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

Abstract

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.

Antibiotic-induced disruption of the microbiome exacerbates chemotherapy-induced diarrhoea and can be mitigated with autologous faecal microbiota transplantation

“…MBI was induced with the chemotherapeutic drug, methotrexate (MTX), obtained from the Pharmachie Holding B.V. (The Netherlands) administered at 45e60 mg/kg as previously described [19]. Briefly, male Wistar rats (150e180 g; Charles River, Germany) were treated with a single intravenous dose of MTX on Day 0 administered via the penile vein under anaesthetic (3% isoflurane).…”

“…The faecal microbiota composition was assessed using 16S rRNA gene sequencing as previously described [19]. Briefly, DNA was extracted using the double beadbeater procedure and the QIAamp DNA Stool Minikit guidelines.…”

“…Although it has been demonstrated that FMT is able to restore the microbial community after 5-fluorouracil and antibiotics [17], it remains unclear if FMT-induced microbial restoration is able to prevent or minimise MBI and its associated clinical manifestations. The present study therefore aimed to determine the impact of microbial manipulation, using antibiotics and FMT, on MBI and its clinical manifestations using a validated model of methotrexate-induced gastrointestinal toxicity [18,19]. By delivering autologous gut microbes after chemotherapy, we aimed to provide new data to aid in defining the causal contribution of the microbiome to MBI and associated symptoms and identify translational methods aimed at strengthening the host microbiome before treatment.…”

Effects of enteral nutrition support combined with enhanced recovery after surgery on the nutritional status, immune function, and prognosis of patients with esophageal cancer after Ivor-Lewis operation

“…Intestinal flora are an important part of the intestinal mucosal barrier, and disturbance of the intestinal flora can increase the risk of perioperative complications (28,29). Gastrointestinal surgery will destroy the intestinal mucosal barrier and increase the risk of postoperative pulmonary infection, anastomotic leakage and other complications (30).…”

Fasting Intervention for Children With Unilateral Renal Tumors to Reduce Toxicity

“…CR can be applied to delay aging or as nutritional preconditioning method before and/or during therapy (18,22,(24)(25)(26). Alternatively, a more stringent and acute method can be used: short-term fasting (STF), which can be performed right before a period of (surgery-induced) stress (22,27,28). Recent studies have shown preventive effects of CR and/or STF on aging, genomic stress, ischemia-reperfusion injury (IRI) and acute stress conditions (22,25,26,(28)(29)(30)(31)(32)(33)(34).…”