Publications by authors named "Hannah R Wardill"

43 Publications

Investigating causality with fecal microbiota transplantation in rodents: applications, recommendations and pitfalls.

Gut Microbes 2021 Jan-Dec;13(1):1941711

Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland.

In recent years, studies investigating the role of the gut microbiota in health and diseases have increased enormously - making it essential to deepen and question the research methodology employed. Fecal microbiota transplantation (FMT) in rodent studies (either from human or animal donors) allows us to better understand the causal role of the intestinal microbiota across multiple fields. However, this technique lacks standardization and requires careful experimental design in order to obtain optimal results. By comparing several studies in which rodents are the final recipients of FMT, we summarize the common practices employed. In this review, we document the limitations of this method and highlight different parameters to be considered while designing FMT Studies. Standardizing this method is challenging, as it differs according to the research topic, but avoiding common pitfalls is feasible. Several methodological questions remain unanswered to this day and we offer a discussion on issues to be explored in future studies.
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http://dx.doi.org/10.1080/19490976.2021.1941711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331043PMC
July 2021

Antibiotic-induced disruption of the microbiome exacerbates chemotherapy-induced diarrhoea and can be mitigated with autologous faecal microbiota transplantation.

Eur J Cancer 2021 Aug 12;153:27-39. Epub 2021 Jun 12.

Department of Medical Microbiology, University Medical Centre Groningen, The University of Groningen, Groningen, the Netherlands.

Background: Chemotherapy is well documented to disrupt the gut microbiome, leading to poor treatment outcomes and a heightened risk of adverse toxicity. Although strong associations exist between its composition and gastrointestinal toxicity, its causal contribution remains unclear. Our inability to move beyond association has limited the development and implementation of microbial-based therapeutics in chemotherapy adjuncts with no clear rationale of how and when to deliver them.

Methods/results: Here, we investigate the impact of augmenting the gut microbiome on gastrointestinal toxicity caused by the chemotherapeutic agent, methotrexate (MTX). Faecal microbiome transplantation (FMT) delivered after MTX had no appreciable impact on gastrointestinal toxicity. In contrast, disruption of the microbiome with antibiotics administered before chemotherapy exacerbated gastrointestinal toxicity, impairing mucosal recovery (P < 0.0001) whilst increasing diarrhoea severity (P = 0.0007) and treatment-related mortality (P = 0.0045). Importantly, these detrimental effects were reversed when the microbiome was restored using autologous FMT (P = 0.03), a phenomenon dictated by the uptake and subsequent expansion of Muribaculaceae.

Conclusions: These are the first data to show that clinically impactful symptoms of gastrointestinal toxicity are dictated by the microbiome and provide a clear rationale for how and when to target the microbiome to mitigate the acute and chronic complications caused by disruption of the gastrointestinal microenvironment. Translation of this new knowledge should focus on stabilising and strengthening the gut microbiome before chemotherapy and developing new microbial approaches to accelerate recovery of the mucosa. By controlling the depth and duration of mucosal injury, secondary consequences of gastrointestinal toxicity may be avoided.
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http://dx.doi.org/10.1016/j.ejca.2021.05.015DOI Listing
August 2021

Prophylactic Treatment with Vitamins C and B2 for Methotrexate-Induced Gastrointestinal Mucositis.

Biomolecules 2020 Dec 29;11(1). Epub 2020 Dec 29.

Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 EB80, 9713 GZ Groningen, The Netherlands.

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 and . 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.
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http://dx.doi.org/10.3390/biom11010034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823339PMC
December 2020

Site-specific contribution of Toll-like receptor 4 to intestinal homeostasis and inflammatory disease.

J Cell Physiol 2021 02 30;236(2):877-888. Epub 2020 Jul 30.

Discipline of Physiology, Adelaide Medical School, The University of Adelaide, Adelaide, Australia.

