The Impact of Gut Microbiota on the Sex Difference in Bladder Cancer

男性患膀胱癌（BCa）和死于膀胱癌的可能性是女性的3-5倍， BCa中这些性别差异的机制知之甚少。这被强调为主要的 资助机会公告（FOA）“膀胱癌生物学（PAR-19-184）”中的知识差距： 1)“确定膀胱癌发病率性别差异背后的生物学机制”;以及2） “调查微生物组在膀胱癌生物学中的作用”。缺乏理解的部分原因是 事实上，性别偏见因素往往是混淆的协变。例如，性染色体 与性激素结合在一起由于混杂的性质，个体性别偏见的影响 这些因素很难量化。肠道微生物群在性别之间存在显著差异。它潜在的性- 尽管有大量证据表明肠道微生物群发挥了 对癌症的发生、发展和治疗有着深远的影响。为了深入了解BCa的性别差异， 我们将检验以下假设：肠道微生物群在调节BCa发病率方面起着性别特异性作用， mortality.为了验证这一假设，我们设计了两个特定的目标，使用创新的遗传和基因组 战略布局首先，我们将确定消除微生物群是否会削弱BCa的性别差异 发病率和死亡率;其次，我们将确定与BCa密切相关的肠道微生物 发病率和死亡率。结论是，该提案预计将大大提高我们对以下问题的认识： 癌症中的性别差异，并确定与BCa密切相关的候选肠道微生物 发病率和死亡率。

Men are 3-5 times more likely than women to develop and die from bladder cancer (BCa) but the underlying mechanisms of these gender disparities in BCa are poorly understood. This is highlighted as the major knowledge gaps in the Funding Opportunity Announcement (FOA) “Biology of Bladder Cancer (PAR-19-184)”: 1) “identifying biological mechanisms underlying disparities in sex in bladder cancer incidence”; and 2) “investigating the role of the microbiome in the bladder cancer biology”. The lack of understanding is due in part to the fact that the sex-biasing factors are often confounding co-variants. For example, the sex chromosomes are coupled with the sex hormones. Because of the confounding nature, the impacts of individual sex-biasing factors are exceedingly difficult to quantify. Gut microbiota differs significantly between sexes. Its potential sex- specific role in BCa remains unknown despite a preponderance of evidence that gut microbiota exerts the profound effects on cancer initiation, progression and therapy. To gain insight onto the sex differences in BCa, we will test the hypothesis that the gut microbiota plays a sex-specific role in regulating BCa incidence and mortality. To test this hypothesis, we have designed two specific aims using the innovative genetic and genomic strategies. First, we will determine whether the eradication of microbiota blunts the sex differences in BCa incidence and mortality; And second, we will identify gut microorganisms that are closely associated with BCa incidence and mortality. Upon conclusion, the proposal is expected to significantly advance our knowledge of the gender disparities in cancer and to identify candidate gut microbes that are tightly associated with BCa incidence and mortality.