Substantial decreases in the number and diversity of microbiota during chemotherapy-induced gastrointestinal mucositis in a rat model.
OBJECTIVE
Earlier, we showed in acute myeloid leukemia (AML) patients that the microbiota changes dramatically during anticancer treatment, coinciding with gastrointestinal mucositis: The commensal anaerobic populations reduce in favor of potential pathogens. Therefore, interventions targeting the microbiota during mucositis might be interesting but can better be tested in animals than in vulnerable mucositis patients. Here, we aimed to study the potential microbial changes during methotrexate (MTX)-induced gastrointestinal mucositis in a well-established rat model and to study whether this model can be used for future microbial intervention studies.


METHODS
After injection with MTX or saline (day 0), rats were sacrificed between days 2 and 11. Plasma citrulline level, jejunal histology, and the number and diversity of intestinal bacteria in feces (using fluorescence in situ hybridization (FISH)) were determined.


RESULTS
Mucositis was most severe on day 4 when food intake, plasma citrulline, and villus length were the lowest, compared with controls (P < 0.0125). At the same time, MTX-treated rats showed an overall decrease (705-fold) in most bacteria (using a universal probe), compared with controls (P < 0.125). Reduced bacterial presence was related with the presence of diarrhea and a reduced villus length (rho = 0.38, P < 0.05). At day 4, there was an absolute and relative decrease of anaerobes (13-fold and -58 %, respectively) and streptococci (296-fold and -1 %, respectively) but a relative increase of Bacteroides (+49 %), compared with controls (P < 0.125).


CONCLUSIONS
In the mucositis rat model, we found substantial decreases in the number and diversity of microbiota, resembling earlier findings in humans. The model therefore seems well suited to study the effects of different microbial interventions on mucositis, prior to performing human studies.
Department of Pediatrics, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands, m.fijlstra@amc.uva.nl.
Margot
M
Fijlstra
Mithila
M
Ferdous
Anne M
AM
Koning
Edmond H H M
EH
Rings
Hermie J M
HJ
Harmsen
Wim J E
WJ
Tissing
D000818:Animals; D002956:Citrulline / Q000097:blood; D017404:In Situ Hybridization, Fluorescence; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000382:microbiology* / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000494:pharmacology; D064307:Microbiota / Q000187:drug effects*; D052016:Mucositis / Q000097:blood / Q000139:chemically induced / Q000382:microbiology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar
D002956:Citrulline; D008727:Methotrexate