NLM DIR Seminar Schedule

Abstract:

The gut microbiome plays a critical role in steroid hormone and cholesterol metabolism, yet the specific enzymes driving these transformations remain poorly characterized. In this talk, I present the identification of two novel enzyme systems in human gut bacteria. First, I describe a Δ4-3-ketosteroid 5β-reductase and a 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase, enzymes that together convert pregnenolone into epipregnanolone, and which are prevalent across healthy populations. We also identify 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase fused with 5β-reductase, which converts pregnenolone into epipregnanolone. Second, I present SpiR, a cholesterol 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase in Eubacterium coprostanoligenes that catalyzes the first step of cholesterol metabolism. Biochemical and metagenomic analyses show that SpiR selectively oxidizes cholesterol to cholestenone, is lineage-specific to a clade of uncultured Acutalibacteraceae where it co-occurs with ismA, and outperforms ismA as a predictive marker for cholesterol conversion across three human cohorts. Together, these findings expand our understanding of how gut bacteria modulate host steroid and cholesterol physiology, and establish new enzymatic and genomic targets for studying microbiome-host metabolic interactions.