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

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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.