Gut microbiota-related mechanisms that impact colorectal cancer risk after bariatric surgery

摘要：减肥手术作为目前治疗病态肥胖症最有效的方法，已变得越来越多。 在美国很常见。除了显著和持续的体重减轻，减肥手术还带来了巨大的变化 在人体生理的许多方面，包括血糖控制、胆汁酸代谢、免疫监测、 和肠道微生物区系。这些变化，如果在手术后持续，可能会影响结直肠癌(CRC)的风险。 一方面，减少肥胖、胰岛素抵抗和全身炎症可能会降低结直肠癌的风险；同时， 暴露于某些胆汁酸(如熊去氧胆酸)和有益细菌(如阿克曼氏菌)的增加 粘液杆菌和普氏杆菌)也可能降低结直肠癌的风险。另一方面，更多的暴露在 对其他胆汁酸(如脱氧胆酸)和细菌(如耐氧细菌)的耐受性可能会增加结直肠癌的风险 减肥手术。而肠道微生物区系与宿主新陈代谢和免疫的相互作用已被牵连 在结直肠癌病因学中，减肥手术引起肠道微生物区系的持续变化尚不清楚。 以及手术后“肠道微生物区系-宿主相互作用”如何影响结直肠癌风险。纵向研究： 需要重复收集生物标本(例如血液和粪便)和患者数据(例如饮食和药物) 来解决这些问题，但目前还缺乏。建立在减肥手术患者纵向队列的基础上， 我们建议在目标1(目标评估)中调查：手术前至术后1年和3年内 可能与结直肠癌相关的细菌(例如核梭杆菌、产肠毒素脆弱杆菌和PKS+大肠杆菌)； 主要微生物代谢物(如胆汁酸和短链脂肪酸)，以及已建立的系统性 和微生物炎症(例如，C反应蛋白和脂多糖结合蛋白)；在目标2(组学范围内的发现)： 最显著和持续变化的细菌、微生物代谢物以及炎症和免疫 使用鸟枪式元基因组学、全球代谢组学、 和蛋白质组学；目标3(活体实验)：后与前的因果关系和分子机制 外科肠道微生物区系在结直肠癌发生中的作用。我们将对抗生素进行粪便微生物区系移植(FMT)- 使用手术前和术后3年保存的粪便治疗的遗传性结直肠癌小鼠模型的比较 这些组之间的腺瘤/肿瘤负担、结肠细胞生物学以及全身和肠道炎症 小鼠接受的一组细菌的术后增幅最大且一致，如 目标2和控制力。利用减肥手术患者的纵向队列，并应用 在临床前模型中，我们的研究将填补关于持续后基因组学的研究空白 减肥手术中肠道微生物区系和微生物分子的变化及其对患者健康的影响 代谢、炎症和免疫学特征，以及最终的结直肠癌风险。我们的结果可能会转化为 就术后肠道健康和结直肠癌风险以及针对肠道微生物区系的新疗法提供更好的患者建议， 微生物分子和/或免疫监测，以降低病态肥胖症患者的CRC风险。

Abstract: Bariatric surgery, currently the most effective treatment for morbid obesity, has become increasingly common in the US. Besides substantial and sustained weight loss, bariatric surgery leads to dramatic changes in many aspects of human physiology, including glycemic control, bile acid metabolism, immunosurveillance, and gut microbiota. These changes, if sustained after surgery, may affect the risk of colorectal cancer (CRC). On one hand, reduced obesity, insulin resistance, and systemic inflammation may lower CRC risk; meanwhile, increased exposures to some bile acids (e.g., ursodeoxycholic acid) and beneficial bacteria (e.g., Akkermansia muciniphila & Faecalibacterium prausnitzii) may also lower CRC risk. On the other hand, increased exposures to other bile acids (e.g., deoxycholic acid) and bacteria (e.g., aerotolerant species) may increase CRC risk after bariatric surgery. While the interplays of gut microbiota with host metabolism & immunity have been implicated in CRC etiology, it is unclear what sustained changes in gut microbiota are induced by bariatric surgery and how post-surgery “gut microbiota-host interactions” may impact CRC risk. Longitudinal studies with repeated collections of biospecimens (e.g., blood & stool) and patient data (e.g., diet & medication) are needed to tackle these questions but currently lacking. ●Building on a longitudinal cohort of bariatric surgery patients, we propose to investigate, in Aim 1 (targeted evaluation): pre- to 1-year and 3-years post-surgery changes in potential CRC-related bacteria (e.g., Fusobacterium nucleatum, enterotoxigenic B. fragilis, & pks+ E. coli), major microbial metabolites (e.g., bile acids & short-chain fatty acids), and established markers of systemic and microbial inflammation (e.g., C-reactive protein & LPS-binding protein); in Aim 2 (omics-wide discovery): the most significantly and consistently altered bacteria, microbial metabolites, and inflammatory & immune response proteins at 1- and 3-years post- vs. pre-surgery, using shotgun metagenomics, global metabolomics, and proteomics; in Aim 3 (in vivo experiments): the causality and molecular mechanisms of post- vs. pre- surgery gut microbiota in CRC carcinogenesis. We will perform fecal microbiota transplant (FMT) on antibiotic- treated, genetic mouse models of CRC using preserved pre- and 3-years post-surgery stools and compare adenoma/tumor burden, colonocyte biology, and systemic & intestinal inflammation between those groups and with mice receiving a group of bacteria with the largest and consistent post-surgery increases as identified in Aim 2 and with control. ●Leveraging a longitudinal cohort of bariatric surgery patients and applying state-of- the-art multi-omics and FMT in pre-clinical models, our study will fill research gaps regarding sustained post- bariatric surgery changes in gut microbiota and microbial molecules and how they contribute to patients' metabolic, inflammatory, and immunological profiles, and eventually CRC risk. Our results may translate into better patient advice on post-surgery gut health and CRC risk and novel therapies targeting gut microbiota, microbial molecules, and/or immunosurveillance to reduce CRC risk among individuals with morbid obesity.