Unraveling strain-level variation in the induction of anti-inflammatory responses in the intestine

项目总结：炎症性肠病（IBD）是一种日益流行的疾病，目前 影响美国约1.3%的成年人。IBD的特征是慢性炎症免疫反应， 对肠道微生物群，并严重阻碍其患者的健康。目前的治疗方法 涉及致病性炎症途径的中和。然而，许多患者无反应或 对治疗变得难治，并且持续施用这些药剂的需要可增强 对感染的易感性一个主要的未满足的临床需求需要开发改进的治疗方案 抑制持续的炎症，同时保留保护性免疫。恢复宿主免疫力的策略- 通过引入促进健康的免疫调节微生物（益生菌）来实现肠道微生物群稳态， 代表阻断免疫功能的有吸引力的替代方案。到目前为止，这些方法已经恶魔- 有限的功效。我们对微生物诱导抗- 炎症反应，以及移植的微生物如何在发炎肠道的恶劣环境中生存， 建立利基市场的时间严重阻碍了这些努力。一种方法，其中最佳特征来自 不同的微生物被组合，所谓的设计师益生菌，代表了一种改进的治疗策略。 知识差距：积极促进肠道抗炎作用的细菌途径的识别 免疫反应和允许益生菌菌株定植在发炎的肠道仍然是个谜， 微生物群的复杂性和困难与肠道微生物的遗传操作。假设： 菌株特异性差异影响肠道细菌物种的益生菌潜力。初步研究：通过 对遗传上易处理的肠道共生体多形拟杆菌的不同菌株的研究，我们有（i） 鉴定了B能力的广泛菌株水平变异。多形核菌菌株，以诱导 在单菌落的gnotobiotic小鼠的结肠Tumor，（ii）揭示了生物膜中显著的菌株水平变化， 不同菌株B的形成能力。thetaiotaomicron，和（iii）发现了一个小说的存在，B.该等─ Taiotaomicron衍生的免疫调节因子，其促进抗炎细胞因子IL-1的产生。 10.我们的系统提供了一个机会，利用一个物种内的菌株的相关性，赋予差异， 参考表型，以提供与益生菌的最佳功能相关的途径的洞察。项目ob- 目的：利用B的品系水平变异和遗传易处理性。以确定细菌的大小， 最有效地赋予肠道微生物抗炎能力的原始基因和分子。影响：结果 其中一些研究将推动开发可提供持久缓解的设计益生菌疗法的努力 对IBD患者来说，目的1：确定细菌驱动的菌株水平变异的分子基础 结肠Treg诱导。目标2：定义B。一种或多种多聚体衍生的免疫调节因子， 结肠炎目的3：确定炎症肠道中介导细菌菌株水平适应性的遗传决定因素。

PROJECT SUMMARY: Inflammatory bowel disease (IBD) is an increasingly prevalent disease that currently affects ~1.3% of adults in the US. IBD is characterized by chronic inflammatory immune responses directed against the gut microbiota, and severely impedes the health of its sufferers. Current therapeutic approaches involve neutralization of pathogenic inflammatory pathways. However, many patients are non-responsive or become refractory to treatment, and the requirement for sustained administration of these agents can enhance susceptibility to infection. A major unmet clinical need entails development of improved therapeutic regimens that quell ongoing inflammation while sparing protective immunity. Strategies that seek to restore host immune- gut microbiota homeostasis through introduction of health-promoting immunomodulatory microbes (probiotics), represent an attractive alternative to blockade of immune function. To date, these approaches have demon- strated limited efficacy. Our incomplete understanding of the mechanisms through which microbes induce anti- inflammatory responses, and how transplanted microbes survive the hostile environment of the inflamed intes- tine to establish a niche have severely hampered these efforts. An approach where the optimal features from different microbes are combined, so-called designer probiotics, represents an improved treatment strategy. Knowledge gap: The identity of the bacterial pathways that actively promote intestinal anti-inflammatory im- mune responses and allow probiotic strains to colonize the inflamed intestine have remained enigmatic due to microbiota complexity and difficulties associated with the genetic manipulation of gut microbes. Hypothesis: Strain-specific differences impact the probiotic potential of gut bacterial species. Preliminary studies: Through the study of distinct strains of the genetically tractable gut symbiont Bacteroides thetaiotaomicron, we have (i) identified extensive strain-level variation in the ability of B. thetaiotaomicron strains to induce accumulation of colonic Tregs in monocolonized gnotobiotic mice, (ii) revealed significant strain-level variation in the biofilm- forming capacity of different strains of B. thetaiotaomicron, and (iii) uncovered the existence of a novel, B. the- taiotaomicron-derived, immunomodulatory factor that promotes production of the anti-inflammatory cytokine IL- 10. Our systems provide an opportunity to leverage the relatedness of strains within a species that impart dif- ferential phenotypes to provide insight into pathways related to the optimal function of probiotics. Project ob- jective: To leverage the strain-level variation and genetic tractability of B. thetaiotaomicron to define the bacte- rial genes and molecules that most potently confer anti-inflammatory capacity to gut microbes. Impact: Results of these studies will advance efforts to develop designer probiotic therapeutics that provide durable remission from disease for IBD patients. Aim 1: Define the molecular basis for strain-level variation in bacterial driven colonic Treg induction. Aim 2: Define the B. thetaiotaomicron-derived immunomodulatory factor(s) that limit colitis. Aim 3: Define the genetic determinants mediating bacterial strain-level fitness in the inflamed intestine.