Maternal obesity programs offspring gut microbiome and liver disease in a sexually dimorphic manner

Abstract

Maternal obesity programs offspring weight gain and predisposition to metabolic syndrome. However, sexual differences in developmental programming are poorly understood. Here we employed a mouse model where female dams were fed either control (17% fat) or high‐fat diets (HFD, 45% fat calories) 12 wk prior to conception and then through weaning. Male and female offspring were provided ad libitum access to either control or HFD for 14 wk beginning at 4 wk of age, during which body weights were monitored weekly. At 18 wk of age hepatic histology was assessed and cecal contents were snap frozen for microbiome analysis. Male offspring gained more body weight than either control or HFD females (p<0.001). Two‐way ANOVA showed a significant effect of diet (p<0.01–0.001) and sex (p<0.001) when offspring were fed HFD. Hepatic histology also showed more severe fatty liver in male offspring relative to females. Pro‐inflammatory cytokines in serum such as IL1b, IL‐2, and IL‐6 were higher in male offspring fed HFD (p<0.05), whereas anti‐inflammatory IL‐5 was lower (p<0.001). Microbial community profiling via 16S rRNA amplicon sequencing showed that overall a‐diversity was lower in females (p<0.05) and in offspring from HFD dams (p<0.05). Two‐way ANOVA showed a significant effect of diet (p<0.001) and sex (p<0.001) on Bacteroidetes and Firmicutes when offspring were fed HFD. Enrichment of Firmicutes in males and Lactococcus, Anaerotruncus and Ruminococcus genera in female offspring were found using LefSe. When offspring were fed HFD, Bacteroidetes were lower and Firmicutes were higher in males (p<0.01). Multivariate association with linear models showed correlation between overall weight gain and abundance of families Lachnospiraceae and Clostridiaceae. Further, functional prediction using PiCRUST showed that bile acid synthesis, immune and bacterial response, protein digestion and cell cycle regulation pathways were enriched when offspring were fed HFD. Importantly, sex differences in functional categories were more pronounced by post‐weaning HFD. In conclusion, our findings suggest that prenatal HFD feeding alters hepatic steatosis and microbiome in offspring, and shows sexually dimorphic differences in response to post‐weaning HFD. Supported by USDA CRIS Project 6206‐51000‐010‐05S.Support or Funding InformationUSDA CRIS 6206‐51000‐010‐05S