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

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Forsgard , R A , Marrachelli , V G , Korpela , K , Frias , R , Carmen Collado , M , Korpela , R , Monleon , D , Spillmann , T & Osterlund , P 2017 , ' Chemotherapy-induced gastrointestinal toxicity is associated with changes in serum and urine metabolome and fecal microbiota in male Sprague-Dawley rats ' , Cancer Chemotherapy and Pharmacology , vol. 80 , no. 2 , pp. 317-332 . https://doi.org/10.1007/s00280-017-3364-z

Title: Chemotherapy-induced gastrointestinal toxicity is associated with changes in serum and urine metabolome and fecal microbiota in male Sprague-Dawley rats
Author: Forsgard, Richard A.; Marrachelli, Vannina G.; Korpela, Katri; Frias, Rafael; Carmen Collado, Maria; Korpela, Riitta; Monleon, Daniel; Spillmann, Thomas; Osterlund, Pia
Contributor organization: Medicum
Research Programs Unit
de Vos & Salonen group
University of Helsinki
Immunobiology Research Program
Department of Bacteriology and Immunology
Riitta Anneli Korpela / Principal Investigator
Departments of Faculty of Veterinary Medicine
Thomas Spillmann / Principal Investigator
Equine and Small Animal Medicine
Department of Oncology
HUS Comprehensive Cancer Center
HUS Abdominal Center
Date: 2017-08
Language: eng
Number of pages: 16
Belongs to series: Cancer Chemotherapy and Pharmacology
ISSN: 0344-5704
DOI: https://doi.org/10.1007/s00280-017-3364-z
URI: http://hdl.handle.net/10138/241185
Abstract: Purpose Chemotherapy-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. Methods A 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). Results Irinotecan 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. Conclusions Chemotherapeutic 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.
Subject: Chemotherapy
Metabolomics
Microbiota
5-FU
Oxaliplatin
Irinotecan
IRINOTECAN HYDROCHLORIDE CPT-11
BETA-GLUCURONIDASE
COLORECTAL-CANCER
INDUCED DIARRHEA
GUT MICROBIOTA
INTESTINAL PERMEABILITY
CROHNS-DISEASE
NITRIC-OXIDE
HUMAN BLOOD
MUCOSITIS
3122 Cancers
317 Pharmacy
413 Veterinary science
Peer reviewed: Yes
Rights: unspecified
Usage restriction: openAccess
Self-archived version: publishedVersion


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