Engineered spermidine-secreting Saccharomyces boulardii ameliorates colitis and colon cancer in mice

Experimental studies suggest that the probiotic yeast Saccharomyces boulardii can mitigate the symptoms of inflammatory bowel disease. However, these results are equivocal and S. boulardii probiotic therapy has not gained widespread acceptance in clinical practice. To assess whether the therapeutic properties of S. boulardii might be improved upon, we engineered S. boulardii to overproduce and secrete spermidine, a pro-regenerative natural metabolite. We employed CRISPR gene deletion and integration of gene cassettes at the Ty2 locus to achieve high level polyamine synthesis and transport. We tested whether spermidine secreting S. boulardii could reduce disease symptoms in dextran sulfate sodium (DSS) and azoxymethane induced models of intestinal inflammation and cancer. We demonstrate that oral delivery of spermidine-secreting S. boulardii in mice populates the gastrointestinal tract with viable spermidine-secreting S. boulardii cells and raises free spermidine levels in the gastrointestinal tract. Strikingly, spermidine-secreting S. boulardii strains were significantly more effective than wild-type S. boulardii in reducing colitis symptoms as well as colitis-associated carcinogenesis in mice. These results suggest that in situ spermidine secretion by engineered synthetic biotic yeast strains may be an effective and low-cost therapy to mitigate inflammatory bowel disease and associated colon cancer.