Mechanism by which H2S-producing bacteria influence development of colorectal cancer

 描述（由申请人提供）：结直肠癌（CRC）是一种常见的恶性肿瘤，是美国癌症相关死亡的第三大原因。患有炎症性肠病（IBD）的患者特别容易发生结肠炎相关的CRC（CAC），其通常表现出快速进展，对治疗反应差和高死亡率。越来越多的证据表明肠道微生物群，更具体地说是微生物生态失调， CRC/CAC的发病机制。特别地，某些肠道细菌可以受到环境因素的影响（例如，炎症）并通过产生促肿瘤代谢物发挥致癌功能。小奇异菌和具核梭杆菌在含硫酸盐化合物如蛋氨酸的发酵过程中产生H2S。这两种产生硫化氢的细菌（HSPB）都是正常肠道微生物群的次要成员，但最近发现在CRC患者中的比例过高。重要的是，H2S具有诱导炎症的能力，并具有遗传毒性和潜在的促肿瘤发生特性。最近，F.在Apcmin/+小鼠模型（一种常用的CRC动物模型）中，显示出具有核质的细胞增强结肠肿瘤的发展。然而，H2S在F.核介导的致癌作用尚未建立。在初步研究中，我们发现A.小儿炎症性肠病的严重程度呈正相关 而A. parvulum通过产生H2S而加重Il 10-/-小鼠的结肠炎。A.小孢子来源的H2S在CRC发病机制中的作用尚不清楚。此外，据报道，饮食蛋氨酸水平调节肠道致癌作用。HSPB是否与膳食蛋氨酸的癌症调节作用有关尚不清楚。我们的中心假设是HSPB，特别是A。parvulum和F.核质，通过产生H2S促进肠肿瘤发生。本项目的目标是确定HSPB和HSPB衍生的H2S在CRC/CAC中的作用，并评估饮食蛋氨酸对HSPB介导的致癌作用的影响。本研究的具体目的如下：1）确定A. parvulum和F.使用无菌的Apcmin/+和IllO-/-;Apcmin/+小鼠; 2）确定膳食甲硫氨酸对HSPB介导的肠肿瘤发生的影响。我们的研究结果将大大推进微生物代谢活动和肠道病理之间的相互作用的研究领域，通过建立热休克蛋白B是肠道肿瘤发生的重要贡献者，饮食干预可以调节这种活动。这些研究结果将构成更详细的分析HSPB基因调控和干预，以减轻其致癌潜力的背景。

 DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is a common malignancy and the third leading cause of cancer-related deaths in the United Sates. Patients with inflammatory bowel diseases (IBD) are particularly susceptible to developing colitis-associated CRC (CAC), which often shows rapid progression, poor response to treatment and high mortality. Growing evidence links the intestinal microbiota, more specifically microbial dysbiosis, to CRC/CAC pathogenesis. In particular, certain commensal bacteria can be influenced by environmental cues (e.g., inflammation) and exert carcinogenic functions by producing pro-tumorigenic metabolites. Atopobium parvulum and Fusobacterium nucleatum produce H2S during fermentation of sulfate-containing compounds such as methionine. Both hydrogen sulfide-producing bacteria (HSPB) are minor members of the normal gut microbiota but were recently found to be overrepresented in CRC patients. Importantly, H2S has the capacity to induce inflammation and possesses genotoxic and potentially pro-tumorigenic properties. Recently, F. nucleatum was shown to enhance colonic tumor development in the Apcmin/+ mouse model, a commonly used animal model for CRC. However, the role of H2S in F. nucleatum-mediated carcinogenesis has not been established. In preliminary studies, we found that the relative abundance of A. parvulum positively correlated with the severity of pediatric IBD and that A. parvulum exacerbated colitis in Il10-/- mice through production of H2S. Whether A. parvulum-derived H2S plays a role in CRC pathogenesis is not clear. Furthermore, dietary methionine levels were reported to modulate intestinal carcinogenesis. Whether HSPB are implicated in the cancer-modulating effect of dietary methionine is unknown. Our central hypothesis is that HSPB, specifically A. parvulum and F. nucleatum, promote intestinal tumorigenesis through production of H2S. The goal of this project is to determine the role of HSPB and HSPB-derived H2S in CRC/CAC and evaluate the impact of dietary methionine on HSPB-mediated carcinogenesis. Our specific aims are as follows: 1) Determine the cancer-promoting potential of A. parvulum and F. nucleatum using germ- free Apcmin/+ and Il10-/-;Apcmin/+ mice; 2) Determine the impact of dietary methionine on HSPB-mediated intestinal tumorigenesis. Our findings will significantly move forward the field of research on the interplay between microbial metabolic activities and intestinal pathologies by establishing that HSPB are important contributors to intestinal tumorigenesis and that dietary intervention could modulate this activity. These findings will constitute the background for more detailed analysis of HSPB gene regulation and intervention to alleviate their carcinogenic potential.