Mesenteric denervation ameliorates post‑infarction heart failure alongside alterations in the gut–nerve–microbiota axis

Sympathetic overactivity and gut microbiota dysbiosis drive chronic heart failure (CHF) progression. This study explored the associations of mesenteric denervation (MDN) with cardioprotection and potential involvement of the nerve–microbiota–heart axis in MI-induced CHF mice. C57BL/6 mice were randomized into control, CHF, and CHF_MDN groups. CHF was induced by LAD ligation, and MDN was performed via phenol ablation of the superior mesenteric artery. MDN was associated with suppressed mesenteric sympathetic activity, improved left ventricular ejection fraction, and reduced myocardial fibrosis and serum BNP. MDN correlated with restoration of colonic tight junction protein expression, reduced myocardial NLRP3 inflammasome activation, and decreased systemic inflammation (LPS, TNF-α, IL-6). 16S rRNA sequencing showed MDN reshaped gut microbiota (decreased F/B ratio, increased facultative anaerobes). Untargeted metabolomics identified 30 differential metabolites in CHF_MDN mice; MDN reduced pro-inflammatory metabolites (hippuric acid, deoxycholic acid) and increased metabolites linked to energy metabolic reprogramming (2-hydroxybutyric acid, ketoleucine, acetylglycine). Integrated analysis revealed that Campylobacterota and Halobacterota (altered by MDN) correlated with sarcosine and linoleic acid. MDN improves cardiac function in MI-induced CHF, alongside inhibition of mesenteric sympathetic activity, restoration of intestinal barrier function, reduction of inflammation, and modulation of gut microbiota and metabolic profiles. These findings suggest the nerve–microbiota–heart axis as a potential therapeutic target.