Chemotherapy-induced Mucositis Research Articles

Melatonin mitigates chemotherapy-induced small intestinal atrophy in rats and reduces cytotoxicity in murine intestinal organoids.

Cancer continues to pose a significant global health challenge, with gastrointestinal (GI) cancers among the most prevalent and deadly forms. These cancers often lead to high mortality rates and demand the use of potent cytotoxic chemotherapeutics. For example, 5-fluorouracil (5-FU) forms the backbone of chemotherapy regimens for various GI cancers, including colorectal cancer. While these chemotherapeutics efficiently kill cancer cells, they frequently cause off-target effects such as chemotherapy-induced mucositis (CIM), characterized by debilitating symptoms like pain, nausea, and diarrhoea, necessitating medical intervention. In this study, we elucidated the potential of melatonin and misoprostol to reduce 5-FU-induced small intestinal mucositis. Morphological and cellular changes in the jejunum, along with colonic faecal water content were quantified in rats as markers for CIM. Additionally, the effects of melatonin were investigated in vitro on 5-FU treated murine intestinal organoids. The results showed that melatonin prevented villus atrophy in the rat jejunal mucosa and upheld cell viability in murine intestinal organoids. In contrast, misoprostol alone or in combination with melatonin did not significantly affect CIM caused by 5-FU. These in vivo and in vitro experiments provided promising insights that melatonin may be used as a preventive and/or adjuvant combination therapy to prevent and reduce CIM, holding the potential to enhance cancer treatment outcomes and improve patient quality-of-life.

RIP3 regulates doxorubicin-induced intestinal mucositis via FUT2-mediated α-1,2-fucosylation.

Intestinal mucositis is one of the common side effects of anti-cancer chemotherapy. However, the molecular mechanisms involved in mucositis development remain incompletely understood. In this study, we investigated the function of receptor-interacting protein kinase 3 (RIP3/RIPK3) in regulating doxorubicin-induced intestinal mucositis and its potential mechanisms. Intestinal mucositis animal models were induced in mice for in vivo studies. Rat intestinal cell line IEC-6 was used for in vitro studies. RNA‑seq was used to explore the transcriptomic changes in doxorubicin-induced intestinal mucositis. Intact glycopeptide characterization using mass spectrometry was applied to identify α-1,2-fucosylated proteins associated with mucositis. Doxorubicin treatment increased RIP3 expression in the intestine and caused severe intestinal mucositis in the mice, depletion of RIP3 abolished doxorubicin-induced intestinal mucositis. RIP3-mediated doxorubicin-induced mucositis did not depend on mixed lineage kinase domain-like (MLKL) but on α-1,2-fucosyltransferase 2 (FUT2)-catalyzed α-1,2-fucosylation on inflammation-related proteins. Deficiency of MLKL did not affect intestinal mucositis, whereas inhibition of α-1,2-fucosylation by 2-deoxy-D-galactose (2dGal) profoundly attenuated doxorubicin-induced inflammation and mucositis. RIP3-FUT2 pathway is a central node in doxorubicin-induced intestinal mucositis. Targeting intestinal RIP3 and/or FUT2-mediated α-1,2-fucosylation may provide potential targets for preventing chemotherapy-induced intestinal mucositis.

Alginate oligosaccharide improves 5-fluorouracil-induced intestinal mucositis by enhancing intestinal barrier and modulating intestinal levels of butyrate and isovalerate

Chemotherapy-induced mucositis (CIM) is the typical side effect of chemotherapy. This study investigates the potential of alginate oligosaccharide (AOS) in ameliorating CIM induced by 5-fluorouracil (5-FU) in a murine model and its underlying mechanisms. AOS effectively mitigated body weight loss and histopathological damage, modulated inflammatory cytokines and attenuated the oxidative stress. AOS restored intestinal barrier integrity through enhancing expression of tight junction proteins via MLCK signaling pathway. AOS alleviated intestinal mucosal damage by inhibiting TLR4/MyD88/NF-κB signaling pathway, downregulating the pro-apoptotic protein Bax and upregulating the anti-apoptotic protein Bcl-2. Moreover, AOS significantly enriched intestinal Akkermansiaceae and increased the production of short-chain fatty acids (SCFAs), most notably butyrate and isovalerate. Pre-treatment with butyrate and isovalerate also alleviated 5-FU-induced CIM. In conclusion, AOS effectively mitigated CIM through strenghthening intestinal barrier, attenuating inflammation, and modulating gut microbiota and intestianl levels of butyrate and isovalerate. These finding indicate that AOS could be potentially utilized as a supplemental strategy for prevention or mitigation of CIM.

