Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Intestinal Microbiology Research Group, Department of Molecular Toxicology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany.
Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Semin Cancer Biol. 2021 Aug;73:347-355. doi: 10.1016/j.semcancer.2020.10.003. Epub 2020 Oct 16.
Colorectal cancer (CRC) risk is predominantly driven by environmental factors, in particular diet. A high intake of dietary fat has been implicated as a risk factor inducing the formation of pre-neoplastic lesions (e.g., adenomatous polyps) and/or exacerbating colonic tumorigenesis. Recent data attributed the tumor-promoting activity of high-fat diets to their effects on gut microbiota composition and metabolism, in particular with regard to bile acids. Bile acids are synthesized in the liver in response to dietary fat and facilitate lipid absorption in the small intestine. The majority of bile acids is re-absorbed during small intestinal transit and subjected to enterohepatic circulation. Bile acids entering the colon undergo complex biotransformation performed by gut bacteria, resulting in secondary bile acids that show tumor-promoting activity. Excessive dietary fat leads to high levels of secondary bile acids in feces and primes the gut microbiota to bile acid metabolism. This promotes an altered overall bile acid pool, which activates or restricts intestinal and hepatic cross-signaling of the bile acid receptor, farnesoid X receptor (FXR). Recent studies provided evidence that FXR is a main regulator of bile acid-mediated effects on intestinal tumorigenesis integrating dietary, microbial and genetic risk factors for CRC. Selective FXR agonist or antagonist activity by specific bile acids depends on additional factors (e.g., bile acid concentration, composition of bile acid pool, genetic instability of cells) and, thus, may differ in healthy and tumorigenic conditions in the intestine. In conclusion, fat-mediated alterations of the gut microbiota link bile acid metabolism to CRC risk and colonic tumorigenesis, exemplifying how gut microbial co-metabolism affects colon health.
结直肠癌（CRC）的风险主要由环境因素驱动，尤其是饮食。高脂肪饮食摄入过多被认为是诱导前肿瘤病变（如腺瘤性息肉）形成和/或加剧结肠肿瘤发生的危险因素。最近的数据将高脂肪饮食的促肿瘤活性归因于它们对肠道微生物群组成和代谢的影响，特别是与胆汁酸有关。胆汁酸在肝脏中合成，以响应饮食中的脂肪，并促进小肠中的脂质吸收。大部分胆汁酸在小肠转运过程中被重新吸收，并进行肠肝循环。进入结肠的胆汁酸经历肠道细菌的复杂生物转化，导致具有促肿瘤活性的次级胆汁酸。过量的膳食脂肪导致粪便中次级胆汁酸水平升高，并使肠道微生物群适应胆汁酸代谢。这促进了整体胆汁酸池的改变，激活或限制了胆汁酸受体法尼醇 X 受体（FXR）在肠道和肝脏中的交叉信号转导。最近的研究提供了证据，表明 FXR 是胆汁酸介导的对肠道肿瘤发生作用的主要调节剂，整合了 CRC 的饮食、微生物和遗传风险因素。特定胆汁酸的选择性 FXR 激动剂或拮抗剂活性取决于其他因素（例如，胆汁酸浓度、胆汁酸池的组成、细胞的遗传不稳定性），因此，在肠道的健康和肿瘤发生条件下可能不同。总之，脂肪介导的肠道微生物群改变将胆汁酸代谢与 CRC 风险和结肠肿瘤发生联系起来，说明了肠道微生物共代谢如何影响结肠健康。
