Chemotherapy-induced Diarrhea Research Articles

Probiotics in Mitigating Adverse Effects of Intestinal Resection and Chemotherapy: A Meta-analysis

Introduction: Colorectal cancer (CRC) imposes a significant burden on global healthcare systems, particularly in Europe, where it ranks among the most diagnosed cancers and leading causes of cancer-related deaths. With an estimated 50,000 deaths attributed to CRC in 2023 alone, a pressing need for innovative approaches to prevention, early detection, and treatment is evident. While chemotherapy and surgical resection remain crucial therapeutic strategies, they often entail significant adverse effects, such as chemotherapy-induced diarrhea and post-surgical complications. Methods: Recent research underscores the role of the microbiota in modulating these side effects, with dysbiosis associated with increased risks. Probiotics, known for their ability to restore microbial balance, have emerged as a promising adjunctive therapy for mitigating treatment-related complications in CRC patients. However, the efficacy of probiotics remains debated, necessitating a metaanalysis to provide a comprehensive assessment. Hence, this study aimed to evaluate the efficacy of probiotics in reducing complications in CRC patients undergoing chemotherapy and intestinal surgery. For this purpose, thirteen randomized controlled trials (RCTs) meeting strict inclusion criteria were included in the meta-analysis. Results: Probiotic administration was associated with significant reductions in postoperative infections, including surgical site infections (SSI), pneumonia, urinary tract infections (UTI), and central line infections, showing a Risk Ratio (RR) of 0.74 with a Confidence Interval (CI) of 95%. Moreover, probiotics demonstrated efficacy in mitigating chemotherapy-induced diarrhea and postsurgical complications, such as anastomosis loosening and abdominal disorders, with an RR of 0.35 and 0.74, respectively, with a CI of 95%. While promising, further research is needed to optimize probiotic interventions and address potential interactions with concurrent therapies. Integrating probiotics into perioperative care protocols presents a convincing opportunity to enhance surgical outcomes and improve patient prognosis following CRC resection. Conclusion: Future randomized controlled trials should focus on identifying optimal probiotic strains, dosages, and administration timing to maximize therapeutic benefits.

Efficacy and Safety of Probiotics as Adjunctive Therapy in Cancer Treatment: A Comprehensive Systematic Review and Meta-Analysis.

The gut microbiome is crucial in influencing cancer progression and response to treatment. We evaluate the efficacy and safety of probiotics and synbiotics in cancer treatment, focusing on the incidence of diarrhea, significant complications, surgical site infections, length of hospital stay, progression-free survival (PFS), and overall survival (OS). Following PRISMA guidelines, a comprehensive literature search was conducted in PubMed, Scopus, Web of Science, and Cochrane CENTRAL up to June 2024. The risk of bias was assessed using the Cochrane Risk-of-Bias tool. Meta-analysis was performed using a random-effects model. Fifteen studies involving 2197 participants were included. Probiotic use was associated with a significant reduction in the incidence of diarrhea (OR=0.39, 95% CI: 0.15-1.00, P=0.049) with moderate heterogeneity (I2=64%). No significant differences were found in major complications (OR=0.50, 95% CI: 0.05-4.92, P=0.4053, I2=73%), surgical site infections (OR=0.36, 95% CI: 0.12-1.09, P=0.058, I2=0%), length of hospital stay (SMD=-0.30, 95% CI: -1.00 to 0.41, P=0.2726, I2=62%), PFS (HR=0.61, 95% CI: 0.03-10.82, P=0.2715, I2=0%), or OS (HR=0.52, 95% CI: 0.00-58.82, P=0.3298, I2=0%). Probiotics significantly reduced the incidence of chemotherapy-induced diarrhea, highlighting their potential as supportive care agents in oncology. However, their impact on significant complications, surgical site infections, length of hospital stay, and survival outcomes remains inconclusive.

Three bioactive compounds from Huangqin decoction ameliorate Irinotecan-induced diarrhea via dual-targeting of Escherichia coli and bacterial β-glucuronidase

Irinotecan (CPT-11) is a commonly prescribed chemotherapeutic for the treatment of colon cancer. Unfortunately, acute and delayed diarrhea are prominent side effects of CPT-11 use, and this limits its therapeutic potential. The curative effect of Huangqin decoction (HQD) on chemotherapy-induced diarrhea has been proven. This study investigated the efficacy of the components of HQD (baicalein, baicalin, and paeoniflorin) on CPT-11-induced diarrhea and their underlying mechanisms. Baicalein was found to be the most effective component in improving CPT-11-induced enterotoxicity by intestinal permeability test, ELISA, fluorescence co-localization, and IHC. The combination of baicalin, baicalin and paeoniflorin can obtain similar therapeutic effect to that of HQD. Mendelian randomization analysis, 16 s rRNA sequencing, and fluorescence imaging revealed that baicalein and baicalin significantly inhibited β-glucuronidase (β-GUS) activity. Bacterial abundance analysis and scanning electron microscopy showed that baicalein inhibited the proliferation of Escherichia coli by destroying its cell wall. The molecular dynamics and site-directed mutagenesis results revealed the structural basis for the inhibition of β-GUS by baicalein and baicalin. The results above provide a new idea for the development of drug therapy for adjuvant chemotherapy and theoretical guidance for the optimization of molecular structure targeting β-GUS.Graphical

The Role of Microbiome and Probiotics in Chemo-Radiotherapy-Induced Diarrhea: A Narrative Review of the Current Evidence.

