Hydroxytyrosol improved insulin resistance in male offspring born to high-fat diet dams by remodeling gut microbiota

Abstract

Maternal obesity during pregnancy and lactation critically influences offspring metabolic programming, increasing insulin resistance (IR) risk through gut microbiome alterations. This study investigated whether hydroxytyrosol (HT), a polyphenol, could exert metabolic benefits through intergenerational regulation of gut microbiota. Through dietary intervention and fecal microbiota transplantation experiments in pregnant and lactating C57BL/6 J dams, combined with 16S rRNA sequencing and interaction analysis, we found that maternal high-fat diet (60% fat for energy) during gestation and lactation caused obesity and IR-associated phenotypes in male offspring at 4 weeks of age, but not in female young pups. Oral gavage of HT (50 mg/kg) during pregnancy and lactation alleviated abnormal adipocyte hypertrophy, hyperplasia, and excessive leptin secretion in male offspring born to obese dams. Additionally, HT reduced systemic insulin intolerance, hyperglycemia, and hyperinsulinemia, decreased liver index and liver injury, attenuated hepatocyte ballooning, hepatic oxidative stress, and systemic inflammation, and restored hepatic PI3K/AKT signaling in male offspring. Furthermore, HT recovered intestinal barrier function and gut microbiota homeostasis in male offspring, especially the community structure represented by β-diversity, microbial dysbiosis index, and short-chain fatty acids content. Importantly, the beneficial effects of maternal HT ingestion on offspring IR were closely associated with gut microbiota remodeling and could be transmitted through intergenerational microbial inheritance between mothers and offspring. Together, our study indicated that the intergenerational transmission of microbiota may underlie maternal obesity-induced IR and that HT intake could be a promising intervention.