Effect of Oral Insulin on the Severity and Recovery of Methotrexate‐Induced Gastrointestinal Mucositis in the Rat

Kuiken, Nicoline S. S.; Rings, Edmond H. H. M.; Havinga, Rick; Aa, Stijn A.J. van der; Groen, Albert K.; Tissing, Wim J. E.

doi:10.1097/mpg.0000000000001237

Cited by 7 publications

(4 citation statements)

References 30 publications

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“…The impact of fasting on MTX-induced GI-M was assessed using a validated preclinical model as previously described. 13,14 Briefly, male Wistar rats (150-180 g, N = 9/group) were treated with a single dose of MTX (45 mg/kg, 50 mg/ml; obtained from Pharmachemie Holding B.V. The Netherlands) or a volume-equivalent dose of 0.9% NaOH administered intravenously via the penile vein under anesthetic (3% isoflurane) on d 0.…”

Section: Preclinical Model Of Mtx-induced Gi-m and Fasting Conditionsmentioning

confidence: 99%

Pre-therapy fasting slows epithelial turnover and modulates the microbiota but fails to mitigate methotrexate-induced gastrointestinal mucositis

et al. 2020

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Background: Recent findings by Tang et al. (2020) show dietary restriction (30%, 2 weeks) prevents methotrexate-induced mortality by modulation of the microbiota, specifically the expansion of Lactobacillus. While fundamentally insightful, upscaling this schedule is a major obstacle to clinical uptake. Here, we evaluate a safe and clinically achievable schedule of pre-therapy fasting for 48 h on microbiota composition, body composition and intestinal proliferation, and assess its impact on the severity of methotrexate-induced gastrointestinal mucositis using a validated preclinical rat model. Methods: Age-and weight-matched male Wistar rats were treated with a sublethal dose of 45 mg/ kg methotrexate with or without pre-therapy fasting. The impact of acute fasting on epithelial proliferation, body composition and the microbiota was assessed using plasma citrulline, Ki67 immunohistochemistry, miniSpec and 16S rRNA sequencing. The severity of gastrointestinal mucositis was evaluated using plasma citrulline and body weight. Results: Whilst pre-therapy fasting slowed epithelial proliferation and increased microbial diversity and richness, it also induced significant weight loss and was unable to attenuate the severity of mucositis in both age-and weight-matched groups. In contrast to Tang et al., we saw no expansion of Lactobacillus following acute fasting. Conclusions: Our findings suggest that the beneficial effects of acute fasting are masked by the detrimental effects on body weight and composition and lacking influence on Lactobacillus. Future studies should consider alternative fasting schedules or aim to induce comparable microbial and mucosal manipulation without compromising body composition using clinically feasible methods of dietary or microbial intervention.

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Section: Preclinical Model Of Mtx-induced Gi-m and Fasting Conditionsmentioning

confidence: 99%

Pre-therapy fasting slows epithelial turnover and modulates the microbiota but fails to mitigate methotrexate-induced gastrointestinal mucositis

et al. 2020

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“…This model has contributed greatly to the understanding of various apects of CIM (203). While (140), milk bioactives with/without other compounds (23,24,37,85,195), oral insulin (109), dexamethasone (115), and feeding strategies such as minimal enteral feeding (108).…”

Section: Models Of Cim In Rodents Strengths and Limitationsmentioning

confidence: 99%

Animal models of chemotherapy-induced mucositis: translational relevance and challenges

Sangild

Shen

Pontoppidan

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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Chemotherapy for cancer patients induces damaging tissue reactions along the epithelium of the gastrointestinal tract (GIT). This chemotherapy-induced mucositis (CIM) is a serious side effect of cytotoxic drugs, and several animal models of CIM have been developed, mainly in rodents and piglets, to help understand the progression of CIM and how to prevent it. Animal models allow highly controlled experimental conditions, detailed organ (e.g., GIT) insights, standardized, clinically relevant treatment regimens, and discovery of new biomarkers. Still, surprisingly few results from animal models have been translated into clinical CIM management and treatments. The results obtained from specific animal models can be difficult to translate to the diverse range of CIM manifestations in patients, which vary according to the antineoplastic drugs, dose, underlying (cancer) disease, and patient characteristics (e.g., age, genetics, and body constitution). Another factor that hinders the direct use of results from animals is inadequate collaboration between basic science and clinical science in relation to CIM. Here, we briefly describe CIM pathophysiology, particularly the basic knowledge that has been obtained from CIM animal models. These model studies have indicated potential new preventive and ameliorating interventions, including supplementation with natural bioactive diets (e.g., milk fractions, colostrum, and plant extracts), nutrients (e.g., polyunsaturated fatty acids, short-chain fatty acids, and glutamine), and growth factor peptides (e.g., transforming growth factor and glucagon-like peptide-2), as well as manipulations of the gut microbiota (e.g., prebiotics, probiotics, and antibiotics). Rodent CIM models allow well-controlled, in-depth studies of animals with or without tumors while pig models more easily make clinically relevant treatment regimens possible. In synergy, animal models of CIM provide the basic physiological understanding and the new ideas for treatment that are required to make competent decisions in clinical practice.