The Effect of Oral Care Intervention in Mucositis Management Among Pediatric Cancer Patients: An Updated Systematic Review.

Chemotherapy-induced mucositis is inflammation that develops in the oral mucosal due to anticancer treatment. Mucositis has negative consequences that may lead to distress in pediatric patients, resulting in escalated expenses, diminished quality of life, hindrance in cancer therapy, and decreased survival rates. However, despite the numerous methods, oral care protocols are suggested for implementation in the pediatric population despite a lack of high-level evidence studies, particularly regarding which appropriate oral care agents should be administered. This systematic review aimed to identify the effect of oral care intervention in mucositis management among pediatric cancer patients. Studies were published between 2014 and 2023 from five databases: PubMed, Embase, Medline, ScienceDirect, and Scopus. They were identified using a search strategy to identify relevant studies that identify oral care interventions for managing mucositis in children with cancer. This study used the Joanna Briggs Institute (JBI) critical appraisal tools to assess the quality of the studies and followed the recommended reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Eight studies met the inclusion criteria, including seven RCTs and one quasi-experimental study. Oral care interventions involving tooth brushing, mouthwash, and lip care are performed entirely or partially. The frequency of oral care ranges from two to six times daily, and the duration of intervention is from 5 days to six weeks. Oral care interventions using honey, olive oil, Aloe Vera, Andiroba, and salivary enzyme toothpaste are beneficial to lower the severity of mucositis, reduce pain, minimize mucositis duration, and reduce the use of analgesics, but not significantly improve the child's quality of life. However, Caphosol mouthwash did not significantly reduce mucositis. Our study highlights that oral care intervention using effective agents integratively, including honey, olive oil, Aloe vera, Andiroba, and salivary enzyme toothpaste, is essential to manage chemotherapy-induced mucositis among children. PROSPERO registration number was CRD42023456278.

Pasteurized Akkermansia muciniphila mitigates 5-FU-induced intestinal mucositis in tumor-bearing mice through suppression of the cGAS-STING pathway and epithelial cell apoptosis

The aim of this study was to examine whether pasteurized Akkermansia muciniphila (pAkk) could protect mice from chemotherapy-induced mucositis (CIM) in tumor-bearing mice. Mice were pretreated with pAkk and then treated with 5-fluorouracil (5-FU). pAkk mitigates symptoms of 5-FU-induced CIM, including slowing the rate of weight loss (14.2%) and increasing the villus height to crypt depth ratio (1.54%) in the ileum, while not impacting the antitumor efficacy of 5-FU. Furthermore, pAkk diminished the levels of proteins associated with apoptosis, including Bax, caspase-3, and Bcl-2, both in vivo and in vitro, and decreased the number of TUNEL-positive cells. pAkk further alleviated the disruption of cell barrier function and inflammation induced by 5-FU in a Caco-2/RAW264.7 co-culture model. Further exploration revealed that the cGAS-STING signaling pathway plays a crucial role in improving CIM by pAkk, with the expression of its related proteins being reversed upon pAkk treatment. The protective effect of pAkk was partially nullified after using a STING activator, further confirming that pAkk exerts its function at least partly through cGAS-STING signaling pathway. These findings provide support for developing Akkermansia muciniphila-based strategies to mitigate chemotherapy-related intestinal toxicity for patients with cancer.

Endoplasmic reticulum stress in the pathogenesis of chemotherapy-induced mucositis: Physiological mechanisms and therapeutic implications.

