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Ion Transport Basis of Diarrhea in a Mouse Model of Adoptive T Cell Transfer Colitis

Digestive Diseases and Sciences volume 65, pages 1700–1709 (2020)Cite this article

Abstract

Background

Diarrhea, a major pathological hallmark of inflammatory bowel disease, is characterized by a significant reduction in the expression and function of key intestinal ion transporters. The adoptive naïve CD4+ T cell transfer colitis is an immune-based, chronic colitis mouse model which resembles human Crohn’s disease. Although mice with T cell transfer colitis demonstrate diarrhea, the ion transporter basis of this phenotype has not been explored.

Aims/Methods

In the current studies, we aimed to determine the mRNA and protein levels of the key NaCl transporters DRA and NHE3 along with the mRNA expression of other transporters in the inflamed intestine.

Results

Naïve CD4+ T cells, transferred to Rag2 knockout mice, induced severe colonic inflammation characterized by histological damage and increased mRNA levels of cytokines in the colon with no effect in the ileum. Diarrheal phenotype was a key feature of the excised colons of mice where loose stools were evident. Our results demonstrated that the key chloride transporter DRA, mRNA, and protein levels were significantly reduced in the inflamed colon. However, expression of the key sodium hydrogen exchanger NHE3 was unaffected. The mRNA expression of other important transporters was also determined; in this regard, the sodium channel ENACα and the monocarboxylate transporters MCT1 and SMCT1 mRNA levels were also significantly lower compared to control mice. However, CFTR mRNA was not altered in the colon or ileum.

Conclusions

The studies conducted herein for the first time demonstrate the downregulation of important intestinal ion transporters in proximal and distal colon in T cell transfer colitis mouse model, providing valuable evidence for the ion transporter basis of diarrhea in this chronic model of inflammation.

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Acknowledgments

Funding was provided by the National Institute of Diabetes and Digestive and Kidney Diseases (Grant Nos. DK92441-01, DK54016-14 to PKD and DK111671 to DO-V), the US Department of Veterans Affairs (Grant Nos. BX002011-VA and VA Sr. Research Career Scientist Award to PKD), and the American Association of Immunologists (Grant Nos. Careers in Immunology Fellowship Program and Careers in Immunology Fellowship to DO-V and AN).

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Author notes

  1. Danyvid Olivares-Villagómez and Pradeep K. Dudeja were co-senior authors.

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Dulari Jayawardena, Sangeeta Tyagi & Pradeep K. Dudeja

  2. Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, USA

    Ali Nazmi & Danyvid Olivares-Villagómez

  3. Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, USA

    Danyvid Olivares-Villagómez

  4. Jesse Brown VA Medical Center, Medical Research Service (600/151), 820 South Damen Avenue, Chicago, IL, 60612, USA

    Pradeep K. Dudeja

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  1. Dulari Jayawardena
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  2. Sangeeta Tyagi
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Correspondence to Pradeep K. Dudeja.

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Jayawardena, D., Tyagi, S., Nazmi, A. et al. Ion Transport Basis of Diarrhea in a Mouse Model of Adoptive T Cell Transfer Colitis. Dig Dis Sci 65, 1700–1709 (2020). https://doi.org/10.1007/s10620-019-05945-4

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Keywords

  • Ion transporters
  • T-cell transfer colitis
  • Diarrhea
  • DRA
  • Inflammatory bowel disease