The bidirectional interaction of the gut microbiome and the innate immune system: Implications for chemotherapy‐induced gastrointestinal toxicity

Online 28 Aug 2018Chemotherapy‐induced gastrointestinal toxicity (CIGT) occurs in up to 80% of all patients undergoing cancer treatment, and leads to symptoms such as diarrhoea, abdominal bleeding and pain. There is currently limited understanding of how to predict an individual patient's risk of CIGT. It is believed the gut microbiome and its interactions with the host's innate immune system plays a key role in the development of this toxicity and potentially other toxicities, however comprehensive bioinformatics modelling has not been rigorously performed. The innate immune system is strongly influenced by the microbial environment and vice‐versa. Ways this may occur include the immune system controlling composition and compartmentalisation of the microbiome, the microbiome affecting development of antigen‐presenting cells, and finally, the NLRP6 inflammasome orchestrating the colonic host‐microbiome interface. This evidence calls into question the role of pre‐treatment risk factors in the development of gastrointestinal toxicity after chemotherapy. This review aims to examine evidence of a bidirectional interaction between the gut microbiome and innate immunity, and how these interactions occur in CIGT. In the future, knowledge of these interactions may lead to improved personalised cancer medicine, predictive risk stratification methods and the development of targeted interventions to reduce, or even prevent, CIGT severity.Kate R. Secombe, Janet K. Coller, Rachel J. Gibson, Hannah R. Wardill and Joanne M. Bowe

Prophylactic treatment with vitamins C and B2 for methotrexate-induced gastrointestinal mucositis

Mucositis is a common side-effect of chemotherapy treatment, inducing alterations in the composition of the gut microbiota. Redox active compounds, such as vitamins B2 and C, have been shown to reduce inflammation and enhance the growth of anaerobic bacteria in the gut. We therefore aimed to (1) validate the ability of these compounds to promote bacterial cell growth in vitro, and (2) determine their prophylactic efficacy in a rat model of methotrexate (MTX)-induced mucositis. Bacterial growth curves were performed to assess the growth kinetics of bacteria exposed to Vitamins C and B2 (0.5 mM). Male wistar rats (150–200 g) received vitamins B2 (12 mg/day) and C (50 mg/day) via daily oral gavage (from day −1 to day 10). MTX (45 mg/Kg) was administrated via I.V. injection (N = 4–8/group) on day 0. Body weight, water/food consumption and diarrhea were assessed daily. Blood and faecal samples were collected longitudinally to assess citrulline levels (mucositis biomarker) and gut microbiota composition. Vitamins C/B2 enhanced the in vitro growth of anaerobic bacteria Blautia coccoides and Roseburia intestinalis. Contrarily to vitamin B2, in vivo administration of Vitamin C significantly attenuated clinical symptoms of mucositis. Despite their influence on the composition of the gut microbiota, both vitamins did not modulate the course of MTX-induced mucositis, as accessed by plasma citrulline. Vitamins B2 and C enhanced anaerobic bacterial growth in vitro, however their ability to mitigate MTX-induced mucositis was limited.Ana Rita da Silva Ferreira, Hannah R. Wardill, Rick Havinga, Wim J. E. Tissing and Hermie J. M. Harmse

Selective MMP inhibition, using AZD3342, to reduce gastrointestinal toxicity and enhance chemoefficacy in a rat model

BACKGROUND:The common cytotoxic mechanisms that underpin chemoefficacy and toxicity have hampered efforts to deliver effective supportive care interventions, particularly for gastrointestinal (GI) toxicity. Matrix metalloproteinases (MMPs) have been implicated in both tumor growth and GI toxicity, and as such MMP inhibitors present as a novel therapeutic avenue to simultaneously enhance treatment efficacy and reduce toxicity. OBJECTIVES:The aim of this study was to determine the efficacy of an MMP-9/12 inhibitor, AZD3342, on tumor growth and GI toxicity in a rat model. METHODS:Female tumor-bearing Dark Agouti rats (n = 90) were divided into 4 groups: vehicle control; methotrexate (MTX); AZD3342, and MTX + AZD3342. Tumors were measured daily (for 5 days) using digital calipers. GI toxicity was assessed using well-established clinical markers (diarrhea/weight loss), histopathological analysis, and functional assessment of intestinal barrier permeability. RESULTS:AZD3342 delayed the onset of severe diarrhea by 1 day (vs. MTX) but was unable to improve the overall severity of diarrhea. No changes were detected in tissue morphology or intestinal barrier function. AZD3342 alone suppressed tumor growth (p = 0.003 vs. vehicle) but did not enhance the efficacy of MTX. CONCLUSIONS:This study showed partial efficacy of AZD3342 in reducing tumor growth and delaying the onset of severe diarrhea caused by MTX in rats. We suggest further studies be undertaken targeting appropriate scheduling of AZD3342 as well as investigating different cytotoxic therapies that strongly activate MMP signaling.Rachel J. Gibson, Ysabella Z.A. van Sebille, Hannah R. Wardill, Anthony Wignall, Joseph Shirren, Imogen A. Ball, Nicole Williams, Kiara Wanner, Joanne M. Bowe

