Development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy

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....

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Autores principales:	A. R. da Silva Ferreira, S. A. J. van der Aa, 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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bf7e652cdc60485a8c52e953e31c3dd1
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spelling	oai:doaj.org-article:bf7e652cdc60485a8c52e953e31c3dd12021-11-28T12:18:59ZDevelopment of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy10.1038/s41598-021-02308-w2045-2322https://doaj.org/article/bf7e652cdc60485a8c52e953e31c3dd12021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02308-whttps://doaj.org/toc/2045-2322Abstract 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 significant 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.A. R. da Silva FerreiraS. A. J. van der AaT. WehkampH. R. WardillJ. P. ten KloosterJ. GarssenL. F. HarthoornA. HartogH. J. M. HarmsenW. J. E. TissingJ. van BergenhenegouwenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q A. R. da Silva Ferreira S. A. J. van der Aa 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 Development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy
description	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 significant 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.
format	article
author	A. R. da Silva Ferreira S. A. J. van der Aa 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
author_facet	A. R. da Silva Ferreira S. A. J. van der Aa 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
author_sort	A. R. da Silva Ferreira
title	Development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy
title_short	Development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy
title_full	Development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy
title_fullStr	Development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy
title_full_unstemmed	Development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy
title_sort	development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/bf7e652cdc60485a8c52e953e31c3dd1
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Development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy

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