Ethanol metabolizing Lactobacillus for cancer prevention

描述（申请人提供）：用于预防癌症的乙醇代谢乳酸杆菌。结直肠癌（CRC）的死亡率仅次于男性肺癌和女性乳腺癌。乙醇消耗是CRC的一个众所周知的危险因素。最近，宿主乙醇代谢基因多态性与乙醇相关癌症（主要是食管癌）的风险增加有关，但也与较小程度的结直肠癌有关。与食道不同，结肠充满了数万亿的细菌，它们将乙醇代谢成致癌物质乙醛。共生菌鼠李糖乳杆菌GG已被用于促进消化系统健康和预防结直肠癌近三十年。然而，这种细菌不代谢乙醇，因此可能对乙醇相关的结直肠癌有有限的作用。通过对乙醇代谢共生菌的分析，分离出两株能将乙醇代谢为乙酸盐的鼠李糖乳杆菌。这些菌株不仅具有鼠李糖L. rhamnosus GG的所有益生菌益处，而且还可以消除宿主肠道中的乙醇及其致癌代谢物乙醛。我们假设乙醇代谢鼠李糖可以降低肠道酒精相关癌症的风险。我们将追求两个具体目标：(i)研究鼠李糖编码乙醇代谢的基因；（ii）测试鼠李糖对小鼠乙醇相关肠道肿瘤发生的抑制作用。由于鼠李糖GG对动物和人类的非乙醇相关性结直肠癌有一定的作用，因此对乙醇代谢鼠李糖的研究可能会导致对乙醇相关性和非乙醇相关性结直肠癌的更有效预防的发展。

DESCRIPTION (provided by applicant): Ethanol metabolizing Lactobacillus for cancer prevention. Mortality from colorectal cancer (CRC) is second only to that from lung cancer in men and breast cancer in women. Ethanol consumption is a well known risk factor for CRC. Recently, the host ethanol metabolism gene polymorphism has been linked to increased risks of ethanol-associated cancers, mainly esophageal cancer, but also to a lesser degree CRC. Unlike the esophagus, the colon is filled with trillions of bacteria that metabolize ethanol to carcinogenc acetaldehyde. The commensal bacterium Lactobacillus rhamnosus GG has been used for nearly three decades to promote the digestive health and to prevent CRC. However, this bacterium does not metabolize ethanol and thus might have a limited effect against ethanol-associated CRC. By analyzing commensal bacteria for ethanol metabolism we have isolated two L. rhamnosus strains that metabolize ethanol to acetate. These strains not only have all the probiotic benefits of L. rhamnosus GG, but they can also eliminate ethanol and its carcinogenic metabolite acetaldehyde from the host intestine. We hypothesize that ethanol metabolizing L. rhamnosus can reduce the risk of ethanol-associated cancers in the gut. We will pursue two specific aims: (i) study L. rhamnosus genes encoding ethanol metabolism; and (ii) test L. rhamnosus for inhibition of ethanol-associated gut tumorigenesis in mice. Because L. rhamnosus GG has shown some effect against ethanol-unassociated CRC in animals and humans, the proposed study with an ethanol-metabolizing L. rhamnosus will likely lead to the development of a more effective prophylaxis against both ethanol-associated and ethanol-unassociated CRC. PUBLIC HEALTH RELEVANCE: It has been well established that consistent alcohol consumption doubles the risk for colon cancer, but current cancer preventive methods, such as the dietary supplement made with probiotic Lactobacillus, do not eliminate alcohol and therefore have a limited effect against alcohol-associated colon cancer. We propose to study an alcohol-metabolizing probiotic Lactobacillus, which will likely lead to the development of a novel, more effective prophylaxis against both alcohol-associated and alcohol- unassociated colon cancer.