Background: Obesity is closely associated with gut microbiota dysbiosis. Nervonic acid (NA; (15Z)-15-tetracosenoic acid) is a bioactive fatty acid with reported metabolic effects. This study aimed to investigate the associations between NA administration, gut microbiota composition changes, and host metabolic phenotypes in high-fat diet (HFD)-fed mice. Methods: C57BL/6J mice were fed an HFD for 12 weeks and concurrently administered NA at doses of 20, 40, and 60 mg/(kg·d) by gavage. Metabolic parameters, histopathological changes, and fecal microbiota composition (via 16S rRNA gene sequencing) were evaluated. Results: NA administration was associated with significantly attenuated HFD-induced increases in body weight and adipose tissue mass, as well as marked reductions in serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol (all p < 0.05). Hepatic steatosis and adipose tissue inflammation were also attenuated. 16S rRNA gene sequencing revealed that NA was associated with the counteraction of HFD-induced gut microbiota dysbiosis, including alterations in α-diversity and community structure. NA was associated with higher relative abundances of taxa such as Blautia, Oscillibacter, Faecalibaculum, Parabacteroides, Dubosiella, and Odoribacter and lower relative abundances of Lachnoclostridium, Mucispirillum, and Alistipes. Within-group correlation analyses showed that genera with higher relative abundances were inversely associated with lipid parameters and adiposity, whereas genera with lower relative abundances correlated positively with these metabolic indicators. Conclusions: NA administration was associated with bidirectional changes in gut microbiota composition—the enrichment of certain taxa and the suppression of others—concomitant with the amelioration of HFD-induced metabolic dysfunction. These findings indicate correlations between NA, gut microbiota alterations, and improved metabolic phenotypes; however, causality remains to be established.

Background: Nervonic acid (NA) is a bioactive long-chain monounsaturated fatty acid with pivotal metabolic regulatory functions; nevertheless, its underlying mechanisms against high-fat diet-induced obesity remain poorly elucidated. This study adopted a fecal metabolomics strategy to systematically investigate the modulatory effects of NA supplementation on gut microbial composition and fecal metabolic signatures in high-fat diet (HFD)-induced obese mice. Methods: Male C57BL/6 mice were subjected to HFD feeding and continuous intervention with gradient doses of NA for 12 weeks. Fecal samples were collected for untargeted metabolomic profiling via ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), while gas chromatography-tandem mass spectrometry (GC-MS/MS) was applied for quantitative detection of targeted short-chain fatty acids (SCFAs). Combined with previously reported 16S rRNA gene sequencing datasets, we further comprehensively analyzed the influences of NA on gut microbiota community structure, fecal metabolic profiles, and microbe-metabolite correlation networks. Results: UHPLC-MS/MS metabolomic analysis demonstrated that NA intervention remarkably reshaped the overall fecal metabolic landscape of obese mice. Differential metabolite screening showed that NA supplementation restored the abnormal depletion of hypoxanthine and uracil, significantly reduced the abundance of arachidonic acid (AA), and markedly elevated the levels of stearidonic acid (SDA), malic acid, citric acid, and phosphatidylcholine PC(18:0_18:2). Functional enrichment analysis indicated that these altered metabolites were predominantly enriched in pyrimidine metabolism, glycine/serine/threonine metabolism, α-linolenic acid metabolism, linoleic acid metabolism, and tricarboxylic acid (TCA) cycle pathways. GC-MS/MS quantification further verified that NA treatment significantly increased fecal contents of acetic acid, propionic acid, butyric acid, and caproic acid in HFD-induced obese mice. Spearman correlation analysis revealed that NA-mediated metabolic remodeling was closely correlated with the modulation of inflammation-associated bacterial genera ( norank_Desulfovibrionaceae , Mucispirillum , and Alistipes ) and potential beneficial gut microbes ( norank_Rikenellaceae ). Conclusions: NA intervention ameliorated HFD-induced obesity-associated metabolic disorders and was accompanied by remodeling of fecal metabolic profiles and alterations in gut microbial structure. This study deepens the mechanistic understanding of NA in alleviating high-fat diet-triggered gut dysbiosis and metabolic perturbation and provides novel insights into the gut microbiota-dependent regulatory mechanism of NA against obesity, laying a theoretical foundation for the application of NA in obesity metabolic intervention.