In this article, we review the most recent research on probiotics effects on diarrhea in both human and animal models of the condition along with the therapeutic potential of these compounds based on their findings. Nearly 50%-80% of cancer patients experience chemotherapy-induced diarrhea (CID), serious gastrointestinal toxicity of chemotherapeutic and radiation regimens that leads to prolonged hospitalizations, cardiovascular problems, electrolyte imbalances, disruptions in cancer treatment, poor cancer prognosis, and death. CID is typically categorized as osmotic diarrhea. The depletion of colonic crypts and villi by radiotherapy and chemotherapy agents interferes with the absorptive function of the intestine, thereby decreasing the absorption of chloride and releasing water into the intestinal lumen. Probiotic supplements have been found to be able to reverse the intestinal damage caused by chemo-radiation therapy by promoting the growth of crypt and villi and reducing inflammatory pathways. In addition, they support the modulation of immunological and angiogenesis responses in the gut as well as the metabolism of certain digestive enzymes by altering the gut microbiota. Beyond the benefits of probiotics, additional clinical research is required to clarify the most effective strain combinations and dosages for preventing chemotherapy and radiotherapy diarrhea.

Exploring the Effects and Potential Mechanisms of Hesperidin for the Treatment of CPT-11-Induced Diarrhea: Network Pharmacology, Molecular Docking, and Experimental Validation.

Chemotherapy-induced diarrhea (CID) is a potentially serious side effect that often occurs during anticancer therapy and is caused by the toxic effects of chemotherapeutic drugs on the gastrointestinal tract, resulting in increased frequency of bowel movements and fluid contents. Among these agents, irinotecan (CPT-11) is most commonly associated with CID. Hesperidin (HPD), a flavonoid glycoside found predominantly in citrus fruits, has anti-oxidation properties and anti-inflammation properties that may benefit CID management. Nevertheless, its potential mechanism is still uncertain. In this study, we firstly evaluated the pharmacodynamics of HPD for the treatment of CID in a mouse model, then used network pharmacology and molecular docking methods to excavate the mechanism of HPD in relieving CID, and finally further proved the predicted mechanism through molecular biology experiments. The results demonstrate that HPD significantly alleviated diarrhea, weight loss, colonic pathological damage, oxidative stress, and inflammation in CID mice. In addition, 74 potential targets for HPD intervention in CID were verified by network pharmacology, with the top 10 key targets being AKT1, CASP3, ALB, EGFR, HSP90AA1, MMP9, ESR1, ANXA5, PPARG, and IGF1. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the PI3K-Akt pathway, FoxO pathway, MAPK pathway, TNF pathway, and Ras pathway were most relevant to the HPD potential treatment of CID genes. The molecular docking results showed that HPD had good binding to seven apoptosis-related targets, including AKT1, ANXA5, CASP3, HSP90AA1, IGF1, MMP9, and PPARG. Moreover, we verified apoptosis by TdT-mediated dUTP nick-end labeling (TUNEL) staining and immunohistochemistry, and the hypothesis about the proteins above was further verified by Western blotting in vivo experiments. Overall, this study elucidates the potential and underlying mechanisms of HPD in alleviating CID.

Preventing chemotherapy-induced diarrhea and microbiota imbalances with prebiotics and probiotics in breast cancer treatment: A case report

Preventing chemotherapy-induced diarrhea and microbiota imbalances with prebiotics and probiotics in breast cancer treatment: A case report

Efficacy of Hangeshashinto in the Prevention of Chemotherapy-Induced Diarrhea: A Systematic Review and Meta-Analysis.

