Dietary restriction increases protective gut bacteria to rescue lethal methotrexate-induced intestinal toxicity

Abstract

Methotrexate (MTX) is a typical chemotherapeutic drug that is widely used in the treatment of various malignant diseases as well as autoimmune diseases, with gastrointestinal toxicity being its most prominent complication which could have a significant effect on the prognosis of patients. Yet effective ways to alleviate such complications remains to be explored. Here we show that 30% dietary restriction (DR) for 2 weeks dramatically increased the survival rate of 2-month-old female mice after lethal-dose MTX exposure. DR significantly reduced intestinal inflammation, preserved the number of basal crypt PCNA-positive cells, and protected the function of intestinal stem cells (ISCs) after MTX treatment. Furthermore, ablating intestinal microbiota by broad-spectrum antibiotics completely eliminated the protective effect achieved by DR. 16S rRNA gene deepsequencing analysis revealed that short-term DR significantly increased the Lactobacillus genus, with Lactobacillus rhamnosus GG gavage partially mimicking the rescue effect of DR on the intestines of ad libitum fed mice exposed to lethal-dose MTX. Together, the current study reveals that DR could be a highly effective way to alleviate the lethal injury in the intestine after highdose MTX treatment, which is functionally mediated by increasing the protective intestinal microbiota taxa in mice.

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

“…Preliminary evidence from our laboratory shows that antibiotic-induced disruption of the microbiota worsens MTX-induced mucositis, increasing MTX-mortality and impairing mucosal recovery. These results align with existing preclinical findings 9 and clinical risk factors, with antibiotic use prior to chemotherapy associated with increased GI-M severity. 10 Similarly, while probiotics have shown some benefits in mitigating the severity of MTX associated GI-M, 11 translational success is variable.…”

“…Contrary to our hypothesis, this did not affect the ability of pretherapy fasting to prevent MTX-induced GI-M, indicating that it is more likely that the lack of fat stores masks the protective cellular and microbial mechanisms induced by fasting. Despite the contradictory findings to those published by Tang et al, (2020) and Raffaghello et al, (2008), there are a number of differences that must be acknowledged. Firstly, both studies reporting positive effects of fasting/dietary modulation used lethal doses of chemotherapy administered to mice.…”

“…We read with interest the recent work by Tang et al, (2020) demonstrating that dietary restriction (DR; 30%) protects against MTX-induced mortality via modulation of the microbiota. 9 While fundamentally insightful, these findings are translationally challenging, with long-term DR unlikely to be feasible in most oncology settings. This is particularly pertinent when considering the DR schedule employed by Tang and colleagues which commenced 2 weeks prior to MTX administration.…”

Mesenchymal Stem Cells Enhance Therapeutic Effect and Prevent Adverse Gastrointestinal Reaction of Methotrexate Treatment in Collagen-Induced Arthritis

“…The disrupted intestinal barrier leads to intestinal LPS translocation into circulation [ 30 ]. Therefore, the gastrointestinal toxicity of MTX could result in loss of body weight ever increased mortality [ 31 ]. MSCs have been thought of as an effective method to alleviate different types of small intestinal injuries [ 32 – 34 ].…”

Connecting the dots: targeting gut microbiota in drug toxicity

“…In comparison, dietary control offers a safer alternative herein. It was found that dietary restriction remarkably enhanced the survival rate of mice exposed to a lethal dose of MTX and ameliorated MTX-induced intestine inflammation with Lactobacillus rhamnosusplaying a critical role (Tang et al, 2020). In this case, dietary restriction needless of specific diet, drug, or probiotics intervened achieved remarkable results in reducing MTX-induced gastrointestinal side effects, suggesting what we eat, which constitutes the major part of gastrointestinal contents, probably determines therapeutic and toxic outcomes of orally administered drugs somehow.…”