Contribution of phytochemicals to gut symbiont colonization and synthesis of immunomodulatory sphingolipids

项目总结 共生微生物区系对宿主免疫发育起着至关重要的作用。在最初的几年里 人的生命，在老鼠体内的头三周，肠道微生物区系经历了戏剧性的变化，主要是在 对主机环境中的变化做出响应。时间变化和宿主-微生物区系的相互适应 形状粘膜免疫仍然难以捉摸；然而，环境因素的贡献(例如 生命过程中的饮食)需要对益生菌/益生菌的影响进行分子水平的研究。 我们之前已经证明，普遍存在的人类肠道共生菌脆弱类杆菌可以调节宿主结肠 自然杀伤T(NKT)细胞通过产生独特的鞘磷脂(α-半乳糖基神经酰胺，或 BfaGCs)。在我们最初的R01下，我们描述了人类微生物区系相关小鼠(HMA小鼠)的特征。 向HMA小鼠补充植物化学物质可抑制其后代的结肠NKT细胞水平。值得注意的是， 在成年HMA小鼠中，补充植物化学物质可以瞬间强烈地诱导脆弱芽孢杆菌的丰富。 提示脆弱芽孢杆菌在出生前和出生后阶段的诱导对结肠NKT细胞的发育至关重要。 在目前的提案中，我们将剖析早期开发的时间进程，并调查 植物化学物质对复杂的微生物区系和随后的粘膜免疫发展的早期生命。这 研究将提供有价值的信息，说明孕期有益微生物对益生元的影响 因素，以及孕期/哺乳期补充对微生物区系和免疫的影响 后代的发育。

PROJECT SUMMARY Symbiotic microbiota make critical contributions to host immune development. During the first few years of human life, and the first three weeks in mice, the gut microbiota undergoes dramatic transformation, mostly in response to changes in the host environment. How temporal changes and mutual host-microbiota adaptations shape mucosal immunity remains elusive; however, the contribution of environmental factors (such as shifts in diet over the life course) warrants molecular-level investigation of the effects of prebiotics/probiotics. We have previously shown that the ubiquitous human gut symbiont Bacteroides fragilis can modulate host colonic natural killer T (NKT) cell development by producing unique sphingolipids (alpha-galactosylceramides, or BfaGCs). Under our original R01, we characterized human microbiota-associated mice (HMA mice). Supplementation of phytochemicals to HMA mice suppressed colonic NKT cell levels in their offspring. Of note, in adult HMA mice, phytochemical supplementation can transiently induce the abundance of B. fragilis, strongly implying that induction of B. fragilis during pre- and postnatal stages is critical for colonic NKT cell development. In the current proposal, we will dissect the time course of early development and investigate the impact of phytochemicals on the complex microbiota and subsequent mucosal immune development in early life. This study will provide valuable information on the effect of beneficial microbes in pregnancy in response to prebiotic factors, as well as the impact of supplementation during gestation / lactation on the microbiota and immune development of offspring.