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 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

Network Pharmacology-based to Investigate Pharmacological Mechanisms of Active Ingredients in Gegen Qinlian Pill to Ameliorate Irinotecan-induced Diarrhea

Background: The application of natural extracts or compounds derived from Chinese medicine is deemed to a promising strategy to prevent irinotecan (CPT-11)-induced gut toxicity. Based on the protective activity of Gegen Qinlian decoction in our previous study, we speculated that Gegen Qinlian Pill (GQP) would exhibit similar therapeutic effects. However, the effective material basis and the potential mechanisms underlying the effect of GQP in the treatment of diarrhea induced by CPT-11 have not been fully elucidated. Herein, we primarily investigated amelioration effect of GQP on the CPT-11 induced gut toxicity, and further explore its anti-diarrhea mechanism.Methods: Firstly, the protective effect of GQP towards alleviating diarrhea in mice following CPT-11 administration was investigated. Furthermore, the effective ingredients of GQP in serum sample of mice by HPLC-Q-TOF-MS analysis was obtained. Next, based on these active components, an interaction network linking “compound-target-pathway” was established. Finally, a predicted mechanism within vivo validation of GQP based on Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were obtained. Results: A total of 19 chemical compounds derived from the GQP were identified in its serum sample. Then, an interaction network linking “compound-target-pathway” was established to illuminate the interaction between these components absorbed into serum and their targets for diarrhea. GQP exerted a curative effect on diarrhea and diarrhea-related diseases by targeting different targets, regulating inflammation, oxidative stress, and proliferation processes. Conclusion: Taken together, this study provides a novel and scientific strategy to discover the potential effective constituents of herbs or herbal formula, and elucidated basic pharmacological effects and underlying mechanisms of GQP in the treatment of CPT-11 induced gut toxicity.

Prevotella copri is associated with carboplatin-induced gut toxicity

As a widely used cancer drug, carboplatin often results in serious side effects, such as gut toxicity. In this study, we examined the effects of gut microbiota on mice with carboplatin-induced intestinal mucosal damage. Carboplatin resulted in intestinal mucositis, as indicated by weight loss, diarrhoea, and infiltration of inflammatory cells. It markedly increased the expression of inflammatory cytokines/chemokines in intestine. Carboplatin also altered the diversity and composition of the gut microbiota. A significantly higher abundance of Prevotella copri (P. copri) was observed in carboplatin-treated mice. Moreover, the content of P. copri was positively correlated with the severity of intestinal mucositis. Pretreatment with metronidazole reduced the content of P. copri and relieved the intestinal mucosal injury and inflammation that was induced by carboplatin. Further study revealed that supplementation with P. copri in carboplatin-treated mice resulted in more severe tissue damage, lower tight junction protein expression and higher cytokine expression, and it enhanced both local and systemic immune responses. These data demonstrated that P. copri was involved in the pathological process of carboplatin-induced intestinal mucositis, suggesting a potential attenuation of carboplatin-induced intestinal mucositis by targeting P. copri.