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

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

doi:10.1038/s41598-021-02308-w

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

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

^*Corresponding author voor dit werk

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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.

Originele taal-2	English
Artikelnummer	22911
Aantal pagina's	11
Tijdschrift	Scientific Reports
Volume	11
DOI's	https://doi.org/10.1038/s41598-021-02308-w
Status	Published - 25-nov.-2021

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10.1038/s41598-021-02308-wLicentie: CC BY

Development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapyFinal publisher's version, 3,57 MBLicentie: CC BY

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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., & van Bergenhenegouwen, J. (2021). Development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy. Scientific Reports, 11, Artikel 22911. https://doi.org/10.1038/s41598-021-02308-w

@article{6e0c4c2e57f34291b94ce6dd2296d838,

title = "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. 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.",

author = "{da Silva Ferreira}, {A R} and {van der Aa}, {S A J} and T Wehkamp and Wardill, {H R} and {Ten Klooster}, {J P} and J Garssen and Harthoorn, {L F} and A Hartog and Harmsen, {H J M} and Tissing, {W J E} and {van Bergenhenegouwen}, J",

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year = "2021",

month = nov,

day = "25",

doi = "10.1038/s41598-021-02308-w",

language = "English",

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journal = "Scientific Reports",

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da Silva Ferreira, AR, van der Aa, SAJ, Wehkamp, T, Wardill, HR, Ten Klooster, JP, Garssen, J, Harthoorn, LF, Hartog, A, Harmsen, HJM , Tissing, WJE & van Bergenhenegouwen, J 2021, 'Development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy', Scientific Reports, vol. 11, 22911. https://doi.org/10.1038/s41598-021-02308-w

TY - JOUR

T1 - Development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy

AU - da Silva Ferreira, A R

AU - van der Aa, S A J

AU - Wehkamp, T

AU - Wardill, H R

AU - Ten Klooster, J P

AU - Garssen, J

AU - Harthoorn, L F

AU - Hartog, A

AU - Harmsen, H J M

AU - Tissing, W J E

AU - van Bergenhenegouwen, J

PY - 2021/11/25

Y1 - 2021/11/25

N2 - 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.

AB - 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.

U2 - 10.1038/s41598-021-02308-w

DO - 10.1038/s41598-021-02308-w

M3 - Article

C2 - 34824316

SN - 2045-2322

VL - 11

JO - Scientific Reports

JF - Scientific Reports

M1 - 22911

ER -

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

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