Functional impact of bile acids conversion by the gut microbiome on colorectal cancer

人类肠道微生物区系与结直肠癌(CRC)的发生有关。西化社会中结直肠癌发病率的增加与总体上有害的饮食习惯有关，并伴随着肠道微生物区系的变化。流行病学和微生物学研究指出饮食(如增加脂肪和红肉的摄入量)与结直肠癌发病率之间的联系，以及胆汁酸的潜在作用和肠道细菌对胆汁酸的代谢。然而，缺乏支持这些关系的实验证据。在本项目中，基于(I)自己的初步结果表明，在独特的APC1311/+猪结直肠癌模型中，饮食诱导的肠道微生物群的变化与病理恶化有关，以及(Ii)我们从猪肠分离的最先进的细菌菌株收集，我们将使用粪便微生物区系转移实验和定义的细菌群落，对次级胆汁酸在结直肠癌中的因果关系提供新的机制见解。我们将使用新产生的无菌Apc1638/N小鼠疾病模型，并结合分子方法，包括微生物区系和单细胞RNA测序以及代谢谱来评估影响微生物生态系统和宿主病理生理的变化。为了从机制上理解胆汁酸代谢的微生物生态并采取干预策略，我们将利用针对次级胆汁酸产生细菌的噬菌体，并在连续培养系统中使用最小的细菌联合体来测试它们对群落动态的影响。综上所述，该项目将使用创新的临床前模型对肠道微生物组活动在结直肠癌中的功能作用提供重要的见解。

The human gut microbiota has been implicated in the development of colorectal cancer (CRC). The increased incidence of CRC in Westernized societies is linked to overall detrimental dietary habits accompanied by shifts in intestinal microbiota profiles. Epidemiological and microbiological studies point at the association between diet (e.g. increased fat and red meat consumption) and the incidence of CRC and at the underlying role of bile acids and their metabolism by gut bacteria. However, experimental evidence underpinning these relationships is lacking. In the present project, based on (i) own preliminary results demonstrating diet-induced shifts in the gut microbiome linked to worsening of pathology in the unique APC1311/+ pig model of CRC, and (ii) our state-of-the-art collection of bacterial strains isolated from the pig intestine, we will provide novel mechanistic insights into the causal role of secondary bile acids in CRC using fecal microbiota transfer experiments and defined bacterial communities. We will use the newly generated germfree Apc1638/N mouse model of disease in combination with molecular methods, including microbiota and single-cell RNA sequencing as well as metabolic profiling to assess changes affecting both the microbial ecosystem and host pathophysiology. For mechanistic understanding of the microbial ecology of bile acid metabolism and towards interventional strategies, we will utilize phages targeting secondary bile acid-producing bacteria and test their impact on community dynamics using minimal bacterial consortia in continuous culture systems. Taken together, this project will deliver important insights into the functional role of gut microbiome activities in CRC using innovative pre-clinical models.