Hangeshashinto has attracted attention owing to its potential to prevent chemotherapy-induced diarrhea. However, studies on the efficacy of Hangeshashinto have had conflicting results. Evaluating the efficacy of Hangeshashinto may contribute to reducing the use and adverse events caused by drug therapy for chemotherapy-induced diarrhea. Medical Literature Analysis and Retrieval System Online (MEDLINE), PubMed, Ichushi, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov were searched to retrieve all the relevant studies. Randomized controlled trials (RCTs) comparing the administration of Hangeshashinto with that of other treatments in patients with cancer receiving chemotherapy were included. The primary outcome was severe (grade3-4) diarrhea assessed using the Common Terminology Criteria for Adverse Events. The secondary outcome was mild (grade0-2) diarrhea. Out of 324 records identified, three studies were selected for the meta-analysis. Irinotecan was used for chemotherapy in all these studies. Hangeshashinto did not reduce the incidence of severe diarrhea compared with other treatments (risk ratio (RR) 0.40, 95% confidence interval (CI) 0.11-1.41, P = 0.15; low-quality evidence). Moreover, Hangeshashinto did not reduce the incidence of mild diarrhea (RR 1.35, 95% CI 0.87-2.09, P = 0.18; low-quality evidence). However, in the subgroup analysis compared with no treatment, the Hangeshashinto group had a significantly lower incidence of severe diarrhea (RR 0.17, 95% CI 0.03-0.88, P = 0.03; low-quality evidence). At present, insufficient evidence exists to support the claim that Hangeshashinto prevents diarrhea caused by irinotecan-based chemotherapy.

Patient Recorded Outcomes from a Randomized, Controlled Phase 2 Trial of E-Selectin Inhibition with Uproleselan Vs Placebo to Reduce GI Toxicity during Melphalan-Conditioned Autologous Hematopoietic Cell Transplantation for Multiple Myeloma

Background: The use of high-dose melphalan conditioning followed by autologous hematopoietic cell transplant (AHCT) continues to be a key component in the treatment of patients with multiple myeloma (MM). However, high-dose melphalan is associated with a high rate of GI toxicity (>90%), which adversely impacts clinical outcomes and negatively influences patient quality of life (QoL). Indeed, it has been reported that AHCT leads to short-term deterioration of health-related QoL in patients with MM, and QoL typically improves by 2-3 months post-AHCT. Pre-clinical and clinical data suggest that E-selectin inhibition may play a role in reducing immune-mediated GI epithelial injury following cytotoxic chemotherapy. We hypothesized that uproleselan (upro), a synthetic, competitive E-selectin antagonist, may improve health-related QoL by reducing risk of chemotherapy-induced diarrhea in patients undergoing AHCT. Methods: We conducted a Phase 2, single-center, randomized, double-blind, placebo-controlled trial in patients with MM receiving high-dose melphalan (200 mg/m2) as conditioning for AHCT for MM. Patients were randomized 1:1 to receive prophylactic upro+standard of care (SoC) vs placebo+SoC. Uproleselan was given in 6 doses of 800 mg IV starting on day-3 through day 0. The primary endpoint was diarrhea severity as assessed by CTCAE v5.0 (secondary endpoint - Bristol Stool Scale). In addition, a key secondary endpoint was patient reported outcomes (PRO) of GI-related QoL using the National Cancer Institute (NCI) PRO-CTCAE Measurement System, a validated PRO tool developed to evaluate symptomatic toxicities in patients with cancer in clinical trials. Significance level of p<0.2 was pre-specified for all endpoints, per protocol. Patients were surveyed during the peri-transplant period at day-3 (baseline), day+8, and day+14 or day of discharge (DoD). Responses were graded on a scale of 1-5, with 1 indicating absence of symptoms or zero interference with daily activities and 5 indicating very severe symptoms or very significant interference with daily activities. GI-specific domains assessed included swallowing, mouth sores, appetite, nausea, vomiting, heartburn, bloating, abdominal pain, flatulence, and incontinence. Results: Fifty adult patients with MM were enrolled from 5/2021-10/2022. Baseline PRO symptoms were similar between the upro+SoC and placebo+SoC arms at baseline (day-3). By day+8 post-AHCT patients in the upro+SoC arm reported a significant improvement in severity of GI-related symptoms across 30% (6/20) of domains surveyed vs placebo+SoC (p=0.07-0.14). Furthermore, improvement in mouth sore-related symptoms continued to day+14 post-AHCT in the upro+SoC arm vs placebo+SoC (p=0.17). The remaining GI-related symptoms returned to baseline by D+14 or DoD (p>0.20). Also of note, a numerically lower mean diarrhea severity score and lower incidence of Grade 3 diarrhea (by CTCAE v5.0) was observed favoring upro+SOC which did not meet the pre-specified significance threshold (p=0.34, p=0.26, respectively). However, a significant reduction in severe diarrhea (by Bristol Stool Scale) was observed favoring upro+SoC (p=0.10) vs placebo+SoC, with improvement in the upro+SoC arm to mild diarrhea (p=0.02). Conclusions: Upro+SoC resulted in a clinically significant improvement in GI-toxicity related symptoms as assessed via PRO-CTCAE in patients with MM undergoing melphalan-conditioned AHCT, when compared to placebo+SoC. These improvements in patient reported outcomes are further supported by data from the primary and additional secondary endpoints of the study. Taken together, these results suggest prophylactic E-selectin inhibition may represent a promising strategy to mitigate chemotherapy-associated GI-toxicity. Further studies are needed to verify these findings and to further define the optimal dosing of upro in the peri-AHCT period.