Toll-like receptor 4 (TLR4) is a highly conserved protein of innate immunity, responsible for the regulation and maintenance of homeostasis, as well as immune recognition of external and internal ligands. TLR4 is expressed on a variety of cell types throughout the gastrointestinal tract, including on epithelial and immune cell populations. In a healthy state, epithelial cell expression of TLR4 greatly assists in homeostasis by shaping the host microbiome, promoting immunoglobulin A production, and regulating follicle-associated epithelium permeability. In contrast, immune cell expression of TLR4 in healthy states is primarily centred on the maturation of dendritic cells in response to stimuli, as well as adequately priming the adaptive immune system to fight infection and promote immune memory. Hence, in a healthy state, there is a clear distinction in the site-specific roles of TLR4 expression. Similarly, recent research has indicated the importance of site-specific TLR4 expression in inflammation and disease, particularly the impact of epithelial-specific TLR4 on disease progression. However, the majority of evidence still remains ambiguous for cell-specific observations, with many studies failing to provide the distinction of epithelial versus immune cell expression of TLR4, preventing specific mechanistic insight and greatly impacting the translation of results. The following review provides a critical overview of the current understanding of site-specific TLR4 activity and its contribution to intestinal/immune homeostasis and inflammatory diseases.
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http://dx.doi.org/10.1002/jcp.29976DOI Listing
February 2021

The microbiota-gut-brain axis: An emerging therapeutic target in chemotherapy-induced cognitive impairment.

Neurosci Biobehav Rev 2020 09 15;116:470-479. Epub 2020 Jul 15.

Discipline of Physiology, Adelaide Medical School, University of Adelaide, SA, Australia; Department of Pediatric Oncology/Hematology, University of Groningen, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, the Netherlands.

Chemotherapy-induced cognitive impairment (CICI) is an ill-defined complication of chemotherapy treatment that places a significant psychosocial burden on survivors of cancer and has a considerable impact on the activities of daily living. CICI pathophysiology has not been clearly defined, with candidate mechanisms relating to both the direct cytotoxicity of chemotherapy drugs on the central nervous system (CNS) and more global, indirect mechanisms such as neuroinflammation and blood brain barrier (BBB) damage. A growing body of research demonstrates that changes to the composition of the gastrointestinal microbiota is an initiating factor in numerous neurocognitive conditions, profoundly influencing both CNS immunity and BBB integrity. Importantly, chemotherapy causes significant disruption to the gastrointestinal microbiota. While microbial disruption is a well-established factor in the development of chemotherapy-induced gastrointestinal toxicities (largely diarrhoea), its role in CICI remains unknown, limiting microbial-based therapeutics or risk prediction strategies. Therefore, this review aims to synthesise and critically evaluate the evidence addressing the microbiota-gut-brain axis as a critical factor influencing the development of CICI.
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http://dx.doi.org/10.1016/j.neubiorev.2020.07.002DOI Listing
September 2020

Pitfalls and novel experimental approaches to optimize microbial interventions for chemotherapy-induced gastrointestinal mucositis.

Curr Opin Support Palliat Care 2020 06;14(2):127-134

Department of Medical Microbiology.

Purpose Of Review: There is a growing number of studies implicating gut dysbiosis in mucositis development. However, few studies have shed light on the causal relationship limiting translational potential. Here, we detail the key supportive evidence for microbial involvement, candidate mechanisms by which the microbiome may contribute to mucositis and emerging approaches to model host-microbe interactions with clinical relevance and translational potential.

Recent Findings: Synthesis of existing clinical data demonstrate that modulating the microbiome drastically alters the development and severity of mucositis, providing a strong rationale for its involvement. Review of the literature revealed potential microbiome-dependent mechanisms of mucosal injury including altered drug metabolism, bile acid synthesis and regulation of the intestinal barrier. Current studies are limited in their mechanistic insight due to cross-sectional and would benefit from longitudinal analyses and baseline phenotyping.

Summary: The causative role of the microbiome in mucositis development remains unclear. Future studies must adopt comprehensive microbial analyses with functional assessment, and utilize emerging ex-vivo models to interrogate host-microbe interactions in mucositis.
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http://dx.doi.org/10.1097/SPC.0000000000000497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259380PMC
June 2020

Systematic review of agents for the management of cancer treatment-related gastrointestinal mucositis and clinical practice guidelines.

Support Care Cancer 2019 Oct 8;27(10):4011-4022. Epub 2019 Jul 8.

Oral Medicine, Eastman Institute for Oral Health, University of Rochester Medical Center, Rochester, NY, USA.

Purpose: The aim of this study was to update the clinical practice guidelines for the use of agents for the prevention and/or treatment of gastrointestinal mucositis (GIM).

Methods: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: Recommendation, Suggestion, and No Guideline Possible.

Results: A total of 78 papers across 13 interventions were examined of which 25 were included in the final review. No new guidelines were possible for any agent due to inadequate and/or conflicting evidence. Existing guidelines for probiotics and hyperbaric oxygen were unchanged.

