Tolerance defenses in host-microbiota interactions

 描述（由申请人提供）：消瘦综合征是一种代谢失调状态，其中肌肉和脂肪组织严重耗竭，伴有体重减轻。消瘦是感染性和炎症性疾病的重要后遗症，导致显著的发病率和死亡率。目前的范例是炎症驱动消耗，然而目前通过抑制炎症反应来拮抗消耗的努力几乎没有成功。所提出的研究表明，哺乳动物肠道微生物群的特定成分可以拮抗由肠道损伤和肠道病原体鼠伤寒沙门氏菌引发的消耗性病理。这种保护不能归因于限制导致消耗性发病机制的典型炎症介质或通过增强宿主免疫应答，这表明微生物群可以通过限制消耗性病理来促进宿主耐受性防御。这一建议的中心假设是，肠上皮细胞，E。coli O21：H+直接操纵宿主生理学，通过拮抗感染/炎症诱导的消耗而不影响消耗的典型炎症介质来促进耐受性。拟议的研究将解决：1）确定肠道微生物群保护骨骼肌免于消耗的机制。初步研究结果表明，该菌的Escherosal、E.大肠杆菌O21：H+通过操纵IGF-1信号通路来限制由肠损伤和感染诱导的骨骼肌消耗，IGF-1信号通路是骨骼肌大小的关键调节器。2)确定肠道微生物群如何影响 脂肪组织生理学初步数据表明，肠道定植与E。coli O 21：H+足以防止白色脂肪组织（WAT）的浪费。此外，初步研究表明，E.大肠杆菌O21：H+阻止了与棕色脂肪相关的WAT的生理变化--一个称为WAT布朗宁的过程。这些研究将通过关注有助于这些过程的已知机制-通过交感神经系统和先天免疫系统的信号传导来确定这种植物如何限制WAT萎缩和布朗宁。3)保护微生物群免受肠道感染和损伤引起的消耗所需的细胞和遗传因素是什么？将使用细菌突变体来确定防止浪费所必需的微生物因素。小鼠突变体将用于确定感受E. coli O21：H+介导该微生物赋予的保护作用。这些研究将集中在先天免疫系统的一个关键协调者，称为炎性小体。耐受性防御介导宿主-微生物群相互作用的发现，微生物已经进化出促进耐受性的机制，以及拮抗消耗的抗生素的鉴定代表了对宿主-微生物群相互作用的基本新见解，并形成了该提议的基础。

 DESCRIPTION (provided by applicant): Wasting syndrome is a dysregulated metabolic state in which there is a profound depletion of muscle and fat tissue accompanied by weight loss. Wasting is an important sequela of infectious and inflammatory conditions that accounts for significant morbidity and mortality. A current paradigm is that inflammation drives wasting, however current efforts to antagonize wasting by inhibiting the inflammatory response have met with little success. The studies presented demonstrate that specific constituents of the mammalian intestinal microbiota can antagonize wasting pathology triggered by intestinal injury and the intestinal pathogen Salmonella Typhimurium. This protection cannot be attributed to limiting the canonical inflammatory mediators that contribute to wasting pathogenesis or by heightening the host immune response, suggesting that the microbiota can promote host tolerance defenses by limiting wasting pathology. The central hypothesis of this proposal is that the intestinal commensal, E. coli O21:H+, directly manipulates host physiologies to promote tolerance by antagonizing infection/inflammation induced wasting without impacting the canonical inflammatory mediators of wasting. The proposed studies will address: 1) Determine the mechanism of protection from skeletal muscle wasting by the intestinal microbiota. Preliminary results show that the commensal, E. coli O21:H+ limits skeletal muscle wasting induced by intestinal injury and infection via manipulation of the IGF-1 signaling pathway, which is a critical regulator of skeletal muscle size. 2) Determine how the intestinal microbiota impacts adipose tissue physiology during wasting. Preliminary data demonstrates that intestinal colonization with E. coli O21:H+ is sufficient to prevent wasting of white adipose tissue (WAT). Furthermore, preliminary studies suggest that E. coli O21:H+ prevents the physiological changes in WAT that are associated with brown fat - a process called WAT browning. These studies will determine how this commensal limits WAT atrophy and browning by focusing on known mechanisms that contribute to these processes - signaling via the sympathetic nervous system and the innate immune system. 3) What are the cellular and genetic factors required for microbiota protection from intestinal infection and injury induced wasting? Bacterial mutants will be used to determine the microbial factors that are necessary to confer protection from wasting. Mouse mutants will be used to determine the cells and tissues that sense E. coli O21:H+ to mediate the protective effects conferred by this microbe. These studies will be focused on a key orchestrator of the innate immune system called the inflammasome. The discovery that tolerance defenses mediate host-microbiota interactions, that a microbe has evolved mechanisms to promote tolerance, and the identification of commensals that antagonize wasting represent fundamental new insights into host-microbiota interactions, and form the basis for this proposal.