Conjugated Linoleic Acid‐Enriched Fermented Dairy Modulates Microbiota and Metabolites to Alleviate MASLD: Insights From Multi‐Omics and Causal Mediation Analysis
Fei Mi, Yanjiao Wang, Jia Xiong, Yiyuan Ma, Hongmei Pan, Jianzhong Yin, Yunmei Chai, Yao Wang, Xin Xu, Ai Zhang, Qingwen Ma, Hui Wang, Dongbai Liu, Shaoxiong WuABSTRACT
Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a prevalent metabolic disorder linked to gut–liver axis dysregulation. Dietary interventions targeting gut microbiota and host metabolism are promising, yet the effects of specific bioactive components remain unclear. Conjugated linoleic acid (CLA), a functional fatty acid in dairy, may regulate lipid metabolism and inflammation, but its clinical efficacy and mechanisms in MASLD are not well defined. This study evaluated CLA‐enriched fermented dairy using a multi‐omics and causal modeling framework. In a 120‐day randomized controlled trial, 60 MASLD patients consumed CLA‐enriched fermented dairy or standard yogurt. Fecal samples underwent 16S rRNA sequencing, and serum samples were analyzed by untargeted liquid chromatography–mass spectrometry (LC–MS) metabolomics. Liver function and metabolic markers were assessed before and after the intervention. Causal mediation analyses explored mechanistic links among the intervention, microbiota, metabolites, and clinical outcomes. The intervention group showed significant reductions in serum alanine aminotransferase (ALT), total cholesterol (TC), creatinine, and high‐sensitivity C‐reactive protein (hs‐CRP). Gut microbiota shifts included increased Bacteroides , Blautia , and Fusicatenibacter and decreased Enterococcus and Sutterella . Metabolomics revealed upregulated energy pathways and negative associations between liver enzymes, phosphatidylcholines, and acylcarnitines. Causal mediation identified key microbial (e.g., Lachnospiraceae UCG‐008) and metabolic (e.g., 5‐Benzylacyclouridine and vaccenic acid) mediators linking the intervention to clinical improvements. CLA‐enriched fermented dairy beneficially modulates gut microbiota and host metabolism, improving liver and systemic metabolic health in MASLD patients. The study highlights CLA's therapeutic potential and demonstrates the value of multi‐omics and causal inference to elucidate diet–host interactions.