New insights into the mechanisms of modified Pulsatilla decoction in alleviating chemotherapy-induced intestinal mucositis

Abstract

Chemotherapy-induced intestinal mucositis (IM) is a prevalent complication affecting up to 80% of cancer patients undergoing treatment. Current therapies focus on symptomatic relief rather than addressing the underlying mechanism. Recent advances in integrative medicine highlight the potential of traditional Chinese medicine formulations as alternatives or adjuncts to existing therapies. In this context, this editorial discusses the recent results of a study published by Qiu et al, which investigates the multifaceted potential of modified Pulsatilla decoction (PD), a formulation of PD with licorice (Glycyrrhiza uralensis) and Ejiao (Colla corii asini), on 5-fluorouracil-induced IM in mice to alleviate clinical symptoms including diarrhea, weight loss, and intestinal damage. A series of histological, biochemical, bioinformatic, and microbiological assays evaluated body weight, diarrhea scores, inflammatory cytokine profiles, oxidative stress modulation, and microbiota composition. The findings indicated a reduction in diarrhea and oxidative stress, as well as an improvement in body weight and intestinal histopathology. Furthermore, the modified PD suppressed the TLR4/MyD88/nuclear factor kappa-B inflammatory pathway and down-regulated key pro-inflammatory cytokines. Moreover, the study underscores the role of gut microbiota in IM pathogenesis. Modified PD treatment reshaped microbial diversity by promoting beneficial genera such as Bacteroides acidifaciens while suppressing pathogenic species like Salmonella. These findings suggest that the therapeutic effects of the modified PD extend beyond inflammation modulation to encompass microbiome reprogramming and mucosal barrier repair. Although the study provides significant insights, several limitations still prevail. The broader implications of modified PD in gastrointestinal disorders and integrative oncology need further exploration.

Key Words: Modified Pulsatilla decoction; Intestinal mucositis; Oxidative stress; Gut microbiota; TLR4/MyD88/nuclear factor kappa-B pathway; Inflammatory response

Core Tip: The modified Pulsatilla decoction could be a promising treatment option for chemotherapy-induced intestinal mucositis, where inflammation, oxidative stress, and alteration of gut microbiota are targeted.

TO THE EDITOR

The gastrointestinal tract is vulnerable to off-target effects of antineoplastic drugs (chemotherapeutic agents) due to the rapid proliferation of intestinal epithelial cells and their intricate immunological interaction with gut microbiota[1]. Chemotherapy-induced intestinal mucositis (IM) is one of the most common inflammatory manifestations. With a prevalence of up to 80%, it is characterized by histological changes and inflammation in the intestinal mucosa, rooting from stem cell apoptosis and disrupted cellular renewal and maturation processes, leading to various symptoms such as ulceration, abdominal pain, nausea, diarrhea, and more[2,3]. Reducing the dose of chemotherapeutics lowers anticancer efficacy and can be life-threatening. Clinical management of the symptoms is the mainstay of the treatment for IM, rather than addressing the pathophysiology. For instance, loperamide is a commonly used μ-opioid receptor agonist for alleviating diarrhea, but it leads to certain side effects such as constipation and cardiotoxicity. This highlights the urgent need for the development of novel, safe, and effective therapeutic options for IM management.

Traditional Chinese medicine (TCM) is being increasingly recognized globally for its benefits, including minimal side effects, cost-effectiveness, and holistic treatment approaches. Among TCM formulations, the modified Pulsatilla decoction (PD) has shown promise for treating IM[4]. PD has been traditionally used to treat diarrhea and related gastrointestinal disorders. The enhanced version of PD incorporates licorice (Glycyrrhiza uralensis) and Ejiao (Colla corii asini). The pharmacological properties of the modified PD components include anti-inflammatory effects, modulation of oxidative stress, rebalancing of gut microbiota, and protection against gastrointestinal ulcers, thus underscoring its potential for treating IM[5,6]. Ejiao has previously been shown to inhibit the activation of nuclear factor kappa-B (NF-κB) and the production of reactive oxygen species (ROS), thereby reducing inflammation and oxidative stress while stabilizing gut microbiota and addressing fatigue and anemia[7].

IM pathogenesis is a multifaceted process involving dysregulated inflammation, oxidative stress, apoptosis, and disturbances in gut microbiota. Chemotherapy induces DNA strand breaks which results in elevated ROS production, thus activating the NF-κB signaling pathway[8]. NF-κB is a key transcription factor that promotes pro-inflammatory cytokines like tumor necrosis factor-α, interleukin (IL)-6, and IL-1β. These cytokines induce mucosal toxicity by targeting intestinal epithelial cells and disrupting mucosal integrity. Prolonged inflammation aggravates intestinal epithelial cell apoptosis and compromises the mucosal barrier, thereby reducing mucoproteins, disrupting tight junctions, increasing intercellular permeability, and facilitating pathogen colonization. These events ultimately lead to microbial dysbiosis and mucosal damage. A bidirectional relationship exists between gut microbiota and cytokine regulation, suggesting that chronic inflammation caused by elevated levels of pro-inflammatory cytokines disrupts microbial composition. Meanwhile, bacteria such as Bacteroides acidifaciens restore gut homeostasis by producing short chain fatty acids (e.g., butyrate, propionate, and acetate), which stimulate the production of anti-inflammatory cytokines (e.g., IL-10), thereby modulating inflammatory responses and aiding in gut healing. Furthermore, lipopolysaccharide of gram-negative bacteria contributes to NF-κB activation through the TLR4/MyD88 signaling pathway, causing inflammation and microbial imbalance.

