Treatment of murine colitis bySaccharomyces boulardiisecreting atrial natriuretic peptide

Inflammatory bowel disease is a lifelong disorder that involves chronic inflammation in the small and large intestines. Current therapies, including aminosalicylates, corticosteroids, and anti-inflammatory biologics, can only alleviate the symptoms and often cause adverse effects with long-term usage. Engineered probiotics provide an alternative approach to treat inflammatory bowel disease in a self-renewable and local delivery fashion. In this work, we utilized a yeast probioticSaccharomyces boulardiifor this purpose. We developed a robust method to integrate recombinant genes into the Ty elements ofS. boulardii. Stable yeast cell lines that secreted various anti-inflammatory proteins, including IL-10, TNFR1-ECD, alkaline phosphatase, and atrial natriuretic peptide (ANP), were successfully created and investigated for their efficacies to the DSS-induced colitis in mice through oral administration. While IL-10, TNFR1-ECD, and alkaline phosphatase did not show therapeutic effects, the ANP-secretingS. boulardiieffectively ameliorated the mouse conditions as reflected by the improvements in body weight, disease activity index, and survival rate. A post-mortem examination revealed that the ANP-treated mice exhibited significant downregulations of TNF-alpha and IL-1 beta and an upregulation of IL-6 in colon tissues. This observation is consistent with the previous reports showing that TNF-alpha and IL-1 beta are responsible for initiating the pathogenesis, whereas IL-6 plays a protective role in colitis. Overall, we demonstrated thatS. boulardiiis a safe and robust vehicle for recombinant protein delivery in the gastrointestinal tract, and ANP is a potential anti-inflammatory drug for colitis treatment. Key messages Recombinant genes can be robustly integrated into the transposable elements of Oral administration of secreting IL-10 or TNF-alpha inhibitor did not exert therapeutic effects for DSS-induced colitis in mice. Atrial natriuretic peptide-secreting effectively ameliorated the murine colitis as reflected by improved body weight, disease activity index, and survival rate. The ANP-treated mice exhibited decreased mRNA levels of TNF-alpha and IL-1 beta and an increased mRNA level of IL-6 in colon tissues.