Abstract

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, causal