Chemotherapy is a common and effective treatment for cancer, but these drugs are also associated with significant side effects affecting patients' well-being. One such debilitating side effect is mucositis, characterized by inflammation, ulcerations, and altered physiological functions of the gastrointestinal (GI) tract's mucosal lining. Understanding the mechanisms of chemotherapy-induced intestinal mucositis (CIM) is crucial for developing effective preventive measures and supportive care. Chemotherapeutics not only target cancer cells but also rapidly dividing cells in the GI tract. These drugs disrupt endoplasmic reticulum (ER) homeostasis, leading to ER-stress and activation of the unfolded protein response (UPR) in various intestinal epithelial cell types. The UPR triggers signaling pathways that exacerbate tissue inflammation and damage, influence the differentiation and fate of intestinal epithelial cells, and compromise the integrity of the intestinal mucosal barrier. These factors contribute significantly to mucositis development and progression. In this review, we aim to give an in-depth overview of the role of ER-stress in mucositis and its impact on GI function. This will provide valuable insights into the underlying mechanisms and highlighting potential therapeutic interventions that could improve treatment-outcomes and the quality of life of cancer patients.

Atorvastatin attenuates intestinal mucositis induced by 5-fluorouracil in mice by modulating the epithelial barrier and inflammatory response

Chemotherapy-induced intestinal mucositis is a major side effect of cancer treatment. Statins are 3-hydroxy-3-methyl glutaryl coenzyme reductase inhibitors used to treat hypercholesterolemia and atherosclerotic diseases. Recent studies have demonstrated that atorvastatin (ATV) has antioxidant, anti-inflammatory, and resulting from the regulation of different molecular pathways. In the present study, we investigated the effects of ATV on intestinal homeostasis in 5-fluorouracil (5-FU)-induced mucositis. Our results showed that ATV protected the intestinal mucosa from epithelial damage caused by 5-FU mainly due to inflammatory infiltrate and intestinal permeability reduction, downregulation of inflammatory markers, such as Tlr4, MyD88, NF-κB, Tnf-a, Il1β, and Il6 dose-dependent. ATV also improved epithelial barrier function by upregulating the mRNA transcript levels of mucin 2 (MUC2), and ZO-1 and occludin tight junction proteins. The results suggest that the ATV anti-inflammatory and protective effects on 5-FU-induced mice mucositis involve the inhibition of the TLR4/MYD88/NPRL3/NF-κB, iNos, and caspase 3.

Unlocking the Potential of Probiotics: A Comprehensive Review on Research, Production, and Regulation of Probiotics.

This review provides a comprehensive overview of the current state of probiotic research, covering a wide range of topics, including strain identification, functional characterization, preclinical and clinical evaluations, mechanisms of action, therapeutic applications, manufacturing considerations, and future directions. The screening process for potential probiotics involves phenotypic and genomic analysis to identify strains with health-promoting properties while excluding those with any factor that could be harmful to the host. In vitro assays for evaluating probiotic traits such as acid tolerance, bile metabolism, adhesion properties, and antimicrobial effects are described. The review highlights promising findings from in vivo studies on probiotic mitigation of inflammatory bowel diseases, chemotherapy-induced mucositis, dysbiosis, obesity, diabetes, and bone health, primarily through immunomodulation and modulation of the local microbiota in human and animal models. Clinical studies demonstrating beneficial modulation of metabolic diseases and human central nervous system function are also presented. Manufacturing processes significantly impact the growth, viability, and properties of probiotics, and the composition of the product matrix and supplementation with prebiotics or other strains can modify their effects. The lack of regulatory oversight raises concerns about the quality, safety, and labeling accuracy of commercial probiotics, particularly for vulnerable populations. Advancements in multi-omics approaches, especially probiogenomics, will provide a deeper understanding of the mechanisms behind probiotic functionality, allowing for personalized and targeted probiotic therapies. However, it is crucial to simultaneously focus on improving manufacturing practices, implementing quality control standards, and establishing regulatory oversight to ensure the safety and efficacy of probiotic products in the face of increasing therapeutic applications.

Abstract 4192: In-depth evaluation of chemotherapy-induced mucositis in intestinal organoids using holotomography

