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Mast Cells and Serotonin Synthesis Modulate Chagas Disease in the Colon: Clinical and Experimental Evidence

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Abstract

Background

Trypanosoma cruzi (T. cruzi) infects millions of Latin Americans each year and can induce chagasic megacolon. Little is known about how serotonin (5-HT) modulates this condition. Aim We investigated whether 5-HT synthesis alters T. cruzi infection in the colon.

Materials and Methods

Forty-eight paraffin-embedded samples from normal colon and chagasic megacolon were histopathologically analyzed (173/2009). Tryptophan hydroxylase 1 (Tph1) knockout (KO) mice and c-KitW-sh mice underwent T. cruzi infection together with their wild-type counterparts. Also, mice underwent different drug treatments (16.1.1064.60.3).

Results

In both humans and experimental mouse models, the serotonergic system was activated by T. cruzi infection (p < 0.05). While treating Tph1KO mice with 5-HT did not significantly increase parasitemia in the colon (p > 0.05), rescuing its synthesis promoted trypanosomiasis (p < 0.01). T. cruzi-related 5-HT release (p < 0.05) seemed not only to increase inflammatory signaling, but also to enlarge the pericryptal macrophage and mast cell populations (p < 0.01). Knocking out mast cells reduced trypanosomiasis (p < 0.01), although it did not further alter the neuroendocrine cell number and Tph1 expression (p > 0.05). Further experimentation revealed that pharmacologically inhibiting mast cell activity reduced colonic infection (p < 0.01). A similar finding was achieved when 5-HT synthesis was blocked in c-KitW-sh mice (p > 0.05). However, inhibiting mast cell activity in Tph1KO mice increased colonic trypanosomiasis (p < 0.01).

Conclusion

We show that mast cells may modulate the T. cruzi-related increase of 5-HT synthesis in the intestinal colon.

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Acknowledgments

The authors also disclose receipt of the following financial support for the development of this investigation: the National Council for Scientific and Technological Development (CNPQ; 443376/2014-0), Sao Paulo Research Foundation (FAPESP; 2014/06428-5), and Russian Science Foundation (No. 14-50-00069). The funders had no role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Toxicology, Bromatology, and Clinical Analysis, University of Sao Paulo, Ribeirão Preto, 14040-903, Brazil

    Vinicius Kannen, Juliana Y. Sakita, Zumira A. Carneiro, Regina R. Teixeira, Bianca Gasparotto & Sergio A. Uyemura

  2. Department of Pathology, University of Sao Paulo, Ribeirão Preto, Brazil

    Vinicius Kannen, Mariângela O. Brunaldi, Cleverson R. Fernandes & Sérgio B. Garcia

  3. Max Delbrück Center for Molecular Medicine, Berlin, Germany

    Michael Bader & Natalia Alenina

  4. Charité University Medicine Berlin, Berlin, Germany

    Michael Bader

  5. Berlin Institute of Health (BIH), Berlin, Germany

    Michael Bader

  6. Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia

    Natalia Alenina

  7. Department of Surgery, Federal University of Goias, Goiânia, Brazil

    Enio C. de Oliveira

  8. Department of Biochemistry and Immunology, University of São Paulo, Ribeirão Preto, Brazil

    Daniela C. Sartori & João S. Silva

  9. Department of Clinical Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil

    Marcus V. Andrade

  10. Department of Genetics, University of Sao Paulo, Ribeirão Preto, Brazil

    Wilson A. Silva Jr.

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  1. Vinicius Kannen
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  2. Juliana Y. Sakita
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Contributions

Study concept and design: VK and SBG. Acquisition of data: BG, JYS, NA, MB, RRT, ECO, DCS, JSS, MVA, CRF, ZAC, SAU. Statistical analysis: VK and SBG. Analysis and interpretation of data: VK and SBG. Drafting of the manuscript: All. Critical revision of the manuscript: All. Obtained funding: VK. Technical and material support: SAU, NA, MB, ECO, ZAC, DCS, MVA, SBG. Study supervision: SBG.

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Correspondence to Vinicius Kannen.

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Kannen, V., Sakita, J.Y., Carneiro, Z.A. et al. Mast Cells and Serotonin Synthesis Modulate Chagas Disease in the Colon: Clinical and Experimental Evidence. Dig Dis Sci 63, 1473–1484 (2018). https://doi.org/10.1007/s10620-018-5015-6

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  • DOI: https://doi.org/10.1007/s10620-018-5015-6

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