nach oben

Erschienen in:

01.06.2015 | Original Article

Substantial decreases in the number and diversity of microbiota during chemotherapy-induced gastrointestinal mucositis in a rat model

verfasst von: Margot Fijlstra, Mithila Ferdous, Anne M. Koning, Edmond H. H. M. Rings, Hermie J. M. Harmsen, Wim J. E. Tissing

Erschienen in: Supportive Care in Cancer | Ausgabe 6/2015

Einloggen, um Zugang zu erhalten

Abstract

Purpose

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.

Nur mit Berechtigung zugänglich

Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer-Jensen M, Bekele BN, Raber-Durlacher J, Donnelly JP, Rubenstein EB (2004) Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 100:1995–2025CrossRefPubMed

Pacha J (2000) Development of intestinal transport function in mammals. Physiol Rev 80:1633–1667PubMed

Fijlstra M, Rings EH, Verkade HJ, van Dijk TH, Kamps WA, Tissing WJ (2011) Lactose maldigestion during methotrexate-induced gastrointestinal mucositis in a rat model. Am J Physiol Gastrointest Liver Physiol 300:G283–G291CrossRefPubMed

Fijlstra M, Rings EH, van Dijk TH, Plosch T, Verkade HJ, Tissing WJ (2012) Continuous enteral administration can overcome the limited capacity to absorb glucose in rats with methotrexate-induced gastrointestinal mucositis. Cancer, Support Care

Fijlstra M, Schierbeek H, Voortman G, Dorst KY, van Goudoever JB, Rings EH, Tissing WJ (2012) Continuous enteral administration can enable normal amino acid absorption in rats with methotrexate-induced gastrointestinal mucositis. J Nutr 142:1983–1990CrossRefPubMed

Fijlstra M, Tissing WJ, Stellaard F, Verkade HJ, Rings EH (2012) Reduced absorption of long-chain fatty acids during methotrexate-induced gastrointestinal mucositis in the rat. Nutr, Clin

Hann I, Viscoli C, Paesmans M, Gaya H, Glauser M (1997) A comparison of outcome from febrile neutropenic episodes in children compared with adults: results from four EORTC studies. International Antimicrobial Therapy Cooperative Group (IATCG) of the European Organization for Research and Treatment of Cancer (EORTC). Br J Haematol 99:580–588CrossRefPubMed

Sonis ST (2004) The pathobiology of mucositis. Nat Rev Cancer 4:277–284CrossRefPubMed

van Vliet MJ, Harmsen HJ, de Bont ES, Tissing WJ (2010) The role of intestinal microbiota in the development and severity of chemotherapy-induced mucositis. PLoS Pathog 6:e1000879CrossRefPubMedCentralPubMed

10.

van Vliet MJ, Tissing WJ, Dun CA, Meessen NE, Kamps WA, de Bont ES, Harmsen HJ (2009) Chemotherapy treatment in pediatric patients with acute myeloid leukemia receiving antimicrobial prophylaxis leads to a relative increase of colonization with potentially pathogenic bacteria in the gut. Clin Infect Dis 49:262–270CrossRefPubMed

11.

van der Waaij D (1984) The digestive tract in immunocompromised patients: importance of maintaining its resistance to colonization, especially in hospital in-patients and those taking antibiotics. Antonie Van Leeuwenhoek 50:745–761CrossRefPubMed

12.

Stringer AM, Gibson RJ, Logan RM, Bowen JM, Yeoh AS, Keefe DM (2008) Faecal microflora and beta-glucuronidase expression are altered in an irinotecan-induced diarrhea model in rats. Cancer Biol Ther 7:1919–1925CrossRefPubMed

13.

Von Bultzingslowen I, Adlerberth I, Wold AE, Dahlen G, Jontell M (2003) Oral and intestinal microflora in 5-fluorouracil treated rats, translocation to cervical and mesenteric lymph nodes and effects of probiotic bacteria. Oral Microbiol Immunol 18:278–284CrossRef

14.

