Abstract
BACKGROUND: Fetal growth restriction (FGR) increases risk for development of obesity and type 2 diabetes. Using a mouse model of FGR, we tested whether metabolic outcomes were exacerbated by high-fat diet challenge or associated with fecal microbial taxa. METHODS: FGR was induced by maternal calorie restriction from gestation day 9 to 19. Control and FGR offspring were weaned to control (CON) or 45% fat diet (HFD). At age 16 weeks, offspring underwent intraperitoneal glucose tolerance testing, quantitative MRI body composition assessment, and energy balance studies. Total microbial DNA was used for amplification of the V4 variable region of the 16 S rRNA gene. Multivariable associations between groups and genera abundance were assessed using MaAsLin2. RESULTS: Adult male FGR mice fed HFD gained weight faster and had impaired glucose tolerance compared to control HFD males, without differences among females. Irrespective of weaning diet, adult FGR males had depletion of Akkermansia, a mucin-residing genus known to be associated with weight gain and glucose handling. FGR females had diminished Bifidobacterium. Metabolic changes in FGR offspring were associated with persistent gut microbial changes. CONCLUSION: FGR results in persistent gut microbial dysbiosis that may be a therapeutic target to improve metabolic outcomes. IMPACT: Fetal growth restriction increases risk for metabolic syndrome later in life, especially if followed by rapid postnatal weight gain. We report that a high fat diet impacts weight and glucose handling in a mouse model of fetal growth restriction in a sexually dimorphic manner. Adult growth-restricted offspring had persistent changes in fecal microbial taxa known to be associated with weight, glucose homeostasis, and bile acid metabolism, particularly Akkermansia, Bilophilia and Bifidobacteria. The gut microbiome may represent a therapeutic target to improve long-term metabolic outcomes related to fetal growth restriction.