膀胱尿路微生物组组成及功能变化与膀胱癌相关性的研究

Bladder cancer is the most common malignancy of the genitourinary tract while the etiology is complicated and remains unknown. Recently, benefiting from the developed detection methods, many studies detected bacteria and human viruses in urinary bladder of individuals in various conditions. However, due to the fact that the microbes are diverse and unculturable, in current studies of bladder cancer, the microbes as one of the potential causative factors have been ignored. It has been verified by human microbiome studies that microbes deeply impact on human health, thus we hypothesize in this proposal that the development of bladder cancer correlates to the microbes in the microenvironments of urinary bladder. In our previous studies, based on high throughput sequencing and bioinformatics, we developed a series of pipelines for metagenomics analysis of human microbes; using this culture-independent method, through a limited case-control study, we tentatively observed the correlation between alteration of urinary microbiome and bladder cancer. Therefore, this proposed project aims to reveal the differences of microbiome composition and functions in urinary bladder between healthy humans and patients with bladder cancer and on genomic level identify the core microbiome, microbial genes and metabolic pathways that might be significantly correlated with bladder cancer through a large-scale case-control study using developed metagenomics pipelines. Results gained from this study will be helpful to reveal the causative factors of bladder cancer from the microbial angle, find related microbial markers which can be used to screen and monitor bladder cancer in the early stage and after surgery, respectively, and finally, improve the cure rate of the patients.

膀胱癌是我国发病率最高的泌尿系统肿瘤且病因复杂。 近些年检测技术的发展使很多研究证实在各种人的膀胱尿路环境中存在细菌和病毒。然而由于其中微生物的多样性且难以获得纯培养，当前膀胱癌致病因素的研究忽视了可能的微生物因素。人体微生物组学研究证实了微生物高度影响人体健康，这让我们有理由推测膀胱癌的发生和其周围微环境中的微生物存在相关性。 前期工作中，基于高通量测序和生物信息学，我们发展了一系列的元基因组学分析流程，借助这种免培养的微生物学分析方法，在有限的病例对照研究样本中初步观察到膀胱尿路细菌组成变化和膀胱癌的关系。因此，本课题拟通过大规模的病例对照研究，揭示健康人体和膀胱癌患者膀胱尿道内微生物组组成与功能差异，在基因组水平上鉴定与膀胱癌有显著相关的核心微生物组、基因和代谢途径。研究结果将有助于我们从微生物角度揭示膀胱癌成因，发现相关微生物标志物，以期用于膀胱癌早期筛查和术后监控，提高治愈率。

最近的研究表明，微生物可能与膀胱癌的发生和发展有关。本研究的目的是，鉴定与膀胱癌相关的共同核心细菌。我们用16S rRNA基因测序的方法，对膀胱癌患者的尿液微生物进行了分析，我们实验室收集的24份膀胱癌样本结果显示，在属的水平，有31个共同的核心细菌。此外，利用来分析之前两个实验室已发表的膀胱癌和健康人数据，发现有4个共同核心细菌显著地在膀胱癌样品中存在。尤其是Acinetobacter，在膀胱癌样本中的含量更高。据文献报道，Acinetobacter不仅与生物膜的形成有关，还与上皮细胞的粘附和侵袭、粘膜屏障中磷脂降解引起的细菌传播以及宿主免疫反应的逃逸有关。因此，Acinetobacter可能与膀胱癌有关，是膀胱癌潜在的微生物标志物。 但是，由于受试者数量有限，需要进一步研究以更好地了解微生物在膀胱癌中的作用，为其诊断、预后和治疗提供新的生物标志物。