Does chemotherapy-induced gastrointestinal mucositis affect the bioavailability and efficacy of anti-infective drugs?

Antimicrobial prophylaxis is increasingly being used in patients with hematological malignancies receiving high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT). However, few studies have focused on the potential impact of gastrointestinal mucositis (GI-M), a frequently observed side effect of chemotherapy in patients with cancer that affects the gastrointestinal microenvironment, on drug absorption. In this review, we discuss how chemotherapy leads to an overall loss of mucosal surface area and consequently to uncontrolled transport across the barrier. The barrier function is depending on intestinal luminal pH, intestinal motility, and diet. Another factor contributing to drug absorption is the gut microbiota, as it modulates the bioavailability of orally administrated drugs by altering the gastrointestinal properties. To better understand the complex interplay of factors in GI-M and drug absorption we suggest: (i) the longitudinal characterization of the impact of GI-M severity on drug exposure in patients, (ii) the development of tools to predict drug absorption, and (iii) strategies that allow the support of the gut microbiota. These studies will provide relevant data to better design strategies to reduce the severity and impact of GI-M in patients with cancer.Ana Rita da Silva Ferreira, Anne-Grete Märtson , Alyse de Boer, Hannah R. Wardill, Jan-Willem Alffenaar, Hermie J. M. Harmsen and Wim J. E. Tissin

Guidelines for reporting on animal fecal transplantation (GRAFT) studies: recommendations from a systematic review of murine transplantation protocols

Fecal microbiota transplant (FMT) is a powerful tool used to connect changes in gut microbial composition with a variety of disease states and pathologies. While FMT enables potential causal relationships to be identified, the experimental details reported in preclinical FMT protocols are highly inconsistent and/or incomplete. This limitation reflects a current lack of authoritative guidance on reporting standards that would facilitate replication efforts and ultimately reproducible science. We therefore systematically reviewed all FMT protocols used in mouse models with the goal of formulating recommendations on the reporting of preclinical FMT protocols. Search strategies were applied across three databases (PubMed, EMBASE, and Ovid Medline) until June 30, 2020. Data related to donor attributes, stool collection, processing/storage, recipient preparation, administration, and quality control were extracted. A total of 1753 papers were identified, with 241 identified for data extraction and analysis. Of the papers included, 92.5% reported a positive outcome with FMT intervention. However, the vast majority of studies failed to address core methodological aspects including the use of anaerobic conditions (91.7% of papers lacked information), storage (49.4%), homogenization (33.6%), concentration (31.5%), volume (19.9%) and administration route (5.3%). To address these reporting limitations, we developed theGuidelines for Reporting Animal Fecal Transplant (GRAFT) that guide reporting standards for preclinical FMT. The GRAFT recommendations will enable robust reporting of preclinical FMT design, and facilitate high-quality peer review, improving the rigor and translation of knowledge gained through preclinical FMT studies.Kate R. Secombe, Ghanyah H. Al-Qadami, Courtney B. Subramaniam, Joanne M. Bowen, Jacqui Scott, Ysabella Z.A. Van Sebille ... et a

Exposure of anti-infective drugs and the dynamic changes of the gut microbiota during gastrointestinal mucositis in autologous stem cell transplant patients: a pilot study