Conclusions: Of the agents studied for the prevention and treatment of GIM, the evidence continues to support use of probiotics containing Lactobacillus spp. for prevention of chemoradiotherapy and radiotherapy-induced diarrhea in patients with pelvic malignancy, and hyperbaric oxygen therapy to treat radiation-induced proctitis. Additional well-designed research is encouraged to enable a decision regarding palifermin, glutamine, sodium butyrate, and dietary interventions, for the prevention or treatment of GIM.
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http://dx.doi.org/10.1007/s00520-019-04892-0DOI Listing
October 2019

Use of zebrafish to model chemotherapy and targeted therapy gastrointestinal toxicity.

Exp Biol Med (Maywood) 2019 10 11;244(14):1178-1185. Epub 2019 Jun 11.

Adelaide Medical School, University of Adelaide, Adelaide 5000, Australia.

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http://dx.doi.org/10.1177/1535370219855334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802154PMC
October 2019

Early career interview: Hannah Wardill.

Authors:
Hannah R Wardill

Future Sci OA 2019 Apr 12;5(4):FSO382. Epub 2019 Apr 12.

Research Fellow, the University of Adelaide, Australia & the University of Groningen, The Netherlands.

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http://dx.doi.org/10.4155/fsoa-2019-0011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511918PMC
April 2019

Animal models of mucositis: critical tools for advancing pathobiological understanding and identifying therapeutic targets.

Curr Opin Support Palliat Care 2019 06;13(2):119-133

Adelaide Medical School, The University of Adelaide.

Purpose Of Review: Mucositis remains a prevalent, yet poorly managed side effect of anticancer therapies. Mucositis affecting both the oral cavity and gastrointestinal tract predispose to infection and require extensive supportive management, contributing to the growing economic burden associated with cancer care. Animal models remain a critical aspect of mucositis research, providing novel insights into its pathogenesis and revealing therapeutic targets. The current review aims to provide a comprehensive overview of the current animal models used in mucositis research.

Recent Findings: A wide variety of animal models of mucositis exist highlighting the highly heterogenous landscape of supportive oncology and the unique cytotoxic mechanisms of different anticancer agents. Golden Syrian hamsters remain the gold-standard species for investigation of oral mucositis induced by single dose and fractionated radiation as well as chemoradiation. There is no universally accepted gold-standard model for the study of gastrointestinal mucositis, with rats, mice, pigs and dogs all offering unique perspectives on its pathobiology.

Summary: Animal models are a critical aspect of mucositis research, providing unprecedent insight into the pathobiology of mucositis. Introduction of tumour-bearing models, cyclic dosing scheduled, concomitant agents and genetically modified animals have been integral in refining our understanding of mucositis.
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http://dx.doi.org/10.1097/SPC.0000000000000421DOI Listing
June 2019

Acute Colitis Drives Tolerance by Persistently Altering the Epithelial Barrier and Innate and Adaptive Immunity.

Inflamm Bowel Dis 2019 06;25(7):1196-1207

Centre for Nutrition and Gastrointestinal Disease, Adelaide Medical School, University of Adelaide & South Australian Health and Medical Research Institute, Adelaide, Australia.

Background: Inflammatory bowel disease (IBD) has a remitting and relapsing disease course; however, relatively little is understood regarding how inflammatory damage in acute colitis influences the microbiota, epithelial barrier, and immune function in subsequent colitis.

Methods: Mice were administered trinitrobenzene sulphonic acid (TNBS) via enema, and inflammation was assessed 2 days (d2) or 28 days (d28) later. Colitis was reactivated in some mice by re-treating at 28 days with TNBS and assessing 2 days later (d30). Epithelial responsiveness to secretagogues, microbiota composition, colonic infiltration, and immune activation was compared between all groups.

Results: At day 28, the distal colon had healed, mucosa was restored, and innate immune response had subsided, but colonic transepithelial transport (P = 0.048), regulatory T-cell (TREG) infiltration (P = 0.014), adherent microbiota composition (P = 0.0081), and responsiveness of stimulated innate immune bone marrow cells (P < 0.0001 for IL-1β) differed relative to health. Two days after subsequent instillation of TNBS (d30 mice), the effects on inflammatory damage (P < 0.0001), paracellular permeability (P < 0.0001), and innate immune infiltration (P < 0.0001 for Ly6C+ Ly6G- macrophages) were reduced relative to d2 colitis. However, TREG infiltration was increased (P < 0.0001), and the responsiveness of stimulated T cells in the mesenteric lymph nodes shifted from pro-inflammatory at d2 to immune-suppressive at d30 (P < 0.0001 for IL-10). These effects were observed despite similar colonic microbiota composition and degradation of the mucosal layer between d2 and d30.

