Development of genetic systems for human-associated methanogens

 描述（由申请人提供）：这个高风险/高回报项目的目标是开发人类相关产甲烷菌实验操作所需的工具。这些肠道微生物在所有人类中定居，对宿主营养和整体健康做出了重大贡献。产甲烷菌和人类微生物群的其他成员之间的代谢相互作用强烈影响消化过程的效率，以及被宿主吸收的结肠发酵产物。此外，一些与人类相关的产甲烷菌是炎性细胞因子的有效诱导物，而另一些产甲烷菌则产生与动脉粥样硬化和癌症发展相关的代谢物。考虑到这些观察结果，产甲烷菌携带与许多病理状况相关并不奇怪，包括肥胖症、炎性肠病、肠癌和牙周病。人们提出了许多假设来解释产甲烷菌与这些健康问题之间的联系;不幸的是，这些想法的实验支持极其缺乏。三个因素导致了这种稀缺性。首先，所有的产甲烷菌都对氧气非常敏感，需要专门的厌氧技术，但这并没有被广泛采用;其次，人类相关产甲烷菌的遗传操作方法是不存在的;第三，产甲烷菌的研究传统上仅限于环境和能源相关的主题。我们建议补救这种情况的三个人类相关的产甲烷菌的优势物种：史密斯甲烷短杆菌，甲烷球菌stadtmanae和最近发现的甲烷massiliicoccus发光。为了实现这一目标，我们建议开发人类相关产甲烷菌的遗传系统，并获得所需的基因组和转录组资源，以告知和指导正在进行的这些重要微生物的遗传分析。

 DESCRIPTION (provided by applicant): The goal of this high-risk/high-reward project is to develop the tools needed for experimental manipulation of human-associated methanogens. These commensal microorganisms colonize all humans, making significant contributions to host nutrition and overall health. The metabolic interactions between methanogens and other members of the human microbiota strongly influence the efficiency of the digestive process, as well as the colonic fermentation products that are absorbed by the host. Moreover, some human-associated methanogens are potent inducers of inflammatory cytokines, while others produce metabolites linked to the development of atherosclerosis and cancer. Given these observations, it is not surprising that methanogen carriage is correlated with a number of pathological conditions including obesity, inflammatory bowel disease, intestinal cancers and periodontal disease. Numerous hypotheses have been put forward to explain the linkage between methanogens and these health issues; unfortunately, experimental support for these ideas is exceedingly scarce. Three factors have contributed to this scarcity. First, all methanogens are exquisitely sensitive to oxygen and require specialized anaerobic techniques that are not widely employed; second, methods for genetic manipulation of human-associated methanogens are non-existent; and third, methanogen research has traditionally been restricted to the environmental and energy related topics. We propose to remedy this situation for the three of the dominant species of human-associated methanogens: Methanobrevibacter smithii, Methanospheara stadtmanae and the recently discovered Methanomassiliicoccus luminyensis. To achieve this goal we propose to develop genetic systems for human-associated methanogens and to acquire the genomic and transcriptomic resources needed to inform and direct the ongoing genetic analyses of these important microorganisms.