Impact of fiber supplementation on the butyrate synthesis of the intestinal microbiota and how it affects the risk for colorectal cancer.

纤维补充剂对肠道微生物群丁酸盐合成的影响及其如何影响结直肠癌的风险。

• 批准号: 338582098
• 负责人: Dr. Sören Ocvirk
• 金额: --
• 依托单位: Abteilung Molekulare Toxikologie (MTOX)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/338582098?language=en
• 关键词: Impact; fiber; supplementation; butyrate; synthesis

Evidence from epidemiological studies suggests that the consumption of fiber is associated with a reduced risk for colorectal cancer (CRC), but the specific mechanisms underlying the protective effects of fiber and its causal relationship with the human gut microbiota remain unclear. In the intestine, fiber is degraded by the commensal microbiota to short-chain fatty acids such as butyrate. Butyrate serves as energy source for colonic epithelial cells, affects gene transcription and cell cycle regulation and has significant anti-neoplastic and anti-inflammatory effects in vitro. CRC patients often exhibit an altered composition of the intestinal microbiota that is characterized by a reduced diversity and an impaired metabolic capacity to synthesize butyrate. Recent studies in CRC mouse models indicate that members of the intestinal microbiota and their capacity to synthesize butyrate affect colonic tumorigenesis, but evidence with regard to a causal link in a clinically relevant setting is lacking: the question arises, if high fiber consumption can shift a CRC-associated microbiota in such a way that higher amounts of intestinal butyrate are produced, which promote attenuated colonic tumorigenesis and ultimately reduce the risk for CRC in humans?To target this question, we are conducting a randomized controlled intervention trial in healthy Alaska Native (AN) people (n=60), which show one of the world’s highest CRC rates. Using a dietary intervention (fiber supplementation vs. control for 4 weeks) as proof-of-concept study for high fiber-mediated CRC risk reduction, we aim to identify the potentially beneficial effects of fiber on intestinal inflammation, proliferation, the gut microbiota and its metabolome in a CRC high-risk population. The proposal submitted here will enable us to show, if the microbiota-dependent effects of a high fiber diet, observed in the clinical trial, also confer an attenuated colonic tumorigenesis. For this, we will use a CRC mouse model to determine the impact of fiber/butyrate on colonic tumor formation as clinically relevant end-point and identify related microbe-host interactions. Germ-free wild-type mice are associated with the fecal microbiota from representative healthy AN people (“humanized mice”) and receive a high-fiber or control diet. AOM/DSS treatment reveals the impact of microbiota-dependent butyrate synthesis on colonic tumorigenesis including markers of inflammation/proliferation associated with CRC. Completing the observations from the clinical trial, the submitted experiments will provide significant insight into the role of fiber- and microbiota-dependent levels of butyrate in CRC risk. Using this dual approach, correlations from the clinical trial can be validated regarding their functional consequences (=colonic tumorigenesis) and potential markers of human CRC risk identified and analyzed in parallel.

流行病学研究的证据表明，纤维的摄入与结直肠癌（CRC）风险降低有关，但纤维保护作用的具体机制及其与人类肠道微生物群的因果关系仍不清楚。在肠道中，纤维被肠道微生物群降解为短链脂肪酸，如丁酸盐。丁酸作为结肠上皮细胞的能量来源，影响基因转录和细胞周期调控，并在体外具有显著的抗肿瘤和抗炎作用。CRC患者通常表现出肠道微生物群组成的改变，其特征在于多样性降低和合成丁酸盐的代谢能力受损。最近在CRC小鼠模型中的研究表明，肠道微生物群成员及其合成丁酸盐的能力影响结肠肿瘤发生，但缺乏临床相关环境中因果关系的证据：问题是，如果高纤维消耗可以改变CRC相关的微生物群，从而产生更大量的肠丁酸盐，促进减弱结肠肿瘤发生并最终降低人类CRC的风险？为了解决这个问题，我们正在健康的阿拉斯加原住民（AN）中进行随机对照干预试验（n=60），该试验显示出世界上最高的CRC率之一。使用饮食干预（纤维补充与对照4周）作为高纤维介导的CRC风险降低的概念验证研究，我们的目标是确定纤维对肠道炎症，增殖，肠道微生物群及其代谢的潜在有益影响CRC高危人群。这里提交的提案将使我们能够表明，如果在临床试验中观察到的高纤维饮食的微生物群依赖性作用也会减弱结肠肿瘤发生。为此，我们将使用CRC小鼠模型来确定纤维/丁酸盐对结肠肿瘤形成的影响作为临床相关终点，并确定相关的微生物-宿主相互作用。无菌野生型小鼠与来自代表性健康AN人（“人源化小鼠”）的粪便微生物群相关，并接受高纤维或对照饮食。AOM/DSS治疗揭示了微生物群依赖性丁酸盐合成对结肠肿瘤发生的影响，包括与CRC相关的炎症/增殖标志物。完成临床试验的观察，提交的实验将提供对纤维和微生物群依赖性丁酸水平在CRC风险中的作用的重要见解。使用这种双重方法，临床试验的相关性可以验证其功能后果（=结肠肿瘤发生）和平行鉴定和分析的人类CRC风险的潜在标志物。