Ingestion of Fermented Food-Associated Microbial Aryl Metabolites Attenuates High Fat Diet-Induced Liver Lipid Accumulation

Objective: Consumption of fermented foods is associated with lower systemic inflammation and improved metabolic health, yet the underlying mechanisms remain unclear. We investigated if microbial-derived aromatic amino acid metabolites found in fermented foods, specifically phenyllactic acid (PLA), 4-hydroxyphenyllactic acid (4HPLA), and indole-3-lactic acid (ILA), collectively termed aryl-lactates (AL), mitigate liver fat accumulation, a key marker of metabolic-associated steatotic liver disease (MASLD). We also assessed their effects on macrophage phagocytic activity ex vivo. Hypothesis: We hypothesized that AL reduce weight gain and hepatic lipid accumulation when consumed at doses found in fermented foods. Methods: 12-week-old; C57BL/6 male mice were fed either control diet (CD; 15% kcal fat) or high-fat diet (HFD; 45% kcal fat) and provided a combination of AL (4HPLA+PLA+ILA) (0 or 10 µM/d total) in drinking water (n=6/group) for 16 weeks. Body weight, food intake, and water consumption were recorded 3 times/wk. Body composition was analyzed with EchoMRI at wks 8 and 15. After 16 weeks, liver weight was recorded, and hepatic lipid accumulation was assessed via Oil Red O staining. To evaluate the effect of AL on macrophage function, we performed ex vivo assays using macrophages differentiated from human peripheral blood mononuclear cells exposed to 0 or 50 µM of either 4HPLA, ILA, or PLA. Phagocytic activity was assessed using fluorescein stained, lyophilized E. Coli particles. Results: Weight gain, fat mass, and liver weight were increased for HFD compared to CD fed mice. AL decreased weight gain, fat mass, liver weight, and increased lean mass of only HFD fed mice (p<0.05). Additionally, AL attenuated HFD-induced hepatic lipid accumulation (p<0.05). Given the critical role of macrophages in MASLD progression, we examined if these effects were associated with enhanced macrophage function. Ex vivo treatment of macrophages with any of the three AL increased macrophage phagocytosis (p<0.05) with 4HPLA being the most effective. Result summary: AL reduced weight gain, fat mass, and hepatic lipid accumulation of HFD-fed mice. Conclusion: Ingestion of microbial-derived aryl-lactates limited fat accumulation in the liver in response to HFD. Ongoing studies aim to further elucidate the mechanistic contributions of macrophages in this process. These findings highlight the therapeutic potential of fermented food-derived microbial metabolites in mitigating MASLD severity. Funding: USDA-AFRI- 2023-67017-39053 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.