Excess dietary fat and sugar are linked to obesity and metabolic syndrome. Polyamines such as spermidine are implicated in fat accumulation and may support activity-induced weight loss.This study tested interventional spermidine supplementation and voluntary activity against fat- and sucrose-induced systemic and gut microbiota changes.A 3-factorial study design (3 × 2 × 2) was used to test the factors diet, activity, and spermidine. Male 6-wk-old C57BL/6N mice were fed a control diet (CD; carbohydrate:protein:fat, 70%:20%:10% of energy; 7% sucrose), a high-fat diet (HFD; carbohydrate:protein:fat, 20%:20%:60% of energy; 7% sucrose), or a high-sucrose diet (HSD; carbohydrate:protein:fat, 70%:20%:10% of energy; 35% sucrose). Diet groups were left untreated (+0) or had unlimited access to running wheels (+A) or were supplemented with 3 mM spermidine via drinking water (+S) or a combination of both (+A+S) for 30 wk (n = 7-10).In comparison to the CD, the HFD enhanced body weights (by 36%, P < 0.001), plasma lipids (cholesterol by 24%, P < 0.001; triglycerides by 27%, P = 0.004), and glucose concentrations (by 18%, P < 0.001), whereas the HSD increased weight by 13% (P < 0.001) and fasting glucose by 17% (P < 0.001) but did not increase plasma lipids. Microbiota taxonomic composition changed upon the HFD and HSD (both P < 0.001); however, only the HSD increased microbial diversity (P < 0.001) compared with the CD. Activity influenced microbiota composition (P < 0.01) and reduced glucose concentrations in HSD-fed (P = 0.021) and HFD-fed (P < 0.001) mice compared with nonactive mice. The combination of activity and spermidine affected energy intake (P-interaction = 0.037) and reduced body weights of HSD+A+S mice compared with HSD+0 mice (P = 0.024).In male C57BL/6N mice, dietary sucrose and fat caused diverse metabolic and microbiota changes that were differentially susceptible to physical exercise. Spermidine has the potential to augment activity-induced beneficial effects, particularly for sucrose-induced obesity.
