Gastrointestinal Microflora and Mucins May Play a Critical Role in the Development of 5-Fluorouracil-Induced Gastrointestinal Mucositis

Stringer, Andrea M.; Gibson, Rachel J.; Logan, Richard M.; Bowen, Joanne M.; Yeoh, Ann S. J.; Hamilton, Juliette; Keefe, Dorothy

doi:10.3181/0810-rm-301

Cited by 193 publications

(180 citation statements)

References 41 publications

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Section: Discussionmentioning

confidence: 99%

“…In a rat mucositis study, Stringer et al (2009) identified P. aeruginosa and Escherichia coli as 5-FU-resistant species. Furthermore, P. aeruginosa and E. coli were shown to be able to overgrow the oral community and penetrate the damaged underlying mucosa thereby causing local infections (Stringer et al, 2009). Another study with rats reported similar shifts, with Gram-negative rods becoming more abundant upon treatment with 5-FU (Von Bültzingslöwen et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

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5-Fluorouracil sensitivity varies among oral micro-organisms

Vanlancker

Vanhoecke

Smet

et al. 2016

Journal of Medical Microbiology

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5-Fluorouracil (5-FU), a commonly used chemotherapeutic agent, often causes oral mucositis, an inflammation and ulceration of the oral mucosa. Micro-organisms in the oral cavity are thought to play an important role in the aggravation and severity of mucositis, but the mechanisms behind this remain unclear. Although 5-FU has been shown to elicit antibacterial effects at high concentrations (>100 µM), its antibacterial effect at physiologically relevant concentrations in the oral cavity is unknown. This study reports the effect of different concentrations of 5-FU (range 0.1-50 µM) on the growth and viability of bacterial monocultures that are present in the oral cavity and the possible role in the activity of dihydropyrimidine dehydrogenase (DPD), an enzyme involved in 5-FU resistance. Our data showed a differential sensitivity among the tested oral species towards physiological concentrations of 5-FU. Klebsiella oxytoca, Streptococcus salivarius, Streptococcus mitis, Streptococcus oralis, Pseudomonas aeruginosa and Lactobacillus salivarius appeared to be highly resistant to all tested concentrations. In contrast, Lactobacillus oris, Lactobacillus plantarum, Streptococcus pyogenes, Fusobacterium nucleatum and Neisseria mucosa showed a significant reduction in growth and viability starting from very low concentrations (0.2-3.1 µM). We can also provide evidence that DPD is not involved in the 5-FU resistance of the selected species. The observed variability in response to physiological 5-FU concentrations may explain why certain microbiota lead to a community dysbiosis and/or an overgrowth of certain resistant micro-organisms in the oral cavity following cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

5-Fluorouracil sensitivity varies among oral micro-organisms

Vanlancker

Vanhoecke

Smet

et al. 2016

Journal of Medical Microbiology

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“…Their impact on the oral mucosa was reported thereafter [61]. Additional studies have continued to investigate shifts in the ecological balance of the oral and gut flora following anti-cancer treatment [16,17,[62][63][64][65][66].…”

Section: Microbiome Changesmentioning

confidence: 99%

Emerging evidence on the pathobiology of mucositis

Al‐Dasooqi

Sonis

Bowen

et al. 2013

Support Care Cancer

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165

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Background Considerable progress has been made in our understanding of the biological basis for cancer therapyinduced mucosal barrier injury (mucositis). The last formal review of the subject by MASCC/ISOO was published in 2007; consequently, an update is timely. Methods Panel members reviewed the biomedical literature on mucositis pathobiology published between January 2005 and December 2011.Results Recent research has provided data on the contribution of tissue structure changes, inflammation and microbiome changes to the development of mucositis. Additional research has focused on targeted therapyinduced toxicity, toxicity clustering and the investigation of genetic polymorphisms in toxicity prediction. This review paper summarizes the recent evidence on these aspects of mucositis pathobiology. Conclusion The ultimate goal of mucositis researchers is to identify the most appropriate targets for therapeutic interventions and to be able to predict toxicity risk and personalize interventions to genetically suitable patients. Continuing research efforts are needed to further our understanding of mucositis pathobiology and the pharmacogenomics of toxicity.

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“…The gut microbiome has received significant attention for its role in the development of gut toxicity following chemotherapy, with documented changes in the balance of commensal and pathogenic bacteria following numerous chemotherapeutic agents (5)(6)(7). In light of these findings, the interaction between the gut microbiome and innate mucosal immune system has also gained interest, with particular emphasis on the impact of toll-like receptor (TLR) signaling (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms

Wardill

Gibson

Sebille

et al. 2016

Molecular Cancer Therapeutics

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115

124

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Strong epidemiological data indicate that chemotherapy-induced gut toxicity and pain occur in parallel, indicating common underlying mechanisms. We have recently outlined evidence suggesting that TLR4 signaling may contribute to both side effects. We therefore aimed to determine if genetic deletion of TLR4 improves chemotherapy-induced gut toxicity and pain. Forty-two female wild-type (WT) and 42 Tlr4 null (−/−) BALB/c mice weighing between 18 and 25 g (10–13 weeks) received a single 270 mg/kg (i.p.) dose of irinotecan hydrochloride or vehicle control and were killed at 6, 24, 48, 72, and 96 hours. Bacterial sequencing was conducted on cecal samples of control animals to determine the gut microbiome profile. Gut toxicity was assessed using validated clinical and histopathologic markers, permeability assays, and inflammatory markers. Chemotherapy-induced pain was assessed using the validated rodent facial grimace criteria, as well as immunologic markers of glial activation in the lumbar spinal cord. TLR4 deletion attenuated irinotecan-induced gut toxicity, with improvements in weight loss (P = 0.0003) and diarrhea (P < 0.0001). Crypt apoptosis was significantly decreased in BALB/c-Tlr4−/−billy mice (P < 0.0001), correlating with lower mucosal injury scores (P < 0.005). Intestinal permeability to FITC-dextran (4 kDa) and LPS translocation was greater in WT mice than in BALB/c-Tlr4−/−billy (P = 0.01 and P < 0.0001, respectively). GFAP staining in the lumbar spinal cord, indicative of astrocytic activation, was increased at 6 and 72 hours in WT mice compared with BALB/c-Tlr4−/−billy mice (P = 0.008, P = 0.01). These data indicate that TLR4 is uniquely positioned to mediate irinotecan-induced gut toxicity and pain, highlighting the possibility of a targetable gut/CNS axis for improved toxicity outcomes. Mol Cancer Ther; 15(6); 1376–86. ©2016 AACR.

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Gastrointestinal Microflora and Mucins May Play a Critical Role in the Development of 5-Fluorouracil-Induced Gastrointestinal Mucositis

Cited by 193 publications

References 41 publications

5-Fluorouracil sensitivity varies among oral micro-organisms

5-Fluorouracil sensitivity varies among oral micro-organisms

Emerging evidence on the pathobiology of mucositis

Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms

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