Abstract Intestinal mucositis is a prevalent adverse event associated with antineoplastic therapies, such as chemotherapy, which still lacks a targeted and effective treatment regimen. The difficulty in preclinical prediction and prevention of drug-induced intestinal mucositis is attributed to the intricate underlying mechanisms of its onset and the broad spectrum of patient-specific responses to chemotherapeutic agents. Advancements in regenerative medicine have enabled the generation of intestinal organoids from adult stem cells, serving as a personalized model to emulate disease pathology and simulate individual drug responses. Various imaging techniques are employed to evaluate the responses of the organoids to pharmacological agents, but the inherent complexity of their three-dimensional (3D) architecture poses significant challenges in organoid imaging. These challenges are exacerbated by the standard preparation processes for imaging, including fixation and staining, which do not allow for the observation of dynamic, real-time effects of drugs on living organoids. In this study, we focused on meticulously examining the histopathological alterations in small intestinal organoids subjected to chemotherapeutic agents that induce mucositis, specifically 5-fluorouracil and irinotecan. Employing holotomography, a label-free real-time 3D imaging technology, we were able to visualize the destructive processes affecting the intestinal organoids, including the breakdown of the epithelial lining, the exfoliation of dead cells, and the alteration of the villus/crypt structure. Furthermore, we propose a novel methodology for quantifying the viability of intestinal organoids. This quantification is essential for assessing the extent of damage caused by the chemotherapeutic agents and for determining the maximum drug concentrations that can be deemed safe for use, thereby minimizing the risk of inducing mucositis while maintaining therapeutic efficacy. These results provide new insights into the toxic mechanisms of chemotherapeutic drugs and highlight the importance of using organoid models in drug safety evaluation throughout the development phase. Citation Format: Mahn Jae Lee, Jaehyeok Lee, Weisun Park, Geon Kim, Hye-Jin Kim, YongKeun Park. In-depth evaluation of chemotherapy-induced mucositis in intestinal organoids using holotomography [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4192.

Eubacterium coprostanoligenes alleviates chemotherapy-induced intestinal mucositis by enhancing intestinal mucus barrier

Chemotherapy-induced mucositis represents a severe adverse outcome of cancer treatment, significantly curtailing the efficacy of these treatments and, in some cases, resulting in fatal consequences. Despite identifying intestinal epithelial cell damage as a key factor in chemotherapy-induced mucositis, the paucity of effective treatments for such damage is evident. In our study, we discovered that Eubacterium coprostanoligenes promotes mucin secretion by goblet cells, thereby fortifying the integrity of the intestinal mucus barrier. This enhanced barrier function serves to resist microbial invasion and subsequently reduces the inflammatory response. Importantly, this effect remains unobtrusive to the anti-tumor efficacy of chemotherapy drugs. Mechanistically, E. copr up-regulates the expression of AUF1, leading to the stabilization of Muc2 mRNA and an increase in mucin synthesis in goblet cells. An especially significant finding is that E. copr activates the AhR pathway, thereby promoting the expression of AUF1. In summary, our results strongly indicate that E. copr enhances the intestinal mucus barrier, effectively alleviating chemotherapy-induced intestinal mucositis by activating the AhR/AUF1 pathway, consequently enhancing Muc2 mRNA stability.

Markers of intestinal mucositis to predict blood stream infections at the onset of fever during treatment for childhood acute leukemia.

Despite chemotherapy-induced intestinal mucositis being a main risk factor for blood stream infections (BSIs), no studies have investigated mucositis severity to predict BSI at fever onset during acute leukemia treatment. This study prospectively evaluated intestinal mucositis severity in 85 children with acute leukemia, representing 242 febrile episodes (122 with concurrent neutropenia) by measuring plasma levels of citrulline (reflecting enterocyte loss), regenerating islet-derived-protein 3α (REG3α, an intestinal antimicrobial peptide) and CCL20 (a mucosal immune regulatory chemokine) along with the general neutrophil chemo-attractants CXCL1 and CXCL8 at fever onset. BSI was documented in 14% of all febrile episodes and in 20% of the neutropenic febrile episodes. In age-, sex-, diagnosis- and neutrophil count-adjusted analyses, decreasing citrulline levels and increasing REG3α and CCL20 levels were independently associated with increased odds of BSI (OR = 1.6, 1.5 and 1.7 per halving/doubling, all p < 0.05). Additionally, higher CXCL1 and CXCL8 levels increased the odds of BSI (OR = 1.8 and 1.7 per doubling, all p < 0.0001). All three chemokines showed improved diagnostic accuracy compared to C-reactive protein and procalcitonin. These findings underline the importance of disrupted intestinal integrity as a main risk factor for BSI and suggest that objective markers for monitoring mucositis severity may help predicting BSI at fever onset.

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.

Study of prevalence and risk factors of chemotherapy-induced mucositis in gastrointestinal cancer using machine learning models.

