Chemotherapy-induced gastrointestinal toxicity is associated with changes in serum and urine metabolome and fecal microbiota in male Sprague–Dawley rats

Abstract

PurposeChemotherapy-induced gastrointestinal toxicity (CIGT) is a complex process that involves multiple pathophysiological mechanisms. We have previously shown that commonly used chemotherapeutics 5-fluorouracil, oxaliplatin, and irinotecan damage the intestinal mucosa and increase intestinal permeability to iohexol. We hypothesized that CIGT is associated with alterations in fecal microbiota and metabolome. Our aim was to characterize these changes and examine how they relate to the severity of CIGT.MethodsA total of 48 male Sprague–Dawley rats were injected intraperitoneally either with 5-fluorouracil (150 mg/kg), oxaliplatin (15 mg/kg), or irinotecan (200 mg/kg). Body weight change was measured daily after drug administration and the animals were euthanized after 72 h. Blood, urine, and fecal samples were collected at baseline and at the end of the experiment. The changes in the composition of fecal microbiota were analyzed with 16S rRNA gene sequencing. Metabolic changes in serum and urine metabolome were measured with 1 mm proton nuclear magnetic resonance (1H-NMR).ResultsIrinotecan increased the relative abundance of Fusobacteria and Proteobacteria, while 5-FU and oxaliplatin caused only minor changes in the composition of fecal microbiota. All chemotherapeutics increased the levels of serum fatty acids and N(CH3)3 moieties and decreased the levels of Krebs cycle metabolites and free amino acids.ConclusionsChemotherapeutic drugs, 5-fluorouracil, oxaliplatin, and irinotecan, induce several microbial and metabolic changes which may play a role in the pathophysiology of CIGT. The observed changes in intestinal permeability, fecal microbiota, and metabolome suggest the activation of inflammatory processes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-017-3364-z) contains supplementary material, which is available to authorized users.

Risk factors for bloodstream infections in gynecological cancer

“…Escherichia coli was the most frequent pathogen found in all blood cultures; skin contaminants (eg, Staphylococcus epidermidis) were also common, but not as frequent as expected based on the number of patients who had a central venous catheter. Chemotherapy changes the microbiome, potentially selecting more virulent bacterial species,31 and at the same time the microbiome plays a pivotal role in the response and toxicity of chemotherapy 32. Interactions between the microbiome and chemotherapy drugs are complex and not fully understood, but they are a promising candidate in explaining chemotherapy toxicity not directly linked to bone marrow suppression 33…”

Pharmacomicrobiomics: exploiting the drug-microbiota interactions in anticancer therapies

“…In addition, in rats treated with irinotecan, a correlation between changes in fecal microbiota and drug-induced gastrointestinal toxicity was uncovered. A significant decrease in microbial diversity and an increase in Fusobacteria and Proteobacteria were observed, which have been all associated with intestinal inflammation [ 26 ].…”

The Aftermath of Surviving Acute Radiation Hematopoietic Syndrome and its Mitigation

“…Our observation that the gut microbiome alters in favor of Firmicutes and Actinobacteria and away from Bacteroidetes at the time of LATE EFFECTS OF ACUTE RADIATION HEMATOPOIETIC SYNDROME peak diarrhea is not too dissimilar to the microbiome shifts that have been observed in patients with intestinal and oral cancer during radiotherapy (48,49) and may serve as a DEARE biomarker (50). Such dynamic changes at the hostmicrobiome interface may ultimately affect the manifestation of tissue toxicity as seen in mucositis (51), chemotherapy-induced gastrointestinal toxicity (52) and gut dysbiosis (41) and may, at least in part, account for the sporadic nature of DEARE, a variability that is perhaps its most confusing aspect.…”