<i>E. coli</i> genetically modified for purine nucleobase release promotes butyrate generation and colonic wound healing during DSS insult

The gut microbiota transforms energy stored as undigestible carbohydrates into a remarkable number of metabolites that fuel intestinal bacterial communities and the host tissue. Colonic epithelial cells at the microbiota-host interface depend upon such microbiota-derived metabolites (MDMs) to satisfy their energy requisite. Microbial dysbiosis eliciting MDM loss contributes to barrier dysfunction and mucosal disease. Recent work has identified a role for microbiota-sourced purines (MSPs), notably hypoxanthine, as an MDM salvaged by the colonic epithelium for nucleotide biogenesis and energy balance. Here, we investigated the role of MSPs in mice during disease-modeled colonic energetic stress using a strain of <i>E. coli</i> genetically modified for enhanced purine nucleobase release (<i>E. coli</i> Mutant). <i>E. coli</i> Mutant colonization protected against DSS-induced tissue damage and permeability while promoting proliferation for wound healing. Metabolite and metagenomic analyses suggested a colonic butyrate-purine nucleobase metabolic axis, wherein the <i>E. coli</i> Mutant provided purine substrate for Clostridia butyrate production and host purine salvage, altogether supplying the host substrate for efficient nucleotide biogenesis and energy balance.