Work

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

Year: 2026

Type: article

Abstract: Background & Aims Oral and gut Bacteroidota species produce bioactive glycine lipids, including the core Lipid 342 (L342), 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 glycine lipids 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 glycine lipids, whereas fermentable fiber supplementation restored fecal levels (∼7-fold increase), with hepatic glycine lipid 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 Trem2 expression, associated with lipid sensing and MASLD protection, while L654 modulated splenic CD4 + effector memory T cells. Conclusions Microbiome-derived glycine lipids are diet-sensitive molecules that protect against MASLD via mitochondrial enhancement, revealing a novel nutritional–microbial axis for liver disease intervention.

Source: Gastro Hep Advances

DOI: 10.1016/j.gastha.2026.101064