Metabolic imprinting due to small litter size preserves gut microbiota diversity and SCFA output despite high-sucrose diet.

According to the Developmental Origins of Health and Disease (DOHaD), early-life nutritional exposure can affect long-term metabolic health. Gut microbiota development during lactation plays a pivotal role in regulating metabolism, with short-chain fatty acids (SCFAs) serving as key mediators connecting early microbial colonization to future metabolic outcomes. Diet composition strongly affects gut microbiome, and high-sucrose diets (HSD) promote dysbiosis and metabolic dysfunction. We investigated whether small litter size (SL) modulates susceptibility to HSD-induced metabolic disruptions by assessing gut microbiota composition, SCFA production, and microbial co-occurrence networks. Male Wistar rats (n=29) were allocated to control (CL, 8 pups/dam) or small litter (SL, 4 pups/dam) groups, then, after weaning, assigned to either a standard diet (STD) or HSD (30% sucrose) for 8 weeks. HSD reduced gut microbial diversity and increased the Firmicutes/Bacteroidetes ratio only in the CL group. In contrast, SL rats fed an HSD exhibited specific bacterial enrichment and maintained butyrate concentrations comparable to control rats, suggesting preserved metabolic stability. Network analysis revealed that HSD-SL rats developed complex microbial interactions driven by SCFA biosynthesis pathways. These findings suggest that early-life nutritional programming due to SL may promote greater functional stability of the gut microbiota under dietary challenges, potentially mitigating future metabolic disturbances.