Conclusions: Collectively, these results indicate that acute colitis chronically alters epithelial barrier function and both innate and adaptive immune responses. These effects reduce the consequences of a subsequent colitis event, warranting longitudinal studies in human IBD subjects.
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http://dx.doi.org/10.1093/ibd/izz011DOI Listing
June 2019

Selective MMP Inhibition, Using AZD3342, to Reduce Gastrointestinal Toxicity and Enhance Chemoefficacy in a Rat Model.

Chemotherapy 2018 7;63(5):284-292. Epub 2019 Feb 7.

Discipline of Physiology, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.

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.
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http://dx.doi.org/10.1159/000495470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425820PMC
March 2019

Immuno-PET of Innate Immune Markers CD11b and IL-1β Detects Inflammation in Murine Colitis.

J Nucl Med 2019 06 9;60(6):858-863. Epub 2018 Nov 9.

Centre for Nutrition and Gastrointestinal Diseases, Adelaide Medical School, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, Australia

Inflammatory bowel disease (IBD) is a chronic relapsing and remitting inflammatory disease of the gastrointestinal tract. The diagnosis and monitoring of IBD are reliant on endoscopy, which is invasive and does not provide information on specific mediators. Symptom flare in IBD is associated with increased activation of innate immune pathways. Immuno-PET approaches have previously demonstrated the ability to detect colitis; however, a direct comparison of antibodies targeted to innate immune mediators and cells has not been done. We aimed to compare immuno-PET of antibodies to IL-1β and CD11b against standard F-FDG and MRI approaches to detect colonic inflammation. Colonic concentrations of IL-1β and myeloperoxidase were determined by ELISA, and colonic infiltration by CD11b-positive CD3-negative innate immune cells was determined by flow cytometry and compared between healthy and dextran sodium sulphate-treated colitic mice. PET of Zr-lα-IL-1β, Zr-α-CD11b, and F-FDG was compared by volume-of-interest analysis and with MRI by region-of-interest analysis. Imaging results were confirmed by ex vivo biodistribution analysis. Colonic inflammation was associated with impaired colonic epithelial barrier permeability, increased colonic IL-1β and myeloperoxidase concentrations, and increased CD11b-positive CD3-negative innate immune cell infiltration into the colon. Zr-α-IL-1β and Zr-α-CD11b immuno-PET detected colonic inflammation, as did F-FDG, and all PET tracers were more sensitive than MRI. Although F-FDG volumes of interest correlated with colitis severity and a strong trend was observed with Zr-α-IL-1β, no correlation was observed for Zr-α-CD11b or MRI. Zr-α-IL-1β was distributed mainly to the gastrointestinal tract, whereas Zr-α-CD11b was distributed to more tissue types. Immuno-PET using antibodies directed to innate immune markers detected colonic inflammation, with Zr-α-IL-1β providing a more tissue-specific signal than Zr-α-CD11b. Development of these technologies for human subjects will potentially provide a less invasive approach than endoscopy for diagnosing and monitoring IBD.
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http://dx.doi.org/10.2967/jnumed.118.219287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581233PMC
June 2019

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

Int J Cancer 2019 05 1;144(10):2365-2376. Epub 2018 Oct 1.

Cancer Treatment Toxicities Group, Discipline of Physiology, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.

Chemotherapy-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.
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http://dx.doi.org/10.1002/ijc.31836DOI Listing
May 2019

Advances in Imaging Specific Mediators of Inflammatory Bowel Disease.

Int J Mol Sci 2018 Aug 21;19(9). Epub 2018 Aug 21.

Centre for Nutrition and GI Diseases, Adelaide Medical School, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide 5000, Australia.

Inflammatory bowel disease (IBD) is characterized by chronic remitting and relapsing inflammation of the lower gastrointestinal tract. The etiology underlying IBD remains unknown, but it is thought to involve a hypersensitive immune response to environmental antigens, including the microbiota. Diagnosis and monitoring of IBD is heavily reliant on endoscopy, which is invasive and does not provide information regarding specific mediators. This review describes recent developments in imaging of IBD with a focus on positron emission tomography (PET) and single-photon emission computed tomography (SPECT) of inflammatory mediators, and how these developments may be applied to the microbiota.
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http://dx.doi.org/10.3390/ijms19092471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164364PMC
August 2018

Colonic migrating motor complexes are inhibited in acute tri-nitro benzene sulphonic acid colitis.

