Development of genetic systems for human-associated methanogens

 描述(由申请者提供)：这个高风险/高回报项目的目标是开发实验操作人类相关产甲烷菌所需的工具。这些共生微生物在所有人类中定居，对宿主的营养和整体健康做出了重大贡献。产甲烷菌与人类微生物区系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者，而另一些则产生与动脉粥样硬化和癌症的发展有关的代谢物。鉴于这些观察结果，甲烷菌携带与包括肥胖、炎症性肠病、肠癌和牙周病在内的许多病理疾病相关也就不足为奇了。已经提出了许多假说来解释产甲烷菌和这些健康问题之间的联系；不幸的是，这些想法的实验支持非常少。造成这种稀缺的原因有三个。首先，所有产甲烷菌对氧气都非常敏感，需要专门的厌氧技术，但没有得到广泛应用；其次，目前还不存在对与人类相关的产甲烷菌进行基因操作的方法；第三，产甲烷菌的研究传统上仅限于与环境和能源有关的主题。我们建议对与人类相关的三种主要产甲烷菌：史密斯甲烷短杆菌、斯塔特曼氏甲烷杆菌和最近发现的发光甲烷杆菌进行补救。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.