Published online: 17 January 2023Gastrointestinal mucositis could potentially compromise drug absorption due to functional loss of mucosa and other pathophysiological changes in the gastrointestinal microenvironment. Little is known about this effect on commonly used anti-infectives. This study aimed to explore the association between different stages of gastrointestinal mucositis, drug exposure, and gut microbiota. A prospective, observational pilot study was performed in HSCT patients aged ≥ 18 years receiving anti-infectives orally. Left-over blood samples and fecal swabs were collected from routine clinical care until 14 days after HSCT to analyze drug and citrulline concentrations and to determine the composition of the gut microbiota. 21 patients with a median age of 58 (interquartile range 54-64) years were included with 252 citrulline, 155 ciprofloxacin, 139 fluconazole, and 76 acyclovir concentrations and 48 fecal swabs obtained. Severe gastrointestinal mucositis was observed in all patients. Due to limited data correlation analysis was not done for valacyclovir and fluconazole, however we did observe a weak correlation between ciprofloxacin and citrulline concentrations. This could suggest that underexposure of ciprofloxacin can occur during severe mucositis. A follow-up study using frequent sampling rather than the use of left-over would be required to investigate the relationship between gastrointestinal mucositis, drug exposure, and gut microbiome.Anne-Grete Märtson, Ana Rita da Silva Ferreira, Anette Veringa, Lei Liu, Hannah R. Wardill, Lenneke A. T. Junier, Tjip S. van der Werf, Hermie J. M. Harmsen, Marieke G. G. Sturkenboom, Lambert F. Span, Wim J. E. Tissing, Jan-Willem C. Alffenaa

Whey-based diet containing medium chain triglycerides modulates the gut microbiota and protects the intestinal mucosa from chemotherapy while maintaining therapy efficacy.

Cytotoxicity (i.e. cell death) is the core mechanism by which chemotherapy induces its anti-cancer effects. Unfortunately, this same mechanism underpins the collateral damage it causes to healthy tissues. The gastrointestinal tract is highly susceptible to chemotherapy’s cytotoxicity, resulting in ulcerative lesions (termed gastrointestinal mucositis, GI-M) that impair the functional capacity of the gut leading to diarrhea, anorexia, malnutrition and weight loss, which negatively impact physical/psychological wellbeing and treatment adherence. Preventing these side effects has proven challenging given the overlapping mechanisms that dictate chemotherapy efficacy and toxicity. Here, we report on a novel dietary intervention that, due to its localized gastrointestinal effects, is able to protect the intestinal mucosal from unwanted toxicity without impairing the anti-tumor effects of chemotherapy. The test diet (containing extensively hydrolyzed whey protein and medium chain triglycerides (MCTs)), was investigated in both tumor-naïve and tumor-bearing models to evaluate its effect on GI-M and chemo-efficacy, respectively. In both models, methotrexate was used as the representative chemotherapeutic agent and the diet was provided ad libitum for 14 days prior to treatment. GI-M was measured using the validated biomarker plasma citrulline, and chemo-efficacy defined by tumor burden (cm3 /g body weight). The test diet significantly attenuated GI-M (P = 0.03), with associated reductions in diarrhea (P < 0.0001), weight loss (P < 0.05), daily activity (P < 0.02) and maintenance of body composition (P < 0.02). Moreover, the test diet showed significant impact on gut microbiota by increasing diversity and resilience, whilst also altering microbial composition and function (indicated by cecal short and brained chain fatty acids). The test diet did not impair the efficacy of methotrexate against mammary adenocarcinoma (tumor) cells. In line with the first model, the test diet minimized intestinal injury (P = 0.001) and diarrhea (P < 0.0001). These data support translational initiatives to determine the clinical feasibility, utility and efficacy of this diet to improve chemotherapy treatment outcomes.Hannah R. Wardill, Ana Rita Da Silva Ferreira, Himanshu Kumar, Emma H. Bateman, Courtney B. Cross, Joanne M. Bowen, Rick Havinga, Hermie J. M. Harmsen, Jan Knol, Bram Dorresteijn, Miriam van Dijk, Jeroen van Bergenhenegouwen, and Wim J. E. Tissin

