Translational model of melphalan-induced gut toxicity reveals drug-host-microbe interactions that drive tissue injury and fever

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dc.contributor.authorWardill, H.R.
dc.contributor.authorde Mooij, C.E.M.
dc.contributor.authorda Silva Ferreira, A.R.
dc.contributor.authorvan de Peppel, I.P.
dc.contributor.authorHavinga, R.
dc.contributor.authorHarmsen, H.J.M.
dc.contributor.authorTissing, W.J.E.
dc.contributor.authorBlijlevens, N.M.A.
dc.date.issued2021
dc.descriptionPublished: 20 April 2021
dc.description.abstractPURPOSE: Conditioning therapy with high-dose melphalan (HDM) is associated with a high risk of gut toxicity, fever and infections in haematopoietic stem cell transplant (HSCT) recipients. However, validated preclinical models that adequately reflect clinical features of melphalan-induced toxicity are not available. We therefore aimed to develop a novel preclinical model of melphalan-induced toxicity that reflected well-defined clinical dynamics, as well as to identify targetable mechanisms that drive intestinal injury. METHODS: Male Wistar rats were treated with 4-8 mg/kg melphalan intravenously. The primary endpoint was plasma citrulline. Secondary endpoints included survival, weight loss, diarrhea, food/water intake, histopathology, body temperature, microbiota composition (16S sequencing) and bacterial translocation. RESULTS: Melphalan 5 mg/kg caused self-limiting intestinal injury, severe neutropenia and fever while impairing the microbial metabolome, prompting expansion of enteric pathogens. Intestinal inflammation was characterized by infiltration of polymorphic nuclear cells in the acute phases of mucosal injury, driving derangement of intestinal architecture. Ileal atrophy prevented bile acid reabsorption, exacerbating colonic injury via microbiota-dependent mechanisms. CONCLUSION: We developed a novel translational model of melphalan-induced toxicity, which has excellent homology with the well-known clinical features of HDM transplantation. Application of this model will accelerate fundamental and translational study of melphalan-induced toxicity, with the clinical parallels of this model ensuring a greater likelihood of clinical success.
dc.description.statementofresponsibilityH. R. Wardill, C. E. M. de Mooij, A. R. da Silva Ferreira, I. P. van de Peppel, R. Havinga, H. J. M. Harmsen ... et al.
dc.identifier.citationCancer Chemotherapy and Pharmacology, 2021; 88(2):173-188
dc.identifier.doi10.1007/s00280-021-04273-7
dc.identifier.issn0344-5704
dc.identifier.issn1432-0843
dc.identifier.orcidWardill, H.R. [0000-0002-6613-3661]
dc.identifier.urihttp://hdl.handle.net/2440/130942
dc.language.isoen
dc.publisherSpringer
dc.rights© The Author(s) 2021. 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/.
dc.source.urihttps://doi.org/10.1007/s00280-021-04273-7
dc.subjectMelphalan
dc.subjectMucositis
dc.subjectGut toxicity
dc.subjectDiarrhea
dc.subjectInfection
dc.subjectMicrobiota
dc.titleTranslational model of melphalan-induced gut toxicity reveals drug-host-microbe interactions that drive tissue injury and fever
dc.typeJournal article
pubs.publication-statusPublished

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