The study by Qiu et al[1] addressed the issue by investigating the therapeutic efficacy of modified PD in a 5-fluorouracil (5-FU) induced IM mouse model. The focus of the study was on targeting the inflammatory signaling pathways in the gut, especially the TLR4/MyD88/NF-κB signaling pathway and gut microbial dysbiosis. Modified PD suppressed the TLR4/MyD88/NF-κB pathway, downregulating key pro-inflammatory cytokines and lowering oxidative stress. Additionally, it reshaped gut microbiota composition by promoting beneficial genera like Bacteroides acidifaciens and suppressing pathogenic species such as Salmonella. Furthermore, it significantly alleviated the clinical symptoms of IM. Their findings propose the therapeutic potential of modified PD in IM by targeting key molecular pathways, modulating oxidative stress, and restoring gut microbiota. These findings contribute to the growing evidence supporting the integration of TCM into modern medicine.

The strengths of the study include the use of comprehensive methodological approaches, mainly histological analysis together with investigation of molecular signaling pathways and gut microbiota profiling, thus allowing for an in-depth understanding of the multifaceted therapeutic effects and mechanism of modified PD in IM. The study provides mechanistic insights into the molecular mechanisms underlying the anti-inflammatory effects of PD by focusing on the TLR4/MyD88/NF-κB pathway, by demonstrating compound-receptor interactions through molecular docking. The inhibition of the pathway reveals the implications of modified PD in treating chemotherapy-induced inflammation beyond IM. Next, the analysis of changes in the intestinal microbiota using 16S rRNA sequencing adds another layer to the depth of the research. The identification of beneficial bacterial genera such as Bacteroides acidifaciens in the treatment group reveals the role of modified PD in restoring microbial balance and promoting mucosal healing. In contrast, the 5-FU group highlights the dysbiotic gut by representation of pathogenic microbes from the phylum Proteobacteria, including Salmonella, Staphylococcus sciuri, and Enterococcus faecalis. Lastly, the study focuses on the association of centuries-old TCM formulas with recent trends in science for developing alternatives to conventional therapies.

The study is robust in many aspects, but there are a few limitations that warrant further attention. The mouse models used to study IM were classified into control (untreated), 5-FU-induced IM model (negative control), 5-FU + loperamide (positive control), and 5-FU + modified PD (3 g/kg, 6 g/kg, 12 g/kg; treatment group). These groupings ensured a comprehensive comparison between standard treatment and modified PD. However, lack of tumor-bearing models induced with 5-FU limits its application in a cancer setting. Secondly, the absence of biodistribution data limits the ability to predict pharmacokinetics. The safety of the formulation is ambiguous and raises concerns about its off-target effects. Systemic distribution could lead to unwanted side effects in tissues where TLR4/MyD88/NF-κB signaling is essential for normal physiological functions, such as immune responses to infection or tissue repair. Even if the formulation selectively mitigates IM without systemic effects, addressing the mechanisms underlying its selectivity could have been beneficial. Furthermore, while three different dosages of modified PD were examined, a more extensive dose-response analysis is necessary to establish the optimal therapeutic range for clinical translation. Lastly, the study was conducted for a span of 7 d which is insufficient to address the long-term safety and efficacy of modified PD. Examination of the long-term effects of modified PD treatment, comprising its effects on survival, chronic inflammation, and potential side effects over extended periods would throw more light on its clinical utility.

IMPLICATIONS FOR CLINICAL APPLICATION

Chemotherapy-induced IM remains a major clinical hurdle, with no widely accepted preventative or therapeutic strategies. The authors show that subjects receiving anti-cancer chemotherapy may benefit from using modified PD as a complementary or adjunct therapeutic drug to treat IM. Additionally, modified PD could reduce the severity of chemotherapy-induced intestinal damage by modulating inflammatory pathways and improving gut barrier integrity. The modulation of the gut microbial composition further underscores the benefits of the therapeutic formulation. The results highlight its potential application in other gastrointestinal disorders, such as inflammatory bowel disease and colitis.

CONCLUSIONS

The research by Qiu et al[1] illustrates an innovative alternative to conventional therapies focusing on symptomatic relief. Through the integration of traditional knowledge with contemporary scientific rigor, the authors address both the symptoms and causes of IM. The study provides a strong foundation for further exploration of TCM-based therapies for the management of chemotherapy-induced intestinal damage. The study could benefit from comparative efficacy studies with other innate immune ligands that act via other Toll-like receptor-dependent (TLR2, TLR9) mechanisms or retinoic acid-mediated pathways. Such studies could be beneficial in finding the other signaling targets of modified PD and demonstrate if there could be any off-target effects if carried out in extended periods of observation. Nevertheless, studies such as this pave the way for the convergence of traditional and modern medicine. Future research should focus on optimizing the dosage, investigating long-term effects, and expanding the scope of human trials, ensuring that modified PD can be effectively adapted for clinical practice for the benefit of cancer patients worldwide.