Commensal microbiota regulate renal gene expression in a sex-specific manner

Abstract

The gut microbiome impacts host gene expression not only in the colon but also at distal sites including the liver, white adipose tissue, and spleen. The gut microbiome also influences the kidney and is associated with renal diseases and pathologies; however, a role for the gut microbiome to modulate renal gene expression has not been examined. To determine if microbes modulate renal gene expression, we used whole organ RNA sequencing to compare gene expression in C57Bl/6 mice that were germ free (lacking gut microbiota) versus conventionalized (gut microbiota reintroduced using an oral gavage of a fecal slurry composed of mixed stool). 16S sequencing showed that male and female mice were similarly conventionalized, although Verrucomicrobia was higher in male mice. We found that renal gene expression was differentially regulated in the presence vs. absence of microbiota and that these changes were largely sex specific. Although microbes also influenced gene expression in the liver and large intestine, most differentially expressed genes (DEGs) in the kidney were not similarly regulated in the liver or large intestine. This demonstrates that the influence of the gut microbiota on gene expression is tissue specific. However, a minority of genes (n = 4 in males and n = 6 in females) were similarly regulated in all three tissues examined, including genes associated with circadian rhythm (period 1 in males and period 2 in females) and metal binding (metallothionein 1 and metallothionein 2 in both males and females). Finally, using a previously published single-cell RNA-sequencing dataset, we assigned a subset of DEGs to specific kidney cell types, revealing clustering of DEGs by cell type and/or sex.