PLoS One 2018 22;13(6):e0199394. Epub 2018 Jun 22.

Adelaide Medical School, University of Adelaide, Adelaide, Australia.

Background: Inflammatory Bowel Disease (IBD) is characterized by overt inflammation of the intestine and is typically accompanied by symptoms of bloody diarrhea, abdominal pain and cramping. The Colonic Migrating Motor Complex (CMMC) directs the movement of colonic luminal contents over long distances. The tri-nitrobenzene sulphonic acid (TNBS) model of colitis causes inflammatory damage to enteric nerves, however it remains to be determined whether these changes translate to functional outcomes in CMMC activity. We aimed to visualize innate immune cell infiltration into the colon using two-photon laser scanning intra-vital microscopy, and to determine whether CMMC activity is altered in the tri-nitro benzene sulphonic (TNBS) model of colitis.

Methods: Epithelial barrier permeability was compared between TNBS treated and healthy control mice in-vitro and in-vivo. Innate immune activation was determined by ELISA, flow cytometry and by 2-photon intravital microscopy. The effects of TNBS treatment and IL-1β on CMMC function were determined using a specialized organ bath.

Results: TNBS colitis increased epithelial barrier permeability in-vitro and in-vivo. Colonic IL-1β concentrations, colonic and systemic CD11b+ cell infiltration, and the number of migrating CD11b+ cells on colonic blood vessels were all increased in TNBS treated mice relative to controls. CMMC frequency and amplitude were inhibited in the distal and mid colon of TNBS treated mice. CMMC activity was not altered by superfusion with IL-1β.

Conclusions: TNBS colitis damages the epithelial barrier and increases innate immune cell activation in the colon and systemically. Innate cell migration into the colon is readily identifiable by two-photon intra-vital microscopy. CMMC are inhibited by inflammation, but this is not due to direct effects of IL-1β.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199394PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014673PMC
April 2019

Role of toll-like receptor 4 (TLR4)-mediated interleukin-6 (IL-6) production in chemotherapy-induced mucositis.

Cancer Chemother Pharmacol 2018 07 29;82(1):31-37. Epub 2018 May 29.

Adelaide Medical School, The University of Adelaide, Adelaide, Australia.

Despite significant advances in our ability to treat cancer, cytotoxic chemotherapy continues to be the mainstay treatment for many solid tumours. Chemotherapy is commonly associated with a raft of largely manageable adverse events; however, gastrointestinal (GI) toxicity (also termed mucositis) remains a significant challenge with little in the way of preventative and therapeutic options. The inability to manage GI complications likely reflects our incomplete understanding of its aetiology and the idiosyncrasies of each chemotherapeutic agent. This review highlights aims to provide a narrative for the involvement of Toll-like receptor (TLR4) in the development of chemotherapy-induced GI mucositis, an already emerging theme within this field. Particular focus will be placed upon the signalling interaction between TLR4 and interleukin (IL)-6. This parallels recent preclinical findings showing that TLR4 knockout mice, which are protected from developing severe GI mucositis, completely lack an IL-6 response. As such, we suggest that this signalling pathway presents as a novel mechanism with potential for therapeutic intervention.
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http://dx.doi.org/10.1007/s00280-018-3605-9DOI Listing
July 2018

Prophylactic probiotics for cancer therapy-induced diarrhoea: a meta-analysis.

Curr Opin Support Palliat Care 2018 06;12(2):187-197

Adelaide Medical School, The University of Adelaide.

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.
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http://dx.doi.org/10.1097/SPC.0000000000000338DOI Listing
June 2018

Advances in the understanding and management of mucositis during stem cell transplantation.

Curr Opin Support Palliat Care 2017 Dec;11(4):341-346

aAdelaide Medical School, University of Adelaide bCentre for Nutrition and Gastrointestinal Disease, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.

Purpose Of Review: Mucositis is a severe and common side effect of anticancer treatments, with an incidence of between 40 and 80% depending on the cytotoxic regimen used. The most profound mucositis burden is experienced during conditioning regimens for hematopoietic stem cell transplant (HSCT), where the use of highly mucotoxic agents with or without total body irradiation leads to serious damage throughout the alimentary tract. Currently, the assessment and management of both oral and gastrointestinal mucositis lack authoritative guideline, with recommendations only achieved in narrow clinical scenarios. This review provides a brief overview of current management guidelines for mucositis in both adult and pediatric patients receiving HSCT, highlights recent advances in mucositis prevention and discusses future research avenues.