Chemotherapy-induced mucositis (CIM) significantly impacts clinical outcomes and diminishes the quality of life in patients with gastrointestinal cancer. This study aims to prospectively determine the incidence, severity, and underlying risk factors associated with CIM in this patient population. To achieve this objective, we introduce a novel Machine Learning-based Toxicity Prediction Model (ML-TPM) designed to analyze the risk factors contributing to CIM development in gastrointestinal cancer patients. Within the winter season spanning from December 15th, 2018 to January 14th, 2019, we conducted in-person interviews with patients undergoing chemotherapy for gastrointestinal cancer. These interviews encompassed comprehensive questionnaires pertaining to patient demographics, CIM incidence, severity, and any supplementary prophylactic measures employed. The study encompassed a cohort of 447 participating patients who provided complete questionnaire responses (100%). Of these, 328 patients (73.4%) reported experiencing CIM during the course of their treatment. Notably, CIM-induced complications led to treatment discontinuation in 14 patients (3%). The most frequently encountered CIM symptoms were diarrhea (41.6%), followed by nausea (37.8%), vomiting (25.1%), abdominal pain (21%), gastritis (10.5%), and oral pain (10.3%). Supplementary prophylaxis was administered to approximately 62% of the patients. The analysis revealed significant correlations between the overall incidence of CIM and gender (p=0.015), number of chemotherapy cycles exceeding one (p=0.039), utilization of platinum-based regimens (p=0.039), and administration of irinotecan (p=0.003). Specifically, the incidence of diarrhea exhibited positive correlations with prior surgical history (p=0.037), irinotecan treatment (p=0.021), and probiotics usage (p=0.035). Conversely, diarrhea incidence demonstrated an adverse correlation with platinum-based treatment (p=0.026). In conclusion, this study demonstrates the successful implementation of the ML-TPM model for automating toxicity prediction with accuracy comparable to conventional physical analyses. Our findings provide valuable insights into the identification of CIM risk factors among gastrointestinal cancer patients undergoing chemotherapy. Furthermore, the results underscore the potential of machine learning in enhancing our understanding of chemotherapy-induced mucositis and advancing personalized patient care strategies.

Development of a Novel Histatin-5 Mucoadhesive Gel for the Treatment of Oral Mucositis: In Vitro Characterization and In Vivo Evaluation.

Antimicrobial peptides have appeared to be promising candidates for therapeutic purposes due to their broad antimicrobial activity and non-toxicity. Histatin-5 (Hst-5) is a notable salivary antimicrobial peptide that exhibited therapeutic properties in the oral cavity. Oral mucositis is an acute inflammation of the oral cavity, following cancer therapy. The current treatment methods of oral mucositis have low effectiveness. The aim of this study was to design, formulate and characterize a mucoadhesive gel delivery system for Hst-5 usage in the treatment of oral mucositis. Carbopol 934 and hydroxypropyl methylcellulose (HPMC) have been used in the development of a Hst-5 mucoadhesive gel that was optimized by using Box-Behnken design. The optimized formulation was evaluated in-vitro, based on mucoadhesive strength, viscoelasticity, spreadability, release rate, peptide secondary structure analysis, antimicrobial activity, and storage stability. The efficacy of Hst-5 gel was assessed in vivo in a chemotherapy-induced mucositis model. The results showed a sustained release of Hst-5 from the new formulation. Hst-5 gel exerted antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Candida albicans. The histopathological, immunohistochemical and statistical analysis showed that the Hst-5 gel had wound healing activity in vivo. The findings of this study indicate that the mentioned compound possesses promising potential as a novel and efficient therapeutic agent in managing oral mucositis. Moreover, the results suggest that the compound is commercially feasible for further development and utilization.

Assessment of Oxidative Stress-Induced Oral Epithelial Toxicity.