Probiotics and Probiotic-like Agents against Chemotherapy-Induced Intestinal Mucositis: A Narrative Review.

Cancer chemotherapy has allowed many patients to survive, but not without risks derived from its adverse effects. Drugs, such as 5-fluorouracil, irinotecan, oxaliplatin, methotrexate, and others, as well as different drug combinations trigger intestinal mucositis that may cause or contribute to anorexia, pain, diarrhea, weight loss, systemic infections, and even death. Dysbiosis is a hallmark of chemotherapy-induced intestinal mucositis and diarrhea, and, therefore, strategies aimed at modulating intestinal microbiota may be useful to counteract and prevent those dreadful effects. This narrative review offers an overview of the studies performed to test the efficacy of probiotics and probiotic-like agents against chemotherapy-induced intestinal mucositis and its consequences. Microbiota modulation through the oral administration of different probiotics (mainly strains of Lactobacillus and Bifidobacterium), probiotic mixtures, synbiotics, postbiotics, and paraprobiotics has been tested in different animal models and in some clinical trials. Regulation of dysbiosis, modulation of epithelial barrier permeability, anti-inflammatory effects, modulation of host immune response, reduction of oxidative stress, or prevention of apoptosis are the main mechanisms involved in their beneficial effects. However, the findings are limited by the great heterogeneity of the preclinical studies and the relative lack of studies in immunocompromised animals, as well as the scarce availability of results from clinical trials. Despite this, the results accumulated so far are promising. Hopefully, with the aid of these agents, intestinal mucositis will be less impactful to the cancer patient in the near future.

Herbal Medicines as Adjuvants for the Treatment of Chemotherapy-Induced Diarrhea.

Chemotherapeutic drugs used in cancer treatment often result in gastrointestinal toxicity, notably diarrhea, impacting patients' quality of life. Complementary and Alternative Medicine (CAM) has garnered increasing interest as an alternative to conventional approaches as a potential solution for managing chemotherapyinduced diarrhea (CID). To summarize current research focusing on herbal medicines as adjuvant therapy to prevent or treat chemotherapy-induced diarrhea, including clinical assessments, mechanism of actions, active components, and potential pharmacokinetic interactions between herbal medicines and chemotherapeutic drugs. We performed the literature review from PubMed, CNKI, Google Scholar, Web of Science, and Scopus using "Chemotherapy", "Diarrhea," and "Complementary and Alternative Medicine" as the search keywords. Using herbal medicines as adjuvants provides an effective approach to treating or preventing CID with improved or unaffected antitumor activity of chemotherapeutic drugs. Among these herbal formulations, scutellaria, ginger, and ginseng are the most frequently used herbs in the prescriptions for CID. The main antidiarrheal components in herbs include wogonin, baicalin, chrysin, quercetin, gingerol, and ginsenosides. These herbs, formulations, and bioactive components relieved CID through different mechanisms, including directly decreasing local drug exposure, anti-inflammation, inhibiting epithelial apoptosis, or promoting epithelium stem cell regeneration. The application of herbal medicines as adjunctive therapies showed efficacy in preventing or treating CID in multiple clinical trials. However, more well-designed clinical studies are expected to validate the results further. Despite some clinical studies demonstrating that certain herbal medicines could potentially attenuate CID and improve efficacy, it remains necessary to evaluate herbal safety. The interactions between herbs and drugs are also potential concerns, but few clinical trials have focused on investigating this aspect. In clinical practise, herbal medications show potential as adjuvant treatments for gastrointestinal toxicities induced by chemotherapy, particularly diarrhoea. Further well-designed clinical studies are needed to validate their efficacy, ensure safety, and explore potential drug-herb interactions.

Equivalence of combined decoction and mixed single decoctions of Gegen Qinlian Decoction in alleviating chemotherapy-associated diarrhea

