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

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. Graphic abstract

Supporting the gastrointestinal microenvironment during high-dose chemotherapy and stem cell transplantation by inhibiting IL-1 signaling with anakinra

“…It must also be acknowledged that limited mechanistic investigations were conducted to identify the way in which anakinra provided mucoprotection. It is well documented that MBI is highly multifactorial, involving mucosal, microbial and metabolic dysfunction 33 , 46 ; each of which is mediated through aberrant cytokine production. It is therefore unlikely that anakinra will affect distinct pathways, instead dampening multiple mechanisms.…”

“…To explore methods of preserving the mucosal barrier, we recently developed a translational preclinical model of HDM-induced MBI 21 . This model recapitulates the complex etiology of MBI, where melphalan injures the gut microbiota and impairs the microbial metabolome, causing expansion and subsequent translocation of enteric pathogens across a damaged mucosal barrier.…”

The Insider: Impact of the Gut Microbiota on Cancer Immunity and Response to Therapies in Multiple Myeloma

“…Similarly, melphalan administration in rats causes severe injury to the small intestine, weight loss and infections ( 115 ). These effects recapitulate the toxicity observed in patients and limit melphalan administration to elderly subjects ( 116 ).…”

“…These effects recapitulate the toxicity observed in patients and limit melphalan administration to elderly subjects ( 116 ). Indeed, melphalan induces dysbiosis, reduction of SCFA production and bacterial translocation ( 115 ). Thus, replenishing SCFA or normalization of microbiota composition might re-establish intestinal homeostasis and improve drug tolerability.…”

Exposure of anti-infective drugs and the dynamic changes of the gut microbiota during gastrointestinal mucositis in autologous stem cell transplant patients: a pilot study

“…Plasma citrulline—a biomarker of enterocyte mass—can be used to objectively monitor and quantify gastrointestinal mucositis severity [ 9 , 10 ]. Citrulline is a nonprotein amino acid produced in the enterocytes by glutamine, which has been increasingly shown to correlate with the intestinal villus length and with radiation-induced and chemotherapy-induced (e.g., methotrexate and melphalan) mucositis in mouse and rat models [ 11 – 13 ]. In HSCT recipients, low citrulline concentrations have been related to severe mucosal barrier injury and showed a strong correlation with the daily gut score [ 14 – 16 ].…”