Tolerance defenses in host-microbiota interactions

宿主-微生物群相互作用中的耐受性防御

• 批准号: 8965330
• 负责人: Janelle S Ayres
• 金额: $ 48.5万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-10 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8965330
• 关键词: Accounting; Address; Adipose tissue; Atrophic; Automobile Driving; Body Weight decreased; Brown Fat; Cells; Communicable Diseases; Complex; Data; Deposition; Endocrine system; Escherichia coli; Fatty acid glycerol esters; Flagellin; Genes; Genetic; Goals; Health; Host Defense; Host resistance; Immune response; Immune system; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Insulin-Like Growth Factor I; Intestines; Investigation; Mediating; Metabolic; Metabolic Diseases; Metabolism; Microbe; Morbidity - disease rate; Muscle; Mutant Strains Mice; Pathogenesis; Pathology; Pathway interactions; Physiological; Physiology; Play; Predisposition; Process; Research; Resistance; Role; Salmonella; Salmonella infections; Salmonella typhimurium; Signal Pathway; Signal Transduction; Skeletal Muscle; Sodium Dextran Sulfate; Sympathetic Nervous System; Testing; Tissues; Up-Regulation; Wasting Syndrome; Work; antimicrobial; base; gut microbiota; insight; meetings; microbial; microbial host; microorganism interaction; mortality; muscle form; mutant; myogenesis; pathogen; prevent; protective effect; public health relevance; response; sensor; signal processing; skeletal muscle wasting; success; wasting

 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.

 描述（由适用提供）：浪费综合征是一种非代谢状态，其中肌肉和脂肪组织伴有体重减轻。浪费是感染和炎症状况的重要后遗症，造成了显着的发病率和死亡率。当前的范式是炎症驱动器浪费，但是目前通过抑制炎症反应来对抗浪费的努力几乎没有成功。研究表明，哺乳动物肠道菌群的特定构成可以拮抗肠损伤和肠道病原体鼠伤寒触发的浪费病理学。 This protection cannot be attributed to limit 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 The central hypothesis of this proposal is that the intestinal commensal, E. coli O21:H+, directly manipulates host physiology to promote tolerance by antagonizing infection/inflammation induced wasting without影响浪费的规范炎症介体。拟议的研究将解决：1）确定肠菌群浪费骨骼肌的保护机理。初步结果表明，通过操纵IGF-1信号传导途径，Consensal，E. Coli O21：H+限制了肠道损伤和感染引起的骨骼肌浪费，这是骨骼肌大小的关键调节剂。 2）确定肠道菌群如何影响 浪费期间脂肪组织生理。初步数据表明，大肠杆菌O21：H+的肠道定植足以防止浪费白脂肪组织（WAT）。此外，初步研究表明，大肠杆菌O21：H+可防止与棕色脂肪相关的WAT的生理变化 - 这一过程称为Wat Browning。这些研究将通过关注有助于这些过程的已知机制来确定这种共同体如何限制WAT萎缩和褐变 - 通过交感神经系统和先天免疫系统发出信号传导。 3）保护肠道感染和损伤浪费所需的细胞和遗传因素是什么？细菌突变体将用于确定赋予保护浪费所需的微生物因子。小鼠突变体将用于确定感知大肠杆菌O21：H+的细胞和组织，以介导该微生物赋予的保护作用。这些研究将集中在称为The Inderamasome的先天免疫系统的关键编排上。耐受性捍卫介导的宿主微生物群相互作用的发现，微生物具有进化的机制来促进耐受性，并鉴定拮抗浪费的共生代表了对宿主微生物群相互作用的基本新见解，并构成了该提案的基础。