This study compared the chemical profiles, component content, dry paste yield, and pharmacological effects of samples obtained from the mixed single decoctions and the combined decoction of Gegen Qinlian Decoction(GQD), aiming to provide an experimental foundation for evaluating the equivalence of the two decocting methods and the suitability of TCM formula granules in clinical application. The same decoction process was used to prepare the combined decoction and mixed single decoctions of GQD. Ultra-performance liquid chromatography coupled with Q-Exactive Orbitrap mass spectrometry(UPLC-Q-Exactive Orbitrap MS) was employed to compare the chemical profiles between the two groups. High-performance liquid chromatography(HPLC) was used to compare the content of nine characteristic components between the two groups. Then, a delayed diarrhea mouse model induced by irinotecan was established to compare the pharmacological effects of the two groups on chemotherapy-induced diarrhea. The UPLC-Q-Exactive Orbitrap MS in ESI~+ and ESI~- modes identified 59 chemical components in the compound decoction and mixed single decoctions, which showed no obvious differences in component species. The content of baicalin and wogonoside was higher in the compound decoction, while that of puerarin, daidzein-8-C-apiosylglucoside, berberine, epiberberine, wogonin, glycyrrhizic acid, and daidzein was higher in the mixed single decoctions. Further statistical analysis revealed no significant difference in the content of the nine characteristic components between the compound decoction and the mixed single decoctions. The dry paste yield had no significant difference between the two groups. Compared with the model group, both compound decoction and mixed single decoctions alleviated the weight loss and reduced diarrhea index in mice. Both of them lowered the levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), cyclooxygenase-2(COX-2), intercellular adhesion molecule-1(ICAM-1), interleukin-10(IL-10), malondialdehyde(MDA), and nitric oxide(NO) in the colon tissue. Furthermore, they significantly increased the levels of glutathione peroxidase(GSH-Px) and superoxide dismutase(SOD). Hematoxylin-eosin(HE) staining showed that colon tissue cells were tightly arranged with clear nuclei in both groups without obvious difference. The compound decoction and mixed single decoctions showed no significant differences in chemical component species, content of nine characteristic components, dry paste yield, or the pharmacological effects on alleviating chemotherapy-induced diarrhea. The findings provide a reference for evaluating the flexibility and superiority of combined or single decocting method in the preparation of TCM decoctions or formula granules.

Relationship between Chemotherapy-Induced Diarrhea and Intestinal Microbiome Composition

Background and Aim: Fluoropyrimidines (FPs) are key drugs in many chemotherapy regimens; however, recipients are often prone to diarrhea due to gastrointestinal toxicity. Disruption of the intestinal epithelial barrier function by FPs leads to dysbiosis, which may exacerbate intestinal epithelial cell damage as a secondary effect and trigger diarrhea. However, despite studies on chemotherapy-induced changes in the intestinal microbiome of humans, the relationship between dysbiosis and diarrhea is unclear. In this study, we aimed to investigate the relationship between chemotherapy-induced diarrhea and the intestinal microbiome. Methods: We conducted a single-center prospective observational study. Twenty-three patients who received chemotherapy, including FPs as first-line chemotherapy for colorectal cancer, were included. Stool samples were collected before the start of chemotherapy and after one cycle of treatment to analyze intestinal microbiome composition and perform PICRUSt predictive metagenomic analysis. Results: Gastrointestinal toxicity was observed in 7 of 23 patients (30.4%), diarrhea was observed in 4 (17.4%), and nausea and anorexia were observed in 3 (13.0%). In 19 patients treated with oral FPs, the α diversity of the microbial community decreased significantly following chemotherapy only in the diarrheal group. At the phylum level, the diarrheal group showed a significant decrease in the abundance of Firmicutes and a significant increase in the abundance of Bacteroidetes with chemotherapy (p = 0.013 and 0.011, respectively). In the same groups, at the genus level, Bifidobacterium abundance was significantly decreased (p = 0.019). In contrast, in the non-diarrheal group, Actinobacteria abundance increased significantly with chemotherapy at the phylum level (p = 0.011). Further, Bifidobacterium, Fusicatenibacter, and Dorea abundance significantly increased at the genus level (p = 0.006, 0.019, and 0.011, respectively). The PICRUSt predictive metagenomic analysis revealed that chemotherapy caused significant differences in membrane transport in KEGG pathway level 2 and in 8 KEGG pathway level 3, including transporters and oxidative phosphorylation in the diarrhea group. Conclusion: Organic-acid-producing bacteria seem to be involved in diarrhea associated with chemotherapy, including FPs.

(-)-Epigallocatechin-3-Gallate Attenuates the Adverse Reactions Triggered by Selenium Nanoparticles without Compromising Their Suppressing Effect on Peritoneal Carcinomatosis in Mice Bearing Hepatocarcinoma 22 Cells.