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“…To evaluate the impact of the dietary intervention on GI-M and resulting symptoms, a validated tumor-naïve model using the chemotherapeutic drug methotrexate (MTX), was used [ 3 , 28 ]. Briefly, male Wistar rats (150–180 g, 6–8 weeks, Charles River Laboratories) were treated with a single dose of MTX (45 mg/kg, 50 mg/ml; obtained from Pharmachemie Holding B.V.…”

Section: Methodsmentioning

confidence: 99%

Whey-based diet containing medium chain triglycerides modulates the gut microbiota and protects the intestinal mucosa from chemotherapy while maintaining therapy efficacy

et al. 2023

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Cytotoxicity (i.e. cell death) is the core mechanism by which chemotherapy induces its anti-cancer effects. Unfortunately, this same mechanism underpins the collateral damage it causes to healthy tissues. The gastrointestinal tract is highly susceptible to chemotherapy’s cytotoxicity, resulting in ulcerative lesions (termed gastrointestinal mucositis, GI-M) that impair the functional capacity of the gut leading to diarrhea, anorexia, malnutrition and weight loss, which negatively impact physical/psychological wellbeing and treatment adherence. Preventing these side effects has proven challenging given the overlapping mechanisms that dictate chemotherapy efficacy and toxicity. Here, we report on a novel dietary intervention that, due to its localized gastrointestinal effects, is able to protect the intestinal mucosal from unwanted toxicity without impairing the anti-tumor effects of chemotherapy. The test diet (containing extensively hydrolyzed whey protein and medium chain triglycerides (MCTs)), was investigated in both tumor-naïve and tumor-bearing models to evaluate its effect on GI-M and chemo-efficacy, respectively. In both models, methotrexate was used as the representative chemotherapeutic agent and the diet was provided ad libitum for 14 days prior to treatment. GI-M was measured using the validated biomarker plasma citrulline, and chemo-efficacy defined by tumor burden (cm3/g body weight). The test diet significantly attenuated GI-M (P = 0.03), with associated reductions in diarrhea (P < 0.0001), weight loss (P < 0.05), daily activity (P < 0.02) and maintenance of body composition (P < 0.02). Moreover, the test diet showed significant impact on gut microbiota by increasing diversity and resilience, whilst also altering microbial composition and function (indicated by cecal short and brained chain fatty acids). The test diet did not impair the efficacy of methotrexate against mammary adenocarcinoma (tumor) cells. In line with the first model, the test diet minimized intestinal injury (P = 0.001) and diarrhea (P < 0.0001). These data support translational initiatives to determine the clinical feasibility, utility and efficacy of this diet to improve chemotherapy treatment outcomes.

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Effect of Oral Insulin on the Severity and Recovery of Methotrexate‐Induced Gastrointestinal Mucositis in the Rat

Abstract: Oral insulin does not alter the severity or the acceleration of recovery of mucositis. Therefore, we conclude that it is not useful to further study oral insulin as possible intervention to prevent or treat chemotherapy-induced GI mucositis.

Cited by 7 publications

References 30 publications

Pre-therapy fasting slows epithelial turnover and modulates the microbiota but fails to mitigate methotrexate-induced gastrointestinal mucositis

Pre-therapy fasting slows epithelial turnover and modulates the microbiota but fails to mitigate methotrexate-induced gastrointestinal mucositis

Animal models of chemotherapy-induced mucositis: translational relevance and challenges

Whey-based diet containing medium chain triglycerides modulates the gut microbiota and protects the intestinal mucosa from chemotherapy while maintaining therapy efficacy

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