Reactive oxygen species (ROS) are highly reactive molecules generated in living organisms and an excessive production of ROS culminates in oxidative stress and cellular damage. Notably, oxidative stress plays a critical role in the pathogenesis of a number of oral mucosal diseases, including oral mucositis, which remains one of cancer treatments' most common side effects. We have shown previously that oral keratinocytes are remarkably sensitive to oxidative stress, and this may hinder the development and reproducibility of epithelial cell-based models of oral disease. Here, we examined the oxidative stress signatures that parallel oral toxicity by reproducing the initial events taking place during cancer treatment-induced oral mucositis. We used three oral epithelial cell lines (an immortalized normal human oral keratinocyte cell line, OKF6, and malignant oral keratinocytes, H357 and H400), as well as a mouse model of mucositis. The cells were subjected to increasing oxidative stress by incubation with hydrogen peroxide (H2O2) at concentrations of 100 μM up to 1200 μM, for up to 24 h, and ROS production and real-time kinetics of oxidative stress were investigated using fluorescent dye-based probes. Cell viability was assessed using a trypan blue exclusion assay, a fluorescence-based live-dead assay, and a fluorometric cytotoxicity assay (FCA), while morphological changes were analyzed by means of a phase-contrast inverted microscope. Static and dynamic real-time detection of the redox changes in keratinocytes showed a time-dependent increase of ROS production during oxidative stress-induced epithelial injury. The survival rates of oral epithelial cells were significantly affected after exposure to oxidative stress in a dose- and cell line-dependent manner. Values of TC50 of 800 μM, 800 μM, and 400 μM were reported for H400 cells (54.21 ± 9.04, p < 0.01), H357 cells (53.48 ± 4.01, p < 0.01), and OKF6 cells (48.64 ± 3.09, p < 0.01), respectively. Oxidative stress markers (MPO and MDA) were also significantly increased in oral tissues in our dual mouse model of chemotherapy-induced mucositis. In summary, we characterized and validated an oxidative stress model in human oral keratinocytes and identified optimal experimental conditions for the study of oxidative stress-induced oral epithelial toxicity.

In-situ fast-prepared mucoadhesive oral gel for palliative treatment of chemotherapy-induced mucositis: preparation, characterizations and pre-post study

In-situ fast-prepared mucoadhesive oral gel for palliative treatment of chemotherapy-induced mucositis: preparation, characterizations and pre-post study

High molecular weight hyaluronic acid drastically reduces chemotherapy-induced mucositis and apoptotic cell death

Oral and intestinal mucositis (OIM) are debilitating inflammatory diseases initiated by oxidative stress, resulting in epithelial cell death and are frequently observed in cancer patients undergoing chemo-radiotherapy. There are currently few preventative strategies for this debilitating condition. Therefore, the development of a safe and effective mucositis mitigating strategy is an unmet medical need. Hyaluronic acid (HA) preparations have been tentatively used in oral mucositis. However, the protective effects of HA in chemotherapy-induced mucositis and their underlying mechanisms remain to be fully elucidated. This study aimed to assess these mechanisms using multiple formulations of enriched HA (Mucosamin®), cross-linked (xl-), and non-crosslinked high molecular weight HA (H-MW-HA) in an oxidative stress-induced model of human oral mucosal injury in vitro and an in vivo murine model of 5-flurouracil (5-FU)-induced oral/intestinal mucositis. All tested HA formulations protected against oxidative stress-induced damage in vitro without inducing cytotoxicity, with H-MW-HA also significantly reducing ROS production. Daily supplementation with H-MW-HA in vivo drastically reduced the severity of 5-FU-induced OIM, prevented apoptotic damage and reduced COX-2 enzyme activity in both the oral and intestinal epithelium. In 5-FU-injected mice, HA supplementation also significantly reduced serum levels of IL-6 and the chemokine CXCL1/KC, while the serum antioxidant activity of superoxide dismutase was elevated. Our data suggest that H-MW-HA attenuates 5-FU-induced OIM, at least partly, by impeding apoptosis, inhibiting of oxidative stress and suppressing inflammatory cytokines. This study supports the development of H-MW-HA preparations for preventing OIM in patients receiving chemotherapy.

Gastrointestinal barrier integrity and mucosal inflammation as risk factors of blood stream infections in children treated for acute lymphoblastic leukaemia.