Increasing evidence shows that selenium and polyphenols are two types of the most reported compounds in tumor chemoprevention due to their remarkable antitumor activity and high safety profile. The cross-talk between polyphenols and selenium is a hot research topic, and the combination of polyphenols and selenium is a valuable strategy for fighting cancer. The current work investigated the combination anti-peritoneal carcinomatosis (PC) effect of selenium nanoparticles (SeNPs) and green tea (Camellia sinensis) polyphenol (-)-epigallocatechin-3-gallate (EGCG) in mice bearing murine hepatocarcinoma 22 (H22) cells. Results showed that SeNPs alone significantly inhibited cancer cell proliferation and extended the survival time of mice bearing H22 cells. Still, the potential therapeutic efficacy is accompanied by an approximately eighty percent diarrhea rate. When EGCG was combined with SeNPs, EGCG did not affect the tumor proliferation inhibition effect but eliminated diarrhea triggered by SeNPs. In addition, both the intracellular selectively accumulated EGCG without killing effect on cancer cells and the enhanced antioxidant enzyme levels in ascites after EGCG was delivered alone by intraperitoneal injection indicated that H22 cells were insensitive to EGCG. Moreover, EGCG could prevent SeNP-caused systemic oxidative damage by enhancing serum superoxide dismutase, glutathione, and glutathione peroxidase levels in healthy mice. Overall, we found that H22 cells are insensitive to EGCG, but combining EGCG with SeNPs could protect against SeNP-triggered diarrhea without compromising the suppressing efficacy of SeNPs on PC in mice bearing H22 cells and attenuate SeNP-caused systemic toxicity in healthy mice. These results suggest that EGCG could be employed as a promising candidate for preventing the adverse reactions of chemotherapy including chemotherapy-induced diarrhea and systemic toxicity in cancer individuals.

Gegen Qinlian standard decoction alleviated irinotecan-induced diarrhea via PI3K/AKT/NF-κB axis by network pharmacology prediction and experimental validation combination

BackgroundThe frequently occurred chemotherapy-induced diarrhea (CID) caused by irinotecan (CPT-11) administration has been the most representative side-effects of CPT-11, resulting in the chemotherapy suspension or failure. Our previous studies indicated that Gegen Qinlian formula exhibited a significant alleviation effect on CPT-11-induced diarrhea. However, referencing to Japanese Kampo medicine, the TCM standard decoction would supply the gap between ancient preparation application and modern industrial production.MethodsThe LC–MS technology combined with network pharmacology was employed to identify the active ingredients and mechanisms of GQD standard decoction for CPT-11-induced diarrhea. The anti-inflammatory activities associated with intestinal barrier function of GQD standard decoction were studied by SN-38 activated NCM460 cells in vitro and CPT-11-induced diarrhea in vivo. Proteins involved in inflammation, mRNA levels, disease severity scores, and histology involved in intestinal inflammation were analysed.ResultsThere were 37 active compounds were identified in GQD standard decoction. Network pharmacology analyses indicated that PI3K-AKT signaling pathway were probably the main pathway of GQD standard decoction in CPT-11-induced diarrhea treatment, and PIK3R1, AKT1, NF-κB1 were the core proteins. Moreover, we found that the key proteins and pathway predicted above was verified in vivo and in vitro experiments, and the GQD standard decoction could protect the cellular proliferation in vitro and ameliorate CPT-11-induced diarrhea in mice model.ConclusionsThis study demonstrated the molecular mechanism of 37 active ingredients in GQD standard decoction against CPT-11-induced diarrhea. And the core proteins and pathway were validated by experiment. This data establishes the groundwork for particular molecular mechanism of GQD standard decoction active components, and this research can provide a scientific reference for the TCM therapy of CID.

CDK4/6 inhibitor modulating active and quiescent intestinal stem cells for prevention of chemotherapy-induced diarrhea.

Chemotherapy-induced diarrhea causes dehydration, debilitation, infection, and even death, but there are currently no Food and Drug Administration (FDA)-approved drugs for treatment of chemotherapy-induced diarrhea. It is generally believed that the timely regulation of intestinal stem cell (ISC) fate may provide a meaningful solution for intestinal injuries. However, the lineage plasticity of ISCs during and after chemotherapy remains poorly understood. Here, we demonstrated that palbociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, regulated the fate of active or quiescent ISCs, provided multilineage protection from the toxicity of several different chemotherapeutics, and accelerated gastrointestinal epithelium recovery. Consistent with in vivo results, we determined that palbociclib enhanced intestinal organoid and ex vivo tissue survival after chemotherapy. Lineage tracing studies have shown that palbociclib protects active ISCs marked by Lgr5 and Olfm4 during chemotherapy and unexpectedly activates quiescent ISCs marked by Bmi1 to immediately participate in crypt regeneration after chemotherapy. Furthermore, palbociclib does not decrease the efficacy of cytotoxic chemotherapy in tumor grafts. The experimental evidence suggests that the combination of CDK4/6 inhibitors with chemotherapy could reduce damage to the gastrointestinal epithelium in patients. © 2023 The Pathological Society of Great Britain and Ireland.

Anakinra and dexamethasone treatment of idarubicin-induced mucositis and diarrhoea in rats.

