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Treatment of murine colitis by Saccharomyces boulardii secreting atrial natriuretic peptide

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Abstract

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 probiotic Saccharomyces boulardii for this purpose. We developed a robust method to integrate recombinant genes into the Ty elements of S. 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-secreting S. boulardii effectively 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-α and IL-1β and an upregulation of IL-6 in colon tissues. This observation is consistent with the previous reports showing that TNF-α and IL-1β are responsible for initiating the pathogenesis, whereas IL-6 plays a protective role in colitis. Overall, we demonstrated that S. boulardii is 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 S. boulardii.

  • Oral administration of S. boulardii secreting IL-10 or TNF-α inhibitor did not exert therapeutic effects for DSS-induced colitis in mice.

  • Atrial natriuretic peptide–secreting S. boulardii 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-α and IL-1β and an increased mRNA level of IL-6 in colon tissues.

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Acknowledgments

We thank the Flow Cytometry Core of Institute of Biomedical Sciences for their technical supports. We also thank the Academia Sinica DNA Sequencing Core Facility (AS-CFII-108-115).

Funding

This work was supported by an Academia Sinica Career Development Award (AS-CDA-108-L07) and the Ministry of Science and Technology, Taiwan (107-2113-M-001-013).

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Authors and Affiliations

  1. Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan

    Cheng-Hao Liu, Jen-Hsuan Chang, You-Chiun Chang & Kurt Yun Mou

  2. Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, 11529, Taiwan

    Cheng-Hao Liu

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CHL and KYM conceived and designed the experiments. CHL, JHC, and YCC performed the experiments. CHL and KYM wrote the manuscript. All authors provided clarification, guidance, and revision on the manuscript.

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Correspondence to Kurt Yun Mou.

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Liu, CH., Chang, JH., Chang, YC. et al. Treatment of murine colitis by Saccharomyces boulardii secreting atrial natriuretic peptide. J Mol Med 98, 1675–1687 (2020). https://doi.org/10.1007/s00109-020-01987-8

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  • DOI: https://doi.org/10.1007/s00109-020-01987-8

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