Wumei Pills enhance intestinal stem cell - mediated repair in chemotherapy-induced mucositis via Lactobacillus reuteri - dependent modulation of the gut microbiota

Abstract

BACKGROUND

Intestinal mucositis is a severe and common complication of chemotherapy, characterized by disruption of the gut microbiota, intestinal inflammation, and epithelial barrier damage. Intestinal stem cells (ISCs) are essential for epithelial renewal and barrier maintenance, yet chemotherapy impairs ISC proliferation and function, delaying mucosal repair. We hypothesized that Wumei Pills (WMP) could protect against chemotherapy-induced intestinal mucositis by modulating gut microbiota - particularly Lactobacillus reuteri (L. reuteri) - to restore ISC activity, preserve microbial balance, reduce inflammation, and promote epithelial regeneration.

AIM

To characterize these changes and the safety of WMP via a 5-fluorouracil (5-FU) induced intestinal mucositis mouse model.

METHODS

In this study, we established a 5-FU induced intestinal mucositis mouse model, to explore the protective effect of WMP regulating L. reuteri on integrity of intestinal mucosa.

RESULTS

We found that intestinal flora is an important mechanism causing chemotherapy-induced intestinal mucositis, but WMP and live L. reuteri were effective in protecting the morphology of intestinal mucositis and normal proliferation of epithelial. L. reuteri colonized in the intestinal mucosa and WMP ameliorated intestinal mucosa damage caused by 5-FU treatment, including improvement of body weight, pathological change, and proliferation level, reducement proinflammatory cytokine secretion (tumor necrosis factor-α, interleukin-6) and the lipopolysaccharides concentration in serum. The repair process stimulated by both L. reuteri and WMP were also accompanied with increased leucine-rich-repeat-containing G-protein-coupled receptor 5 (+) and proliferating cell nuclear antigen of mice intestine. Furthermore, we demonstrated that WMP and L. reuteri activated the Wingless-type/β-catenin pathway to accelerate proliferation of intestinal epithelial, thus recovering damaged intestinal mucosa. However, the relieving effect of L. reuteri on intestinal mucosa was inferior to that of WMP.

CONCLUSION

Our findings indicate that WMP regulating L. reuteri protects intestinal barrier and activates intestinal epithelial proliferation, which sheds light on treatment approaches for intestinal inflammation based on ISCs with traditional Chinese medicine and probiotics L. reuteri.

Keywords: Wumei Pills; Lactobacillus reuteri; Intestinal stem cells; Leucine-rich-repeat-containing G-protein-coupled receptor 5; Wingless-type/β-catenin pathway

Core Tip: In this study, we established a 5-fluorouracil induced intestinal mucositis mouse model, and found that intestinal flora is an important mechanism causing chemotherapy-induced intestinal mucositis. Lactobacillus reuteri colonized in the intestinal mucosa and Wumei Pills ameliorated intestinal mucosa damage caused by 5-fluorouracil treatment, including improvement of body weight, pathological change, and proliferation level, reducement proinflammatory cytokine secretion (tumor necrosis factor-α, interleukin-6) and the lipopolysaccharides concentration. The repair process stimulated were also accompanied with increased leucine-rich-repeat-containing G-protein-coupled receptor 5 (+) and proliferating cell nuclear antigen. Furthermore, Wumei Pills and Lactobacillus reuteri activated the Wingless-type/β-catenin pathway to accelerate proliferation of intestinal epithelial, thus recovering damaged intestinal mucosa.