Chemotherapy-induced mucositis, characterised by diarrhoea and villous atrophy, is a severe side effect contributing to reduced quality of life and premature death in cancer patients treated with cytostatics. Despite its high incidence, there is no effective supportive therapy available. The main objective of this study was to determine if the anti-inflammatory drugs anakinra and/or dexamethasone - which have different mechanism-of-action - might be used to effectively treat idarubicin-induced mucositis in rats. Mucositis was induced through a single injection with 2 mg/kg idarubicin (with saline as control), followed by daily treatments of anakinra (100 mg/kg/day), dexamethasone (10 mg/kg/day), or both during three days. After 72 hours, jejunal tissue was collected for morphological, apoptotic, and proliferative analyses, and colonic faecal water content and body weight change were determined. The diarrhoea that was induced by idarubicin (from 63.5% to 78.6% water content in faeces) was completely reversed by anakinra alone, and the jejunal villus height reduction by 36% was prevented by a combination of anakinra and dexamethasone. Dexamethasone reduced apoptosis in the jejunal crypts, both alone and in combination with anakinra. These positive effects encourage further investigations into the use of anakinra and dexamethasone as supportive therapies for chemotherapy-induced intestinal mucositis and diarrhoea.

Opioid-induced microbial dysbiosis disrupts irinotecan (CPT-11) metabolism and increases gastrointestinal toxicity in a murine model.

Opioids are commonly used for the management of cancer-associated pain and chemotherapy-induced diarrhoea. The chemotherapeutic irinotecan (CPT-11) causes severe gastrointestinal (GI) toxicity due to deconjugation of inactive metabolite SN-38 glucuronide (SN-38G) by bacterial β-glucuronidases to the active 7-ethyl-10-hydroxycamptothecin (SN-38). Opioids are known to cause gut microbial dysbiosis, this study evaluated whether CPT-11 anti-tumour efficacy and GI toxicity are exacerbated by opioid co-administration. Eight-week-old C57BL/6 male mice were co-administration with CPT-11 ± opioid. 16S rRNA sequencing was used for gut microbiome analysis. LC-MS analyses of plasma and intestinal extracts were performed to investigate the pharmacokinetic profile of CPT-11. Histological analysis and quantitative real-time polymerase chain reaction were used to determine the severity of intestinal tissue damage. Human liver microsome In vitro assay was performed to confirm the effects of opioids on CPT-11 metabolism. Gut microbiome analysis showed that morphine treatment induced enrichment of β-glucuronidase-producing bacteria in the intestines of CPT-11-treated mice, resulting in SN-38 accumulation and exacerbation of GI toxicity in the small intestine. Oral administration of both antibiotics and glucuronidase inhibitor protected mice against GI toxicity induced with CPT-11 and morphine co-administration, implicating a microbiome-dependent mechanism. Additionally, morphine and loperamide decreased the plasma concentration of SN-38 and compromised CPT-11 anti-tumour efficacy, this seemed to be microbiome independent. Gut microbiota play a significant role in opioid and chemotherapeutic agent drug-drug interactions. Inhibition of gut microbial glucuronidase may also prevent adverse GI effects of CPT-11 in patients on opioids.

HALT-D: a randomized open-label phase II study of crofelemer for the prevention of chemotherapy-induced diarrhea in patients with HER2-positive breast cancer receiving trastuzumab, pertuzumab, and a taxane

PurposeTo assess whether crofelemer would prevent chemotherapy-induced diarrhea (CID) diarrhea in patients with HER2-positive, any-stage breast cancer receiving trastuzumab (H), pertuzumab (P), and a taxane (T; docetaxel or paclitaxel), with/without carboplatin (C; always combined with docetaxel rather than paclitaxel).MethodsPatients scheduled to receive ≥ 3 consecutive TCHP/THP cycles were randomized to crofelemer 125 mg orally twice daily during chemotherapy cycles 1 and 2 or no scheduled prophylactic medication (control). All received standard breakthrough antidiarrheal medication (BTAD) as needed. The primary endpoint was incidence of any-grade CID for ≥ 2 consecutive days. Secondary endpoints were incidence of all-grade and grade 3/4 CID by cycle/stratum; time to onset and duration of CID; stool consistency; use of BTAD; and quality of life (Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea [FACIT-D] score).ResultsFifty-one patients were randomized to crofelemer (n = 26) or control (n = 25). There was no statistically significant difference between arms for the primary endpoint; however, incidence of grade ≥ 2 CID was reduced with crofelemer vs control (19.2% vs 24.0% in cycle 1; 8.0% vs 39.1%, in cycle 2). Patients receiving crofelemer were 1.8 times more likely to see their diarrhea resolved and had less frequent watery diarrhea.ConclusionDespite the choice of primary endpoint being insensitive, crofelemer reduced the incidence and severity of CID in patients with HER2-positive breast cancer receiving P-based therapy. These data are supportive of further testing of crofelemer in CID.Trial registrationClinicaltrials.gov, NCT02910219, prospectively registered September 21, 2016.