Chemotherapy-induced mucositis increases the risk of blood stream infections (BSI) due to translocation of bacteria across the intestinal epithelium. Our study investigated if quantitative measures of intestinal mucositis severity, including plasma citrulline (a marker of functional enterocytes) and CCL20 (an intestinal immune homeostatic chemokine), could identify patients at risk of BSI. A total of 106 children with ALL undergoing induction treatment (NOPHO ALL 2008) were included and information regarding BSI episodes was collected from the patients' medical records. Twenty-seven patients (25%) developed BSI during induction. Patients with BSI had a larger decrease in citrulline after chemotherapy than patients without BSI, and nearly all BSI episodes (25/27) occurred in the group of patients exhibiting a drop in citrulline (OR = 6.4 [95% CI: 1.4-29.3], P = .008). Patients who developed BSI had higher plasma CCL20 levels on days 8, 15 and 22 than patients without BSI (all P < .05), and elevated CCL20 levels on day 8 increased the risk of subsequent BSI (OR = 1.57 [1.11-2.22] per doubling of CCL20 level, P = .01) in a multivariable logistic regression analysis. These findings suggest that children with ALL who develop BSI during chemotherapy are characterised by more severe intestinal mucositis, as measured by plasma citrulline and CCL20. These markers may be useful in early risk stratification to guide treatment decisions.

Synergistic synbiotic containing fructooligosaccharides and Lactobacillus delbrueckii CIDCA 133 alleviates chemotherapy-induced intestinal mucositis in mice.

Intestinal mucositis is a commonly reported side effect in oncology patients undergoing chemotherapy and radiotherapy. Probiotics, prebiotics, and synbiotics have been investigated as alternative therapeutic approaches against intestinal mucositis due to their well-known anti-inflammatory properties and health benefits to the host. Previous studies showed that the potential probiotic Lactobacillus delbrueckii CIDCA 133 and the prebiotic Fructooligosaccharides (FOS) alleviated the 5-Fluorouracil (5-FU) chemotherapy-induced intestinal mucosa damage. Based on these previous beneficial effects, this work evaluated the anti-inflammatory property of the synbiotic formulation containing L. delbrueckii CIDCA 133 and FOS in mice intestinal mucosa inflammation induced by 5-FU. This work showed that the synbiotic formulation was able to modulate inflammatory parameters, including reduction of cellular inflammatory infiltration, gene expression downregulation of Tlr2, Nfkb1, and Tnf, and upregulation of the immunoregulatory Il10 cytokine, thus protecting the intestinal mucosa from epithelial damage caused by the 5-FU. The synbiotic also improved the epithelial barrier function by upregulating mRNA transcript levels of the short chain fatty acid (SCFA)-associated GPR43 receptor and the occludin tight junction protein, with the subsequent reduction of paracellular intestinal permeability. The data obtained showed that this synbiotic formulation could be a promising adjuvant treatment to be explored against inflammatory damage caused by 5-FU chemotherapy.

Biobehavioral Influences of Stress and Inflammation on Mucositis in Adolescents and Young Adults with Cancer: Results from a Pilot Study.

Purpose: Chemotherapy-induced mucositis is a prevalent and burdensome toxicity among adolescent and young adults (AYAs) with cancer and impedes the delivery of optimal therapy. Its development is not well understood, but baseline stress and inflammation may be contributory factors. This pilot study evaluates stress and inflammation as risk factors for mucositis, identifies effect size estimates, and evaluates the feasibility of a prospective study to investigate mucositis development. Methods: Thirty AYAs receiving chemotherapy with substantial risk of mucositis completed baseline stress measures, and serum was collected for inflammatory biomarker analysis. Regression and mediation analyses determined the relationship between stress/inflammation and mucositis. Results: Stress appears to be a significant risk factor for incidence of mucositis (odds ratio 1.13, p = 0.125) and predicts total mucositis score (β = 0.281, p = 0.023) as well as peak incidence (β = 0.052, p = 0.018). Baseline levels of interleukin (IL)-1a and epidermal growth factor (EGF) predicted mucositis development, and EGF and IL-8 may mediate the relationship between stress and mucositis. Findings suggest that stress-induced inflammation exacerbates symptom development. Conclusion: Results from this pilot study inform mucositis symptom models, suggesting that psychosocial and physiologic factors are involved in development. Importantly, this pilot study provides initial effect size estimates, including magnitude and direction of relationships, that are essential to informing larger, more robustly powered studies. High enrollment, low attrition, and minimal missing data in this study suggest this model is feasible for research in this population. Importantly, this work is a first step in identifying new risk factors for mucositis and targets for nurse-led interventions to prevent toxicity development.