The effects of sex and age on the gut microbiota and gut homeostasis in mice.

Background: The gut microbiota and gastrointestinal tract serve essentials roles in regulating host metabolism, but how sex and age regulates their function remains unclear.
Methods: Young (3-month-old) and old (16-23-month-old) C57BL6 female and male chow-fed mice (10-14/group) were metabolically phenotyped. Terminal plasma was collected for biochemistry measured by ELISA, and small and large intestines were formalin- or Carnoy’s fixed for gut histological outcomes analyzed by microscopy. Cecal contents were collected for metabolomics. Intraepithelial lymphocytes and lamina propria mononuclear cells (LPMCs) were isolated from mouse colon, stained for specific cell surface and intracellular cytokine markers, and enumerated by flow cytometry.
Results: Old female and male mice had higher body weight, adiposity, lean mass and plasma insulin levels compared to young controls, but there was no effect of age on glucose tolerance in either sex. Circulating lipopolysaccharide (LPS) and cecal levels of short-chain fatty acids (acetate, butyrate, propionate, valerate) were increased in old female mice versus young female controls but not different in young and old male mice. Similarly, there was a distinct lipidome signature (sphingolipids, sphingomyelins, triacylglycerides) that was differentially regulated by sex in young and old mice. Colon mucus thickness was not different between young and old female mice but was increased in old male mice versus young male controls. By contrast, colonic levels of intraepithelial TCRɤδ, a key gut barrier regulator, and CD4+ T-cell cytokines (IL-10, TNFα) from LPMCs are reduced in old male versus old female mice.
Conclusions: There are distinct effects of sex that regulates multiple components of the gut microbial metabolome and gut epithelium. These differences may lead to sex-specific strategies that leverage the gut to improve host metabolism across the lifespan.