New pharmacotherapy options for chemotherapy-induced alimentary mucositis

Introduction: Chemotherapy-induced alimentary mucositis is an extremely common condition that is caused by a breakdown of the mucosal barrier. It occurs in between 40 - 100% of cancer patients depending on the treatment regimen. Symptoms typically include pain from oral ulceration, vomiting and diarrhoea. Alimentary mucositis often necessitates chemotherapy reductions or treatment breaks, overall potentially compromising survival outcomes. Consequently, alimentary mucositis creates a burden not only on patients' quality of life but also on healthcare costs. Despite this, currently, there is no clinically effective localised/pharmacological therapy intervention strategy to prevent alimentary mucositis. Areas Covered: Over recent years, a number of novel pharmacotherapy agents have been trialed in various preclinical and clinical settings. This critical review will therefore provide an overview of emerging pharmacotherapies for the treatment of alimentary mucositis following chemotherapy with particular emphasis on studies published in the last 2 years. A Pubmed literature search was conducted to identify eligible articles published before 30 November 2013 and each article was reviewed by all authors. All articles were written in English. Expert Opinion: Currently, there is no clinically effective localised therapeutic intervention strategy to prevent the condition. New emerging areas of research have recently been proposed to play key roles in the development of alimentary mucositis and these areas may provide researchers and clinicians with new research directions. Hopefully this will continue, and evidence-based informed guidelines can be produced to improve clinical practice management of this condition.Hannah R Wardill, Joanne M Bowen, Rachel J Gibso

Using real world data to advance the provision of supportive cancer care: Mucositis as a case study

Purpose of review: For decades, clinical decision making and practice has been largely informed by data generated through randomized clinical trials (RCTs). By design, RCTs are highly restricted in both scope and scale, resulting in narrow indications and iterative advances in clinical practice. With the transition to electronic health records, there are now endless opportunities to utilize these ‘real world’ data (RWD) to make more substantive advances in our understanding that are, by nature, more applicable to reality. This review discusses the current paradigm of using big data to advance and inform the provision of supportive cancer care, using mucositis as a case study. Recent findings: Global efforts to synthesize RWD in cancer have almost exclusively focused on tumor classification and treatment efficacy, leveraging on routine tumor pathology and binary response outcomes. In contrast, clinical notes and billing codes are not as applicable to treatment side effects which require integration of both clinical and biological data, as well as patient-reported outcomes. Summary: Cancer treatment-induced toxicities are heterogeneous and complex, and as such, the use of RWD to better understand their etiology and interaction is challenging. Multidisciplinary cooperation and leadership are needed to improve data collection and governance to ensure the right data is accessible and reliable.Hannah R. Wardill, Steve T. Sonis, and Nicole M.A. Blijleven

Prophylactic probiotics for cancer therapy-induced diarrhoea: A meta-analysis

PURPOSE OF REVIEW: Strong preclinical data support prophylactic probiotics as an effective preventive strategy for diarrhoea secondary to anticancer therapies. To determine the composite evidence that this approach translates to the clinic, we performed a meta-analysis of randomized controlled trials (RCTs) of prophylactic probiotics for the prevention of cancer therapy-induced diarrhoea. RECENT FINDINGS: A three-step search strategy was used to identify relevant studies (1 June 2000-1 June 2017) investigating probiotic intervention for diarrhoea secondary to any cancer therapy (cytotoxic, targeted and immunotherapies). RCTs across PubMed, Embase, CINAHL and CENTRAL were assessed for eligibility and assessed using RevMan 5.3 (The Cochrane Collaboration). Seven trials with a total of 1091 patients were included in this meta-analysis. Compared with placebo, prophylactic probiotics did not prevent or reduce the overall incidence of diarrhoea or severe CTCAE Grade at least 3 diarrhoea [relative risk (RR) = 0.81, 95% confidence interval (95% CI) = 0.60-1.09, Z = 1.41, P = 0.16; RR = 0.54, 95% CI = 0.25-1.16, Z = 1.58, P = 0.11], nor did it influence the use of rescue medication (RR = 0.93, 95% CI = 0.53-1.65, Z = 0.24, P = 0.81). SUMMARY: Current evidence does not support widespread implementation of probiotics for diarrhoea secondary to cytotoxic therapy and the tyrosine kinase inhibitor, dacomitinib. Research efforts should be diverted to pair specific forms of gastrointestinal toxicity and their unique microbial phenotype to develop the ideal microbial protectant.Hannah R. Wardill, Ysabella Z.A. Van Sebille, Matthew A. Ciorba, and Joanne M. Bowe