# Differential susceptibility to colonic ulceration in mice with genetic deletion of Prostaglandin E synthase

## TL;DR

This study shows that mice lacking a key enzyme for PGE2 production develop colonic ulcers, revealing how genetic and environmental factors influence gut inflammation.

## Contribution

A novel genetic model for studying NSAID-induced colitis and interindividual variability in intestinal disease susceptibility.

## Key findings

- Ptges-deficient mice on strain A develop spontaneous colonic ulcers, while those on C57BL/6 do not.
- A/D:KO mice show increased pro-inflammatory gene expression before tissue damage occurs.
- F1 hybrids of A/D:KO and B6D:KO mice are mostly free of colonic ulceration, suggesting genetic background plays a key role.

## Abstract

Prostaglandin E2 (PGE2) exerts pleiotropic and context-dependent effects on inflammation, cancer and maintenance of intestinal mucosal homeostasis. To further define its role in intestinal diseases, we genetically inactivated its rate-limiting synthesis, Ptges, in two mouse lines. An unexpected phenotype consisting of spontaneous mucosal ulceration was found exclusively in the colons of strain A mice. This study aims to characterize the phenotype that may have a clinical relevance to NSAID-induced enteropathies.

Mucosal ulcerations were characterized in Ptges-deficient mice maintained on strain A (A/D:KO) and C57BL/6 (B6D:KO) backgrounds. RNA sequencing of colons identified inflammatory signatures in sensitive A/D:KO mice. Microbial dysbiosis was evaluated in the fecal stream using 16S rRNA sequencing. The potential role of genetic and environmental factors in the etiology of differential susceptibility to colonic ulceration was examined through the co-housing experiment and by generating F1 hybrid of A/D:KO and B6D:KO mice.

Progressive colonic ulcerations develop spontaneously in A/D:KO mice, a phenotype that is absent in B6D:KO mice. RNAseq analysis revealed robust expression of pro-inflammatory genes in A/D:KO mice prior to the development of tissue damage, suggesting a subtle defect in intrinsic immune regulation. In B6D:KO colons, there was potent enrichment of genes associated with protection against mucosal injury in. While distinct gut microbial community structures were identified, co-housing of these mice did not rescue the inflammatory phenotype in A/D:KO, nor confer sensitivity to the colons of B6D:KO mice. However, F1 hybrids of A/D:KO with B6D:KO mice were mostly free of colonic ulceration.

These results suggest that genetic blockage of Ptges causes a dramatic shift in the inflammatory milieu in strain A mice, an effect that may be augmented by a complex interaction between genetic background, microbiome and metabolite imbalance. These mice may provide a genetic model for studying interindividual variability in human sensitivity to NSAID-induced colitis.