Published online Aug 28, 2022. doi: 10.3748/wjg.v28.i32.4574
Peer-review started: September 14, 2021
First decision: December 27, 2021
Revised: January 5, 2022
Accepted: July 18, 2022
Article in press: July 18, 2022
Published online: August 28, 2022
Radiotherapy and chemotherapy can kill tumor cells and improve the survival rate of cancer patients. However, they can also damage normal cells and cause serious intestinal toxicity, leading to gastrointestinal mucositis. Traditional Chinese medicine is effective in improving the side effects of chemotherapy. Wumei pills (WMP) is a classic prescription in Treatise on Febrile Diseases. It has a significant effect on chronic diarrhea and other gastrointestinal diseases, but it is not clear if it has an effect on chemotherapy-induced intestinal mucositis (CIM).
To explore the potential mechanism of WMP in the treatment of CIM using experimental research.
Exploring the mechanism of WMP to alleviate chemotherapy-induced intestinal mucosal inflammation may be to regulate the intestinal flora, thereby inhibiting the activation of downstream inflammatory signaling pathways and exerting anti-inflammatory effects.
We used an intraperitoneal injection of 5-fluorouracil (5-Fu) to establish a mouse model of CIM and oral gavage of WMP decoction (11325 and 22650 mg/kg) to evaluate the efficacy of WMP in CIM. We evaluated the effect of WMP on CIM by observing the general conditions of mice (body weight, food intake, spleen weight, diarrhea score, and hematoxylin and eosin staining). To explore the potential mechanism of WMP in CIM, the expression of the inflammatory factors tumor necrosis factor-α (TNF-α), interleukin- 6 (IL-6), IL-1β, and myeloperoxidase (MPO), Toll-like receptor 4/myeloid differentiationfactor 88/nuclear factor-κB (TLR4/MyD88/NF-κB) signaling pathway proteins, and tight junction proteins [zonula occludens-1 (ZO-1), claudin-1, E-cadherin, and mucin-2] was determined. Furthermore, intestinal permeability, intestinal flora, and the levels of short-chain fatty acids (SCFA) were also assessed in the mice.
WMP effectively improved the body weight, spleen weight, food intake, diarrhea score, and inflammatory pathological status of mice with intestinal mucositis, which preliminarily confirmed the efficacy of WMP in CIM. Further experiments showed that WMP did not only reduce the levels of TNF-α, IL-1β, IL-6, and MPO, and inhibited the expression of TLR4/MyD88/NF-κB, but also repaired the integrity of the mucosal barrier of mice, regulated the intestinal flora, and increased the levels of SCFA (such as butyric acid).
In summary, our results demonstrate the beneficial effects of WMP against CIM in mice and the associated mechanisms. WMP activates the NF-κB pathway by restraining p65 translocation from the cytoplasm to the nucleus and inhibiting the expression of TLR4/MyD88/NF-κB proteins, resulting in the downregulated expression of inflammatory factors (IL-1β, IL-6, MPO, and TNF-α) and increased expression of tight junction proteins (ZO-1, claudin-1, E-cadherin, and mucin-2). Moreover, WMP restores the diversity and abundance of the intestinal flora. In particular, WMP increases the relative abundance of Lactobacilli but decreases the relative abundance of Bacteroides, Helicobacter, and Parabacteroides.
WMP has potential therapeutic effects against CIM, and further fecal bacterial transplantation or the downstream-mediated potential mechanisms of specific bacteria are worth exploring.