Myeloperoxidase deficiency impacts the composition of the gut microbiome: a case for variable disease penetrance?

Abstract

Abstract The most abundant proteolytic enzyme found in neutrophilic granules, myeloperoxidase (MPO) is a heme peroxidase with microbicidal activity. While MPO inhibition has therapeutic promise for treatment of inflammatory illness, differential disease penetrance has been observed in MPO-deficient mice during various disease models. In our studies using the DSS-colitis mouse model, MPO-deficient mice under conventional specific pathogen-free (SPF) conditions experienced similar disease penetrance to co-housed, wildtype controls. In contrast, when housed in restricted SPF conditions lacking norovirus and Helicobacter species, MPO-deficient mice experienced more severe colitis while wildtype mice were unchanged. From these data, we hypothesized that an interplay between MPO (microbicidal activity) and the composition of the gut microbiome impacts disease penetrance of colitis. To investigate, we performed 16S rRNA-sequencing on the intestines of MPO-deficient and wildtype mice housed in restricted SPF conditions and found a proportionate increase in Ruminococcus gnavus, which is associated with intestinal dysbiosis. Correspondingly, we found proportionate decreases in the gut beneficial bacteria Akkermansia muciniphilia and Prevotella sp. These data show that MPO does affect the composition of the gut bacteria, and supports an interplay between inflammatory mediators, the microbiome, and altered disease penetrance.