Development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy
Date
2021
Authors
da Silva Ferreira, A.R.
van der Aa, S.A.J.
Wehkamp, T.
Wardill, H.R.
ten Klooster, J.P.
Garssen, J.
Harthoorn, L.F.
Hartog, A.
Harmsen, H.J.M.
Tissing, W.J.E.
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Journal article
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Scientific Reports, 2021; 11(1):22911-1-22911-11
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A. R. da Silva Ferreira, S.A. J. van derAa, T. Wehkamp, H. R. Wardill, J. P. ten Klooster, J.Garssen, L. F. Harthoorn, A. Hartog, H. J. M. Harmsen, W. J. E.Tissing, J. van Bergenhenegouwen
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Abstract
Gastrointestinal mucositis is a complication of anticancer treatment, with few validated in vitro systems suitable to study the complex mechanisms of mucosal injury. Therefore, we aimed to develop and characterize a chemotherapeutic-induced model of mucositis using 3D intestinal organoids. Organoids derived from mouse ileum were grown for 7 days and incubated with different concentrations of the chemotherapeutic agent methotrexate (MTX). Metabolic activity, citrulline levels and cytokine/chemokine production were measured to determine the optimal dosage and incubation time. The protective effects of folinic acid on the toxicity of MTX were investigated by pre-treating organoids with (0.0005–50 µg/mL) folinic acid. The impact of microbial-derived short-chain fatty acids was evaluated by supplementation with butyrate in the organoid model. MTX caused a dose-dependent reduction in cell metabolic activity and citrulline production that was salvaged by folinic acid treatment. Overall, MTX causes signifcant organoid damage, which can be reversed upon removal of MTX. The protective effect of folinic acid suggest that the organoids respond in a clinical relevant manner. By using the model for intervention, it was found that prophylactic treatment with butyrate might be a valuable strategy for prophylactic mucositis prevention.
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© The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.