Recent Findings: The Multinational Association of Supportive Care in Cancer and International Society for Oral Oncology (MASCC/ISOO) guidelines for the prevention of mucositis in HSCT are scarce, with low level laser therapy (photobiomodulation) and palifermin only recommended for oral mucositis. Loperamide and octreotide remain gold-standard for the treatment of diarrhea, despite poor efficacy. Although several interventions have been trialled in pediatric cohorts, no recommendations currently exist for children receiving high-dose chemotherapy or total body irradiation for HSCT.

Summary: HSCT continues to be associated with mucositis, which impacts on patients' ability and willingness to receive engraftment, and worsens clinical outcome. Research into the prevention and treatment of mucositis in this setting remains limited, with an overwhelming amount of small, single-center studies that fail to achieve a sufficient level of evidence that warrant recommendation(s). As such, our ability to manage mucotoxic side effects of high-dose chemotherapy and irradiation is limited, particularly in children.
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http://dx.doi.org/10.1097/SPC.0000000000000310DOI Listing
December 2017

Dacomitinib-induced diarrhea: Targeting chloride secretion with crofelemer.

Int J Cancer 2018 01 28;142(2):369-380. Epub 2017 Sep 28.

Discipline of Physiology, Adelaide Medical School, University of Adelaide, Australia.

Dacomitinib, an irreversible small-molecule pan-ErbB TKI, has a high incidence of diarrhea, which has been suggested to be due to chloride secretory mechanisms. Based on this hypothesis, crofelemer, an antisecretory agent may be an effective intervention. T84 monolayers were treated with 1 µM dacomitinib and 10 µM crofelemer, and mounted into Ussing chambers for electrogenic ion analysis. Crofelemer attenuated increases in chloride secretion in cells treated with dacomitinib. Albino Wistar rats (n = 48) were treated with 7.5 mg/kg dacomitinib and/or 25 mg/kg crofelemer via oral gavage for 21 days. Crofelemer significantly worsened dacomitinib-induced diarrhea (p = 0.0003), and did not attenuate weight loss (p < 0.0001). Sections of the ileum and colon were mounted into Ussing chambers, and secretory processes analyzed. This indicated that crofelemer lost its anti-secretory action in the presence of dacomitinib in this model. Mass spectrometry revealed that crofelemer did not change serum concentration of dacomitinib. Serum FITC dextran levels indicated that crofelemer was unable to attenuate dacomitinib-induced barrier dysfunction. Tight junction proteins were visualized with immunofluorescence. Qualitative analysis showed dacomitinib induced proteolysis of ZO-1 and occludin, and internalization of claudin-1, which was not attenuated by crofelemer. Detailed histopathological analysis showed that crofelemer was unable to attenuate dacomitinib-induced ileal damage. Crofelemer worsened dacomitinib-induced diarrhea, suggesting that antisecretory drug therapy may be ineffective in this setting.
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http://dx.doi.org/10.1002/ijc.31048DOI Listing
January 2018

Determining risk of severe gastrointestinal toxicity based on pretreatment gut microbial community in patients receiving cancer treatment: a new predictive strategy in the quest for personalized cancer medicine.

Curr Opin Support Palliat Care 2017 06;11(2):125-132

aAdelaide Medical School, University of Adelaide bCentre for Nutrition and Gastrointestinal Diseases, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia cUniversity Medical Centre Groningen, Groningen, The Netherlands.

Purpose Of Review: Currently, our ability to accurately predict a patient's risk of developing severe gastrointestinal toxicity from their cancer treatment is limited. Risk stratification continues to rely on traditional patient-related and treatment-related factors including age, ethnicity, sex, comorbidities, genetics, agent, dose and schedule. Although informative, these crude measures continue to underestimate toxicity risk, and hence alternative methods of risk prediction must be investigated. Given the increasing focus on the gut microbiome in driving disease, this review will provide an overview of the current literature proposing the gut microbiome as a novel predictive tool for treatment-induced gastrointestinal toxicity.

Recent Findings: Predictive gut microbial phenotypes have been identified for gastrointestinal toxicity induced by radiation and the checkpoint blocker, Ipilimumab. Each study employed slightly different methods of gut microbiome assessment; however, in all cases, separation of toxic versus nontoxic patients was achieved. No studies have investigated chemotherapy-induced gastrointestinal toxicity.

