Association of gut bacterial genes and diet to colorectal neoplasia

 描述(申请人提供)：尽管越来越坚持常规筛查和治疗策略的进步，结直肠癌仍然是一个主要的健康问题。在美国，结直肠癌是癌症死亡的第三大原因。此外，由于老龄化人口的扩大，预计到2030年，这种疾病的发病率将增加52%。然而，除了常规筛查之外，很少有预防结直肠肿瘤(癌前病变和癌病变)的策略可用。大肠肿瘤(CRN)的病因是复杂的，然而，可改变的环境因素，包括饮食、肠道微生物区系和炎症，被认为是导致结直肠癌发生的主要因素。越来越多的证据支持，饮食是调节肠道微生物区系组成的最重要的环境因素之一，肠道微生物区系与CRN的发育有关。然而，促进肠道微生物区系不健康变化的饮食模式(生物失调)和促进CRN的细菌的丰富仍然不完全清楚。更好地了解CRN的促进机制，包括饮食和肠道微生物区系之间的相互作用，将极大地促进当前的知识，并为未来通过调节促进癌症的肠道细菌群来评估基于饮食的CRN预防策略提供平台。大多数研究都集中在特定的细菌或与CRN相关的肠道细菌种类上。然而，肠道细菌发挥CRN促进作用的机制尚未完全阐明。目前建议的主要目标是检查一组编码可能导致结直肠癌发生的促炎和DNA破坏毒素的细菌基因，并评估这些基因是否与癌前病变(高危腺瘤)和特定的饮食模式有关。这项研究的创新之处在于它侧重于对特定毒素编码的评估 细菌基因，而不是肠道细菌种类。我们的中心假设是，患有高危腺瘤的人将有更高的这些有毒基因的患病率，这些毒素通过导致DNA损伤和持久的炎症而导致癌症的发生。我们的研究旨在确定粪便和结肠组织中有毒细菌的基因图谱，并确定它们是否与高危腺瘤有关。我们还将评估有毒细菌基因的存在是否与炎症有关(目标1)。此外，我们将检查饮食模式和这些有毒基因在一年内的流行情况(目标2)。这项研究的意义在于，它解决了关于肠道微生物区系产生的促进CRN的有毒细菌副产物及其与特定饮食模式的关系的科学知识空白。这项研究产生的数据可能有助于阐明肠道微生物区系驱动的致癌机制，以及未来旨在减少接触有害细菌副产品的CRN预防饮食干预措施。

 DESCRIPTION (provided by applicant): Despite increasing adherence to routine screening and advances in therapeutic strategies, colorectal cancer is still a major health problem. Colorectal cancer is the 3rd leading cause of cancer death in the US. Moreover, the incidence of this disease is projected to increase by 52% by 2030 due to the expansion of the aging population. Yet, very few colorectal neoplasia (pre-cancerous and cancerous lesion) prevention strategies are available other than routine screening. The etiology of colorectal neoplasia (CRN) is complex; however, modifiable environmental factors including diet, the gut microbiota, and inflammation, are accepted as major contributors to colorectal carcinogenesis. Accumulating evidence supports that diet is one of the most important environmental factors that modulate gut microbiota composition and the gut microbiota has been implicated in CRN development. However, the dietary patterns that promote unhealthy changes in the gut microbiota (dysbiosis) and the enrichment of CRN-promoting bacteria are still incompletely understood. A better understanding of the CRN-promoting mechanisms, including the interplay between diet and the gut microbiota, would greatly advance current knowledge and serve as a platform for future studies evaluating diet- based CRN prevention strategies via the modulation of the cancer-promoting gut bacterial populations. Most studies have concentrated on specific bacteria or on profiling gut bacterial species associated with CRN. However, the mechanisms by which gut bacteria exert their CRN-promoting effects are not fully elucidated. The main goal of the current proposal is to examine a panel of bacterial genes encoding pro- inflammatory and DNA damaging toxins that may contribute to colorectal carcinogenesis and to evaluate if these genes are associated with pre-cancerous lesions (high-risk adenomas) and specific dietary patterns. The innovative aspect of this study is that it focuses on the evaluation of specific toxin-encoding bacterial genes rather than profiling gut bacterial species. Our central hypothesis is that individuals with high-risk adenomas will have a higher prevalence of these toxic genes and that these toxins contribute to carcinogenesis by causing DNA damage and the perpetuation of inflammation. Our study aims to characterize the toxic bacterial gene profile in stool and colonic tissue and to determine if they are associated with high-risk adenomas. We will also assess if presence of the toxic bacterial genes is associated with inflammation (Aim 1). Furthermore, we will examine dietary patterns and the prevalence of these toxic genes during a 1-year period (Aim 2). The significance of this study is that it addresses a gap in scientific knowledge regarding the CRN-promoting toxic bacterial by-products produced by the gut microbiota and their association with specific dietary patterns. The data generated by this study may shed light on the gut microbiota-driven carcinogenic mechanisms and on future dietary interventions for CRN prevention aiming at reducing exposure to injurious bacterial by-products.