Gut microbiota phospholipids regulate intestinal gene expression and can counteract the effects of antibiotic treatment.

Early-life antibiotic exposure perturbs the developing gut microbiome and increases risk for immune disorders such as type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. Comparing germ-free and conventional mice, we identified 747 intestinal lipid compounds and defined a subset of gut microbially-produced lipids (GMPLs). Antibiotic treatment disrupted GMPL profiles in mice and in human volunteers, with partial restoration in mice after cecal microbiota transplantation. Among affected compounds, four phospholipids: LPG(13:0), LPG(16:0), LPG(18:0), and PG(15:0_15:0), were structurally defined and tested functionally. These lipids suppressed LPS-induced NFkB activation, modulated innate immune gene expression in intestinal epithelial cells, and enhanced epithelial cell mitochondrial respiration. Oral administration of LPG(16:0) or LPG(18:0) to antibiotic-treated NOD mice partially restored microbiome composition, normalized ileal gene expression, and improved epithelial transport and metabolic pathways. These findings identify bacterial phospholipids as regulators of intestinal immunity and metabolism, with potential therapeutic applications for inflammatory diseases.