Summary: The gut microbiome offers an exciting new method of risk stratification for gastrointestinal toxicity. This would enable identification of high-risk patients prior to treatment, enabling tailored treatment regimens based on personalized risk assessment and the proactive provision of supportive care measures. Based on the plasticity of the gut microbiome, methods of risk mitigation may be investigated.
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http://dx.doi.org/10.1097/SPC.0000000000000265DOI Listing
June 2017

Dacomitinib-induced diarrhoea is associated with altered gastrointestinal permeability and disruption in ileal histology in rats.

Int J Cancer 2017 06 28;140(12):2820-2829. Epub 2017 Mar 28.

Cancer Treatment Toxicities Group, Adelaide Medical School, University of Adelaide, Adelaide, Australia.

Dacomitinib-an irreversible pan-ErbB tyrosine kinase inhibitor (TKI)-causes diarrhoea in 75% of patients. Dacomitinib-induced diarrhoea has not previously been investigated and the mechanisms remain poorly understood. The present study aimed to develop an in-vitro and in-vivo model of dacomitinib-induced diarrhoea to investigate underlying mechanisms. T84 cells were treated with 1-4 μM dacomitinib and resistance and viability were measured using transepithelial electrical resistance (TEER) and XTT assays. Rats were treated with 7.5 mg/kg dacomitinib daily via oral gavage for 7 or 21 days (n = 6/group). Weights, and diarrhoea incidence were recorded daily. Rats were administered FITC-dextran 2 hr before cull, and serum levels of FITC-dextran were measured and serum biochemistry analysis was conducted. Detailed histopathological analysis was conducted throughout the gastrointestinal tract. Gastrointestinal expression of ErbB1, ErbB2 and ErbB4 was analysed using RT-PCR. The ileum and the colon were analysed using multiplex for expression of various cytokines. T84 cells treated with dacomitinib showed no alteration in TEER or cell viability. Rats treated with dacomitinib developed severe diarrhoea, and had significantly lower weight gain. Further, dacomitinib treatment led to severe histopathological injury localised to the ileum. This damage coincided with increased levels of MCP1 in the ileum, and preferential expression of ErbB1 in this region compared to all other regions. This study showed dacomitinib induces severe ileal damage accompanied by increased MCP1 expression, and gastrointestinal permeability in rats. The histological changes were most pronounced in the ileum, which was also the region with the highest relative expression of ErbB1.
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http://dx.doi.org/10.1002/ijc.30699DOI Listing
June 2017

Routine assessment of the gut microbiome to promote preclinical research reproducibility and transparency.

Gut 2017 10 9;66(10):1869-1871. Epub 2017 Jan 9.

Division of Health Sciences, University of South Australia, Adelaide, South Australia.

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http://dx.doi.org/10.1136/gutjnl-2016-313486DOI Listing
October 2017

Potential safety concerns of TLR4 antagonism with irinotecan: a preclinical observational report.

Cancer Chemother Pharmacol 2017 02 23;79(2):431-434. Epub 2016 Dec 23.

Discipline of Anatomy and Pathology, Adelaide Medical School, University of Adelaide, Adelaide, Australia.

Purpose: Irinotecan-induced gut toxicity is mediated in part by Toll-Like receptor 4 (TLR4) signalling. The primary purpose of this preclinical study was to determine whether blocking TLR4 signalling by administering (-)-naloxone, a TLR4 antagonist, would improve irinotecan-induced gut toxicity. Our secondary aim was to determine the impact of (-)-naloxone on tumour growth.

Methods: Female Dark Agouti (DA) tumour-bearing rats were randomly assigned to four treatments (n = 6 in each); control, (-)-naloxone (100 mg/kg oral gavage at -2, 24, 48, and 72 h), irinotecan (175 mg/kg intraperitoneal at 0 h), and (-)-naloxone and irinotecan. Body weight and tumour growth were measured daily, and diarrhoea incidence and severity were recorded 4× per day up to 72 h post-treatment.

Results: At 72 h, all rats that received irinotecan lost weight compared to controls (p = 0.03). In addition, rats that received (-)-naloxone and irinotecan lost significantly more weight compared to controls (p < 0.005) than irinotecan only compared to controls (p = 0.001). (-)-Naloxone did not attenuate irinotecan-induced severe diarrhoea at 48 and 72 h. Finally, (-)-naloxone caused increased tumour growth compared to control at 72 h (p < 0.05) and significantly reduced the efficacy of irinotecan (p = 0.001).

