Maternal fructose—induced metabolic reprogramming underlies multi-tissue inflammation and dysbiosis in HF-fed offspring: partial normalization by PCA 2256918

Abstract Introduction Excess maternal fructose intake predisposes offspring to metabolic pathology. p-Coumaric acid (PCA), a phenolic with anti-inflammatory and mitochondria-supporting actions, may counteract such programming across metabolic tissues and the gut microbiome. Methods During gestation and lactation, dams consumed either standard chow, a 60% fructose diet, or the same fructose diet with PCA (1 mg/g in diet). After weaning, all progeny were maintained on a 60%-fat diet for 8 weeks and designated CD-HF, HFr-HF, or HFr+PCA-HF. We profiled metabolic phenotypes; histology of adipose, liver, muscle, and intestine; inflammatory signaling; mitochondrial/glycolytic transcripts; grip strength; and 16S rRNA microbiome composition. Results Maternal fructose exposure impaired glucose control and insulin sensitivity and provoked adipocyte hypertrophy, hepatic steatosis, skeletal-muscle myosteatosis, and reduced grip strength, coincident with amplified inflammatory signaling in adipose, liver, and muscle. HFr-HF exhibited higher Clostridiaceae and Peptostreptococcaceae with lower Bacteroidaceae and Muribaculaceae. Maternal PCA (HFr+PCA-HF) attenuated mitochondrial-stress signatures, improved intestinal morphology, and countered fructose-driven inflammatory signaling, while shifting the microbiome toward a CD-HF-like configuration. Conclusion Maternal fructose perturbs gut—liver—muscle crosstalk, coupling mitochondrial stress, systemic inflammation, and dysbiosis in offspring. Maternal PCA offers partial normalization of inflammatory pathways and microbial composition despite a post-weaning high-fat challenge, indicating a preventive window for intergenerational metabolic health. Funding Source This research was supported by a National Research Foundation of Korea (NRF) 2023-00208776, RS-2023-00221563 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)