Fiber-Dependent Microbiome Glycine Lipids Ameliorate Steatotic Liver Disease in Mice via Mitochondrial Enhancement.

BACKGROUND AND AIMS: Oral and gut Bacteroidota species produce bioactive glycine lipids (GL), including the core Lipid 342, serine-glycine Lipid 654 (L654), and complex Lipid 1256 (L1256) classes. These microbiome-derived molecules are emerging modulators of host metabolism, but their dietary regulation, systemic presence, and therapeutic potential in metabolic dysfunction-associated steatotic liver disease (MASLD) remain unclear. METHODS: Microbiome-derived GLs were quantified in murine systemic and portal blood, intestinal lymph, and in mouse and human liver using targeted mass spectrometry. Their biological effects were assessed in mouse and cell culture models of diet-induced liver disease following treatment with L654- and L1256-enriched lipid extracts. RESULTS: L654 and L1256 species were detected in mouse serum, portal plasma, intestinal lymph, and liver, as well as in human liver tissue. A Western-type high-fat diet lowered fecal and hepatic microbiome GLs, whereas fermentable fiber supplementation restored fecal levels (∼7-fold increase), with hepatic GL content showing an inverse association with liver triglycerides. In a 22-week diet-induced MASLD model, administration of L654- or L1256-enriched lipids for 8 weeks significantly reduced hepatic steatosis and histopathological progression. Treatments enhanced mitochondrial DNA content and metabolic function in liver and HepG2 cells. L1256 increased hepatic triggering receptor expressed on myeloid cells 2 expression, associated with lipid sensing and MASLD protection, while L654 modulated splenic cluster of differentiation 4+ (CD4+) effector memory T cells. CONCLUSION: Microbiome-derived GLs are diet-sensitive molecules that protect against MASLD via mitochondrial enhancement, revealing a novel nutritional-microbial axis for liver disease intervention.