Prisciandaro LD, Geier MS, Butler RN, Cummins AG, Howarth GS (2011) Evidence supporting the use of probiotics for the prevention and treatment of chemotherapy-induced intestinal mucositis. Crit Rev Food Sci Nutr 51:239–247CrossRefPubMed

15.

de Koning BA, Lindenbergh-Kortleve DJ, Pieters R, Rings EH, Buller HA, Renes IB, Einerhand AW (2006) The effect of cytostatic drug treatment on intestine-specific transcription factors Cdx2, GATA-4 and HNF-1alpha in mice. Cancer Chemother Pharmacol 57:801–810CrossRefPubMed

16.

Taminiau JA, Gall DG, Hamilton JR (1980) Response of the rat small-intestine epithelium to methotrexate. Gut 21:486–492CrossRefPubMedCentralPubMed

17.

Verburg M, Renes IB, Van Nispen DJ, Ferdinandusse S, Jorritsma M, Buller HA, Einerhand AW, Dekker J (2002) Specific responses in rat small intestinal epithelial mRNA expression and protein levels during chemotherapeutic damage and regeneration. J Histochem Cytochem 50:1525–1536CrossRefPubMed

18.

Boukhettala N, Leblond J, Claeyssens S, Faure M, Le PF, Bole-Feysot C, Hassan A, Mettraux C, Vuichoud J, Lavoinne A, Breuille D, Dechelotte P, Coeffier M (2009) Methotrexate induces intestinal mucositis and alters gut protein metabolism independently of reduced food intake. Am J Physiol Endocrinol Metab 296:E182–E190CrossRefPubMed

19.

Howarth GS, Tooley KL, Davidson GP, Butler RN (2006) A non-invasive method for detection of intestinal mucositis induced by different classes of chemotherapy drugs in the rat. Cancer Biol Ther 5:1189–1195CrossRefPubMed

20.

Tooley KL, Howarth GS, Lymn KA, Lawrence A, Butler RN (2006) Oral ingestion of streptococcus thermophilus diminishes severity of small intestinal mucositis in methotrexate treated rats. Cancer Biol Ther 5:593–600CrossRefPubMed

21.

Gibson RJ, Keefe DM, Clarke JM, Regester GO, Thompson FM, Goland GJ, Edwards BG, Cummins AG (2002) The effect of keratinocyte growth factor on tumour growth and small intestinal mucositis after chemotherapy in the rat with breast cancer. Cancer Chemother Pharmacol 50:53–58CrossRefPubMed

22.

Stringer AM, Gibson RJ, Logan RM, Bowen JM, Yeoh AS, Hamilton J, Keefe DM (2009) Gastrointestinal microflora and mucins may play a critical role in the development of 5-Fluorouracil-induced gastrointestinal mucositis. Exp Biol Med (Maywood) 234:430–441CrossRef

23.

Reeves PG, Nielsen FH, Fahey GC Jr (1993) AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr 123:1939–1951PubMed

24.

Fijlstra M, Tissing WJE, Verkade HJ, Rings EHHM (2013) Parenteral feeding during methotrexate-induced gastrointestinal mucositis prevents weight loss in the rat. 8:e95–e99

25.

van Eijk HM, Rooyakkers DR, Deutz NE (1993) Rapid routine determination of amino acids in plasma by high-performance liquid chromatography with a 2–3 microns Spherisorb ODS II column. J Chromatogr 620:143–148CrossRefPubMed

26.

van Vliet MJ, Tissing WJ, Rings EH, Koetse HA, Stellaard F, Kamps WA, de Bont ES (2009) Citrulline as a marker for chemotherapy induced mucosal barrier injury in pediatric patients. Pediatr Blood Cancer 53:1188–1194CrossRefPubMed

27.

Brugman S, Klatter FA, Visser JT, Wildeboer-Veloo AC, Harmsen HJ, Rozing J, Bos NA (2006) Antibiotic treatment partially protects against type 1 diabetes in the Bio-Breeding diabetes-prone rat. Is the gut flora involved in the development of type 1 diabetes? Diabetologia 49:2105–2108CrossRefPubMed

28.

