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Translational model of melphalan-induced gut toxicity reveals drug-host-microbe interactions that drive tissue injury and fever
PURPOSE: 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 ar...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236460/ https://www.ncbi.nlm.nih.gov/pubmed/33877390 http://dx.doi.org/10.1007/s00280-021-04273-7 |
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author | Wardill, H. R. de Mooij, C. E. M. da Silva Ferreira, A. R. van de Peppel, I. P. Havinga, R. Harmsen, H. J. M. Tissing, W. J. E. Blijlevens, N. M. A. |
author_facet | Wardill, H. R. de Mooij, C. E. M. da Silva Ferreira, A. R. van de Peppel, I. P. Havinga, R. Harmsen, H. J. M. Tissing, W. J. E. Blijlevens, N. M. A. |
author_sort | Wardill, H. R. |
collection | PubMed |
description | PURPOSE: 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. GRAPHIC ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00280-021-04273-7. |
format | Online Article Text |
id | pubmed-8236460 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-82364602021-07-09 Translational model of melphalan-induced gut toxicity reveals drug-host-microbe interactions that drive tissue injury and fever Wardill, H. R. de Mooij, C. E. M. da Silva Ferreira, A. R. van de Peppel, I. P. Havinga, R. Harmsen, H. J. M. Tissing, W. J. E. Blijlevens, N. M. A. Cancer Chemother Pharmacol Original Article PURPOSE: 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. GRAPHIC ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00280-021-04273-7. Springer Berlin Heidelberg 2021-04-20 2021 /pmc/articles/PMC8236460/ /pubmed/33877390 http://dx.doi.org/10.1007/s00280-021-04273-7 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Article Wardill, H. R. de Mooij, C. E. M. da Silva Ferreira, A. R. van de Peppel, I. P. Havinga, R. Harmsen, H. J. M. Tissing, W. J. E. Blijlevens, N. M. A. Translational model of melphalan-induced gut toxicity reveals drug-host-microbe interactions that drive tissue injury and fever |
title | Translational model of melphalan-induced gut toxicity reveals drug-host-microbe interactions that drive tissue injury and fever |
title_full | Translational model of melphalan-induced gut toxicity reveals drug-host-microbe interactions that drive tissue injury and fever |
title_fullStr | Translational model of melphalan-induced gut toxicity reveals drug-host-microbe interactions that drive tissue injury and fever |
title_full_unstemmed | Translational model of melphalan-induced gut toxicity reveals drug-host-microbe interactions that drive tissue injury and fever |
title_short | Translational model of melphalan-induced gut toxicity reveals drug-host-microbe interactions that drive tissue injury and fever |
title_sort | translational model of melphalan-induced gut toxicity reveals drug-host-microbe interactions that drive tissue injury and fever |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236460/ https://www.ncbi.nlm.nih.gov/pubmed/33877390 http://dx.doi.org/10.1007/s00280-021-04273-7 |
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