217 (PB097) - A preclinical toxicology and pharmacology study of OQL051, a gut-restricted CDK4/6 inhibitor for the prophylaxis of chemotherapy-induced diarrhea

Background: Chemotherapy-induced diarrhea (CID) from fluorouracil (5FU) and irinotecan (IRI, rate 50–80%) leads to therapy interruption/discontinuation and disruption of the intestinal microbiome. Cyclin-dependent kinase 4/ 6 inhibitors (CDK4/6i) induce a “pharmacological quiescence” with transient dosing. OQL051, a gut-restricted CDK4/6i, decreases chemotherapy-induced histological damage to the intestinal wall and reduces CID. We studied OQL051’s toxicology, maintenance of the microbiome, and the impact on tumor growth. Methods: Rats, 20 female, 20 male, 6–7 weeks of age were studied for 8 days. OQL051 was orally administered once daily (100, 250, or 500 mg/kg) for 7 days. Mortality, clinical observations, body weight, and food consumption were recorded daily during treatment. Hematology, coagulation, serum chemistry, gross pathology, and histopathological examination (14 tissue/organ panel including stomach, duodenum, jejunum, and colon) was conducted at D8. Blood was collected from 3 to 5 animals on D1 and D7 at predose, 0.25, 1, 2, 4, 8, and 24 h post-dose to determine the concentration of OQL051. BALB/c mice were subcutaneously injected with 106 CT-26 cells (undifferentiated colon carcinoma cell line), given oral OQL051 (25 mg/kg) or control (CON) at a tumor vol. of 30∼50 mm3, then 6 h later, injected with irinotecan (IRI, 70 mg/kg)/IRI-CON. At a tumor vol. 200∼400 mm3 mice were injected with anti-PD-1 mAb (200 μg)/mAb-CON. Tumor vol. was determined routinely with calipers. The GI tract was sampled for microbiome analysis. Microbiome DNA library (NEBNext® Ultra™ II DNA Kit) was used for sequencing on an Illumina NovaSeq platform. Results: No drug-related mortality or adverse events (AEs) were observed across all dose levels. One female rat had an intussusception event at 250 mg/kg; however, no histopathological abnormality was observed. Compared to vehicle control OQL051 at all doses studied showed no effect on body weight, food intake, hematology, coagulation, serum chemistry, gross pathology, or histopathological examination. In particular, OQL051 being concentrated in the gut showed no histopathological changes in the stomach, duodenum, jejunum, or colon. Microbiome diversity was maintained in OQL051- vs. CON-treated mice, and tumor volume was less in OQL051+IRI+anti-PD-1 vs. CON+IRI+anti-PD-1 (p = 0.035 @ 28 days). Conclusion: OQL051 safety was confirmed as there were no drug-related AEs observed for OQL051 repeat doses up to 500 mg/kg/day for 7 days. CDK 4/6 inhibitor common AEs (neutropenia, leukopenia, thrombocytopenia, anemia, diarrhea, nausea, ALT) were absent indicating a low systemic exposure. The previously observed decrease in intestinal wall damage and CID from chemotherapy led to the maintenance of the gut microbiome and potentially enhanced the efficacy of chemotherapy plus immunotherapy antitumor efficacy at reducing tumor volume. Conflict of interest: Ownership: Shiyi Zhang, Founder, CEO Jie Lou, Co-founder, CSO Hong Tang, Co-founder, CMO Other Substantive Relationships: Wenqin Zeng, employee; Wenxi Li, employee; Shilan Liu, employee; Liping Chen, employee; Robert Tyler, employee.

Evaluation and validation of chemotherapy-specific diarrhoea and histopathology in rats.

Chemotherapy-induced mucositis is characterized by diarrhoea and villous atrophy. However, it is not well-understood why diarrhoea arises, why it only occurs with some chemotherapeutics and how it is related to villus atrophy. The objectives in this study were to determine (i) the relationship between chemotherapy-induced diarrhoea and villus atrophy and to (ii) establish and validate a rat diarrhoea model with clinically relevant endpoints. Male Wistar Han IGS rats were treated with saline, doxorubicin, idarubicin, methotrexate, 5-fluorouracil, irinotecan or 5-fluorouracil+irinotecan. After 72 h, jejunal tissue was taken for morphological, apoptotic and proliferative analyses, and faecal water content and change in body weight were determined. All treatments except methotrexate caused a similar reduction (≈42%) in villus height, but none of them altered mucosal crypt cell proliferation or apoptosis. Doxorubicin, idarubicin, irinotecan and 5-fluorouracil+irinotecan caused body weight reduction, but only irinotecan and idarubicin caused diarrhoea. No direct correlation between diarrhoea and villus height or body weight loss was observed. Therefore, studies of the mechanisms for chemotherapy-induced diarrhoea should focus on functional factors. Finally, the irinotecan and idarubicin diarrhoea models established in this study will be useful in developing supportive treatments of this common and serious adverse effect in patients undergoing chemotherapy.