Jansen GJ, Wildeboer-Veloo AC, Tonk RH, Franks AH, Welling GW (1999) Development and validation of an automated, microscopy-based method for enumeration of groups of intestinal bacteria. J Microbiol Methods 37:215–221CrossRefPubMed

29.

Amann RI, Binder BJ, Olson RJ, Chisholm SW, Devereux R, Stahl DA (1990) Combination of 16S rRNA-targeted oligonucleotide probes with flow cytometry for analyzing mixed microbial populations. Appl Environ Microbiol 56:1919–1925PubMedCentralPubMed

30.

Franks AH, Harmsen HJ, Raangs GC, Jansen GJ, Schut F, Welling GW (1998) Variations of bacterial populations in human feces measured by fluorescent in situ hybridization with group-specific 16S rRNA-targeted oligonucleotide probes. Appl Environ Microbiol 64:3336–3345PubMedCentralPubMed

31.

Langendijk PS, Schut F, Jansen GJ, Raangs GC, Kamphuis GR, Wilkinson MH, Welling GW (1995) Quantitative fluorescence in situ hybridization of Bifidobacterium spp. with genus-specific 16S rRNA-targeted probes and its application in fecal samples. Appl Environ Microbiol 61:3069–3075PubMedCentralPubMed

32.

Manz W, Amann R, Ludwig W, Vancanneyt M, Schleifer KH (1996) Application of a suite of 16S rRNA-specific oligonucleotide probes designed to investigate bacteria of the phylum cytophaga-flavobacter-bacteroides in the natural environment. Microbiology 142(Pt 5):1097–1106CrossRefPubMed

33.

van der Wulp MY, Derrien M, Stellaard F, Wolters H, Kleerebezem M, Dekker J, Rings EH, Groen AK, Verkade HJ (2013) Laxative treatment with polyethylene glycol decreases microbial primary bile salt dehydroxylation and lipid metabolism in the intestine of rats. Am J Physiol Gastrointest Liver Physiol 305:G474–G482CrossRefPubMed

34.

Zhu Q, Jin Z, Wu W, Gao R, Guo B, Gao Z, Yang Y, Qin H (2014) Analysis of the intestinal lumen microbiota in an animal model of colorectal cancer. PLoS One 9:e90849CrossRefPubMedCentralPubMed

35.

Flint HJ, Scott KP, Duncan SH, Louis P, Forano E (2012) Microbial degradation of complex carbohydrates in the gut. Gut Microbes 3:289–306CrossRefPubMedCentralPubMed

36.

Walker AW, Duncan SH, Harmsen HJ, Holtrop G, Welling GW, Flint HJ (2008) The species composition of the human intestinal microbiota differs between particle-associated and liquid phase communities. Environ Microbiol 10:3275–3283CrossRefPubMed

37.

Silva BC, Jung LR, Sandes SH, Alvim LB, Bomfim MR, Nicoli JR, Neumann E, Nunes AC (2013) In vitro assessment of functional properties of lactic acid bacteria isolated from faecal microbiota of healthy dogs for potential use as probiotics. Benef Microbes 4:267–275CrossRefPubMed

38.

Thiennimitr P, Winter SE, Winter MG, Xavier MN, Tolstikov V, Huseby DL, Sterzenbach T, Tsolis RM, Roth JR, Baumler AJ (2011) Intestinal inflammation allows Salmonella to use ethanolamine to compete with the microbiota. Proc Natl Acad Sci U S A 108:17480–17485CrossRefPubMedCentralPubMed

39.

van den Bogert B, Erkus O, Boekhorst J, de Goffau M, Smid EJ, Zoetendal EG, Kleerebezem M (2013) Diversity of human small intestinal Streptococcus and Veillonella populations. FEMS Microbiol Ecol 85:376–388CrossRefPubMed

40.

Teran-Ventura E, Aguilera M, Vergara P, Martinez V (2014) Specific changes of gut commensal microbiota and TLRs during indomethacin-induced acute intestinal inflammation in rats. J Crohns Colitis

41.

