Integrated Metabolomic and Microbiome Profiling Reveals Divergent Effects of No- and High-Fat Coffee in Mice

Background/Objectives Coffee is widely consumed worldwide and is rich in bioactive compounds with potential metabolic benefits. Recently, lipid-enriched coffee formulations have gained popularity; however, their biological effects and underlying mechanisms remain poorly understood. Methods In this study, we employed an integrated multi-omics approach to investigate the impact of coffee and high-fat coffee on the plasma metabolome and gut microbiota of C57BL/6J mice. Eighteen male mice were randomly assigned to three groups (n = 6) and received water, coffee, or high-fat coffee by oral gavage daily for 14 days. The plasma metabolome was analyzed via UHPLC-MS/MS, and the gut microbiota was profiled u 16S rRNA gene sequencing. Results Metabolomic analysis revealed distinct clustering patterns among groups. A total of 200 metabolites were significantly altered in the coffee group compared with the water group, while 86 metabolites were altered in the high-fat coffee group compared with the coffee group, with 56 overlapping metabolites suggesting a core metabolic response. Microbiome analysis showed that coffee consumption increased the abundances of Akkermansia and Bifidobacterium and decreased the levels of Ligilactobacillus and Muribaculum. Coriobacteriaceae UCG-002 and Turicibacter were significantly enriched in the high-fat coffee group, whereas Lachnospiraceae NK4A136 group, Mucispirillum and unclassified Lactobacillaceae were reduced. Association analysis highlighted the top 20 metabolites with the highest degree of connection to gut microbial genera, two of which belong to the chlorogenic acid pathway. Conclusions Reduced levels of ferulic acid and 3-hydroxybenzoic acid, two metabolites potentially involved in antioxidant and anti-inflammatory activities, were observed in the high-fat coffee group, suggesting that dietary cream influences microbiota-associated chlorogenic acid metabolism.