Mixed short-chain fatty acids and high-fiber diet reshape SCFA profiles and attenuate post-infarction cardiac fibrosis in mice.

Background: Short-chain fatty acids (SCFAs) are microbiota-derived metabolites implicated in immunometabolic regulation. How their systemic and myocardial signatures diverge during post-infarction remodeling, and how these signatures relate to cardiac fibrosis, remains poorly characterized. Methods: Permanent LAD ligation was performed in male C57BL/6J mice assigned to five groups: Control (G0), Sham (G1), MI (G2), MI with mixed SCFA gavage from postoperative day 1 (G3), and MI with a high-fiber diet (HFF, G4). Serum and heart tissue were harvested at day 7 and day 28 ( Results: Acetic acid predominated across all groups. MI was associated with an altered serum SCFA profile, and serum profiles separated more clearly by PCA than myocardial profiles, in which hierarchical clustering highlighted a prominent HFF-related shift. MI increased cardiac collagen deposition, an effect attenuated by both SCFA supplementation and HFF, with Collagen III markedly elevated after MI and reduced in the intervention groups. MI caused pronounced ATP depletion at both time points, partially restored by both interventions and more so by HFF. The NAD⁺/NADH ratio was more variable at day 7 and converged across groups by day 28. Serum cTnT and BNP rose after MI and were lower in the intervention groups, whereas serum TGF- Conclusions: Increasing SCFA availability through mixed SCFA supplementation or a high-fiber diet was associated with divergent serum-vs.-cardiac SCFA remodeling, reduced post-MI fibrosis, and improved myocardial energy balance.