BACMETH: Bacterial methylation of the human gut microbiome in response to diet for improvement of cardiometabolic health

肥胖和代谢性疾病是全球健康挑战，也是心血管疾病的主要危险因素。饮食是心脏代谢疾病的关键可改变风险因素，但研究具有挑战性，部分原因是饮食对代谢的反应是高度个性化的。饮食对人体肠道中的微生物群落，即肠道菌群产生重大影响，而肠道菌群又在代谢健康和疾病中起着关键作用。了解饮食、肠道微生物群和心脏代谢健康之间的联系，对于提供解决肥胖危机及其临床后果的工具至关重要。虽然饮食引起的人类肠道微生物群的变化已经在代谢健康和疾病中被确定，但我们对介导这些影响的细菌分子过程的理解仍然有限。我们肠道中细菌的DNA甲基化可能起着关键的机制作用。细菌甲基化在全基因组范围内尚未得到充分的研究，但最近的测序进展表明，甲基化是广泛存在的，在细菌基因功能的调控中起着重要作用，并可能提供有价值的稳定的基因调控生物标志物。该项目将人类肠道细菌甲基化作为一种新工具来揭示介导饮食对心脏代谢健康影响的分子途径。该假说认为，饮食会引起细菌甲基化的变化，从而对肠道环境及其微生物群落产生功能性影响，并影响人类健康。工作流程包括1/饮食干预试验，2/大型特征良好的队列和3/功能实验。该项目将评估饮食诱导的细菌甲基化标记与心脏代谢特征的细菌甲基化标记是否可以解释饮食代谢反应的个体差异及其对健康的下游影响。这些新的机制见解和工具将有助于促进和优化心脏代谢疾病的预防。

Obesity and metabolic disease are a global health challenge and major risk factors for cardiovascular disease. Diet is a key modifiable risk factor for cardiometabolic disease but is challenging to study partly because metabolic response to diet is highly personalised. Diet exerts a major influence on the community of microbes in the human gut, the gut microbiota, which in turn plays a key role in metabolic health and disease. Understanding the links between diet, gut microbiota, and cardiometabolic health is crucial to provide tools to tackle the obesity crisis and its clinical consequences.Although diet-induced changes to the human gut microbiota have been identified in metabolic health and disease, our understanding of the bacterial molecular processes mediating these effects remains limited. DNA methylation of bacteria in our gut could play a key mechanistic role. Bacterial methylation has been under-explored at genome-wide scale, but recent developments in sequencing show that methylation is wide-spread, plays important roles including in regulation of bacterial gene function, and may provide a valuable stable biomarker of gene regulation.This project will characterise human gut bacterial methylation as a novel tool to uncover molecular pathways mediating diet impacts on cardiometabolic health. The hypothesis is that diet induces changes in bacterial methylation, which have functional consequences on the intestinal environment and its microbial community, and affect human health. The workflow includes 1/ diet intervention trials, 2/ large well-characterised cohorts, and 3/ functional experiments. The project will assess if diet-induced bacterial methylation marks together with bacterial methylation signatures of cardiometabolic traits can explain the inter-individual variability in metabolic response to diet, and its downstream effect on health. These novel mechanistic insights and tools will help to promote and optimise cardiometabolic disease prevention.