Matar MJ, Tarrand J, Raad I, Rolston KV (2006) Colonization and infection with vancomycin-resistant Enterococcus among patients with cancer. Am J Infect Control 34:534–536CrossRefPubMed

42.

Sakka V, Tsiodras S, Galani L, Antoniadou A, Souli M, Galani I, Pantelaki M, Siafakas N, Zerva L, Giamarellou H (2008) Risk-factors and predictors of mortality in patients colonised with vancomycin-resistant enterococci. Clin Microbiol Infect 14:14–21CrossRefPubMed

43.

Worth LJ, Thursky KA, Seymour JF, Slavin MA (2007) Vancomycin-resistant Enterococcus faecium infection in patients with hematologic malignancy: patients with acute myeloid leukemia are at high-risk. Eur J Haematol 79:226–233CrossRefPubMed

44.

Harmsen HJ, Raangs GC, He T, Degener JE, Welling GW (2002) Extensive set of 16S rRNA-based probes for detection of bacteria in human feces. Appl Environ Microbiol 68:2982–2990

45.

Salzman NH, de Jong H, Paterson Y, Harmsen HJ, Welling GW, Bos NA (2002) Analysis of 16S libraries of mouse gastrointestinal microflora reveals a large new group of mouse intestinal bacteria. Microbiology 148:3651–3660

46.

Wildeboer-Veloo A, Harmsen H, Degener J, Welling G (2003) Development of a 16S rRNA-based probe for Clostridium ramosum, C. spiroforme and C. cocleatum and its application for the quantification in human faeces from volunteers of different age groups. Microb Ecol Health Dis 15:131–136

47.

Harmsen H, Elfferich P, Schut F, Welling G (1999) A 16S rRNA-targeted probe for detection of lactobacilli and enterococci in faecal samples by fluorescent in situ hybridization. Microb Ecol Health Dis 11

48.

Poulsen LK, Lan F, Kristensen CS, Hobolth P, Molin S, Krogfelt KA (1994) Spatial distribution of Escherichia coli in the mouse large intestine inferred from rRNA in situ hybridization. Infect Immun 62:5191–5194

Titel: Substantial decreases in the number and diversity of microbiota during chemotherapy-induced gastrointestinal mucositis in a rat model
verfasst von: Margot Fijlstra
Mithila Ferdous
Anne M. Koning
Edmond H. H. M. Rings
Hermie J. M. Harmsen
Wim J. E. Tissing
Publikationsdatum: 01.06.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Supportive Care in Cancer / Ausgabe 6/2015
Print ISSN: 0941-4355
Elektronische ISSN: 1433-7339
DOI: https://doi.org/10.1007/s00520-014-2487-6

Neu im Fachgebiet Onkologie

19.04.2024 | EAU 2024 | Kongressbericht | Nachrichten

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Substantial decreases in the number and diversity of microbiota during chemotherapy-induced gastrointestinal mucositis in a rat model

Abstract

Purpose

Methods

Results

Conclusions

Neu im Fachgebiet Onkologie

Prostatakarzinom: EU initiiert neues Screeningkonzept

Blasenkarzinom – Biomarker statt Zytologie?

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Adjuvante Brustkrebstherapie: Doppelt hält besser

Update Onkologie

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 6/2015

Prediction of short- and long-term survival for advanced cancer patients after ICU admission

Nutrition, hydration, and patient’s preferences at the end of life

The interaction between informal cancer caregivers and health care professionals: a survey of caregivers’ experiences of problems and unmet needs

Early referral makes the decision-making about fertility preservation easier: a pilot survey study of young female cancer survivors

The role of volunteers at an outpatient cancer center: how do volunteers enhance the patient experience?

A randomized study of the efficacy and safety of transdermal granisetron in the control of nausea and vomiting induced by moderately emetogenic chemotherapy in Korean patients

Neu im Fachgebiet Onkologie

Prostatakarzinom: EU initiiert neues Screeningkonzept

Blasenkarzinom – Biomarker statt Zytologie?

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Adjuvante Brustkrebstherapie: Doppelt hält besser

Update Onkologie