbial community lacking choline to trimethylamine (TMA) transforming activity plus/minus genetically engineered human commensals (wild-type versus delta cutC mutant), we show that harboring a functional gut microbial cutC gene is sufficient to transmit enhanced TMA(O) production, cerebral infarct size and functional deficits within a host. Collectively, these studies reveal that gut microbiota in general, and the TMAO pathway specifically, directly impacts host susceptibility for stroke and its adverse functional outcomes.

本研究证实，肠道菌群（gut microbiota）可通过膳食胆碱、肠道菌群与三甲胺N-氧化物（TMAO）通路，直接影响宿主对脑卒中（stroke）的易感性及卒中后不良结局。在早期限菌小鼠脑卒中模型研究中，将产TMAO能力存在差异的人类供体的粪便菌群移植到无菌受体小鼠体内，结果显示该移植可同时传递TMAO生成能力与脑卒中严重程度。随后，我们采用独立的常规饲养小鼠脑卒中模型，证实膳食补充胆碱或TMAO均可增大脑梗死体积并加重运动功能缺损。最后，在后续的限菌移植研究中，我们使用缺乏胆碱向三甲胺（TMA）转化活性的合成微生物群落，搭配或不搭配基因工程改造的人类共生菌（野生型与ΔcutC突变株），结果证实，宿主携带具有功能的肠道菌群cutC基因（cutC gene），即可获得增强的TMA(O)生成能力、更大的脑梗死体积及更严重的功能缺损。综上，本系列研究表明，整体肠道菌群，尤其是TMAO通路，可直接影响宿主对脑卒中的易感性及其不良功能结局。