Δ <i>lpp</i> mutant <i>E. coli</i> reduces lipid content in <i>Caenorhabditis elegans</i> via phosphatidylglycerol-mediated inhibition of fatty acid biosynthesis

ABSTRACT Although the gut microbiota is known to influence host metabolism, how specific bacterial genetic mutations modulate lipid metabolism remains unclear. In this study, we integrated in vivo lipid visualization, whole-transcriptome RNA sequencing, and lipidomics to investigate the effects of the Δ lpp mutant of Escherichia coli on Caenorhabditis elegans ( C. elegans ). Our results demonstrated that the Δ lpp mutant significantly reduced fat content across three C. elegans strains. Transcriptome analysis revealed substantial alterations in the expression of genes associated with fatty acid metabolism, particularly those involved in fatty acid biosynthesis, which were notably downregulated. Lipidomic profiling confirmed an upregulation of phosphatidylglycerol (PG) and indicated its potential involvement in regulating fatty acid biosynthesis. Importantly, PG supplementation significantly decreased lipid accumulation in C. elegans . Furthermore, we identified and validated four downregulated genes whose reduced expression was associated with lower lipid levels. These findings underscore the therapeutic potential of engineered probiotics in lipid-related metabolic disorders and offer novel mechanistic insights into how genetic variations in gut microbes influence host metabolic health. IMPORTANCE Our findings carry several potential implications: they not only reveal a novel pathway through which a bacterial mutant affects host lipid metabolism via phosphatidylglycerol-mediated inhibition of fatty acid biosynthesis but also underscore the potential of engineered microbial strains as precision probiotics for the treatment of lipid-associated disorders.