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

H R Wardill, C E M de Mooij, A R da Silva Ferreira, I P van de Peppel, R Havinga, H J M Harmsen, W J E Tissing, N M A Blijlevens

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)173-188
Number of pages16
JournalCancer chemotherapy and pharmacology
Volume88
Issue number2
DOIs
Publication statusPublished - Aug 2021

Keywords

  • Animals
  • Bacterial Translocation
  • Bile Acids and Salts/metabolism
  • Fever/chemically induced
  • Gastrointestinal Microbiome/drug effects
  • Hematopoietic Stem Cell Transplantation/methods
  • Inflammation/chemically induced
  • Intestinal Diseases/chemically induced
  • Male
  • Melphalan/adverse effects
  • Microbiota/drug effects
  • Neutropenia/chemically induced
  • Rats
  • Rats, Wistar
  • Transplantation Conditioning/methods
  • Transplantation, Autologous/methods

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