Degeneration of the intestinal microbial community in PI3Kγ-knockout mice

PI3Kγ is closely related to inflammation and cardiovascular diseases and thus, PI3Kγ inhibitors are candidate drugs for the treatment of these disorders. Considering the potential effect of the intestinal microbiome on inflammation and cardiovascular diseases, this study aimed to identify characteristics of the intestinal microbial community under PI3Kγ deficiency, to help reveal the potential influence of PI3Kγ inhibitors mediated by the microbial community.

Exon 2 of the PI3Kγ gene was knocked out in a Balb/c mouse by using single-guide RNAs. Homozygous PI3Kγ-knockout (PI3Kγ^-/-) mice were obtained by embryo transfer and hybridization. PI3Kγ^-/- and wild-type (WT) mice were raised in the same specific pathogen-free conditions until 8 weeks of age. Then, colonic tissues and feces from the middle segment of the colon were collected and analyzed by Illumina MiSeq sequencing. Differences in intestinal microbial community between the PI3Kγ^-/- and WT mice were detected by bioinformatics analysis.

The richness and alpha diversity of the colonic microbial community were decreased in PI3Kγ^-/- mice. The alpha diversity of the microbial community in feces did not differ between PI3Kγ^-/- and WT mice. The beta diversity of the microbial community in feces of PI3Kγ^-/- mice was obviously different from that in WT mice, whereas the within-group variation in Bray-Curtis distances of the mucosal microbial community was significantly decreased in PI3Kγ^-/- mice. The topological structure of the species-related network of the colonic microbial community in PI3Kγ^-/- mice was more polarized. Finally, we predicted that PI3Kγ deficiency might affect the synthesis of some antibiotics, bile acid, and thiamine through effects on the microbial community.

PI3Kγ dysfunction led to degeneration of the intestinal microbial community and might alter the synthesis of some antibiotics, bile acids, and thiamine. The usage of PI3Kγ inhibitors for inflammation and cardiovascular diseases might lead to knock-on effect on our organism through intestinal microbiota.