Bioengineered Escherichia coli Nissle 1917 Mitigates Intestinal Inflammation in a Porcine Model of DSS-induced Colitis

The probiotic Escherichia coli Nissle 1917 (EcN) is effective in the maintenance of remission in ulcerative colitis (UC), similar to 5-ASA therapy, but has equivocal efficacy in inducing remission probably due to failure to colonize the inflamed intestine. We engineered EcN, by insertion of a ttr operon (from Salmonella enterica ) to confer the capacity to utilize a byproduct of intestinal inflammation, tetrathionate, as an energy source, to provide a fitness advantage for colonizing the inflamed gut. We also developed a microencapsulated EcN:: ttr formulation to enhance colonic delivery. In a dextran sodium sulphate (DSS) porcine colitis model, a single dose of orally administered microencapsulated EcN:: ttr reduced mortality, reduced inflammation in the ileum and colon, reduced bacterial translocation across the gut epithelium and modulated both the intestinal and systemic metabolome. EcN:: ttr also reduced intestinal inflammation in pigs that did not receive DSS. Both evaluated doses were effective, with a dose response for numerous endpoints, and were well tolerated. We show that insertion of the ttr operon combined with a novel microencapsulation formulation ameliorates intestinal inflammation justifying further investigation of EcN:: ttr as a next-generation biotherapeutic to treat intestinal inflammation in humans, pigs and other animals.