Conclusions: (-)-Naloxone in our preclinical model was unable to block irinotecan-induced gut toxicity and decreased the efficacy of irinotecan. As (-)-naloxone-oxycodone combination is used for cancer pain, this may present a potential safety concern for patients receiving (-)-naloxone-oxycodone and irinotecan concurrently and requires further investigation.
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http://dx.doi.org/10.1007/s00280-016-3223-3DOI Listing
February 2017

TLR4-Dependent Claudin-1 Internalization and Secretagogue-Mediated Chloride Secretion Regulate Irinotecan-Induced Diarrhea.

Mol Cancer Ther 2016 11 22;15(11):2767-2779. Epub 2016 Aug 22.

Discipline of Anatomy and Pathology, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.

We have previously shown increased intestinal permeability, to 4-kDa FITC-dextran, in BALB/c mice treated with irinotecan. Importantly, genetic deletion of Toll-like receptor 4 (TLR4; Tlr4) protected against loss of barrier function, indicating that TLR4 is critical in tight junction regulation. The current study aimed (i) to determine the molecular characteristics of intestinal tight junctions in wild-type and Tlr4 BALB/c mice and (ii) to characterize the secretory profile of the distal colon. Forty-two female wild-type and 42 Tlr4 BALB/c mice weighing between 18 and 25 g received a single 270 mg/kg [intraperitoneal (i.p.)] dose of irinotecan hydrochloride or vehicle control and were killed at 6, 24, 48, 72, and 96 hours. The secretory profile of the distal colon, following carbachol and forksolin, was assessed using Ussing chambers at all time points. Tight junction integrity was assessed at 24 hours, when peak intestinal permeability and diarrhea were reported, using immunofluorescence, Western blotting, and RT-PCR. Irinotecan caused internalization of claudin-1 with focal lesions of ZO-1 and occludin proteolysis in the ileum and colon of wild-type mice. Tlr4 mice maintained phenotypically normal tight junctions. Baseline conductance, a measure of paracellular permeability, was increased in irinotecan-treated wild-type mice at 24 hours (53.19 ± 6.46 S/cm; P = 0.0008). No change was seen in Tlr4 mice. Increased carbachol-induced chloride secretion was seen in irinotecan-treated wild-type and Tlr4 mice at 24 hours (wild-type: 100.35 ± 18.37 μA/cm; P = 0.022; Tlr4: 102.72 ± 18.80 μA/cm; P = 0.023). Results suggest that TLR4-dependent claudin-1 internalization and secondary anion secretion contribute to irinotecan-induced diarrhea. Mol Cancer Ther; 15(11); 2767-79. ©2016 AACR.
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http://dx.doi.org/10.1158/1535-7163.MCT-16-0330DOI Listing
November 2016

Cytokine-mediated blood brain barrier disruption as a conduit for cancer/chemotherapy-associated neurotoxicity and cognitive dysfunction.

Int J Cancer 2016 Dec 15;139(12):2635-2645. Epub 2016 Jul 15.

Brigham and Women's Hospital, Boston, MA.

Neurotoxicity is a common side effect of chemotherapy treatment, with unclear molecular mechanisms. Clinical studies suggest that the most frequent neurotoxic adverse events affect memory and learning, attention, concentration, processing speeds and executive function. Emerging preclinical research points toward direct cellular toxicity and induction of neuroinflammation as key drivers of neurotoxicity and subsequent cognitive impairment. Emerging data now show detectable levels of some chemotherapeutic agents within the CNS, indicating potential disruption of blood brain barrier integrity or transport mechanisms. Blood brain barrier disruption is a key aspect of many neurocognitive disorders, particularly those characterized by a proinflammatory state. Importantly, many proinflammatory mediators able to modulate the blood brain barrier are generated by tissues and organs that are targets for chemotherapy-associated toxicities. This review therefore aims to explore the hypothesis that peripherally derived inflammatory cytokines disrupt blood brain barrier permeability, thereby increasing direct access of chemotherapeutic agents into the CNS to facilitate neuroinflammation and central neurotoxicity.
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http://dx.doi.org/10.1002/ijc.30252DOI Listing
December 2016

Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms.

Mol Cancer Ther 2016 06 29;15(6):1376-86. Epub 2016 Mar 29.

Discipline of Physiology, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.

Strong epidemiological data indicate that chemotherapy-induced gut toxicity and pain occur in parallel, indicating common underlying mechanisms. We have recently outlined evidence suggesting that TLR4 signaling may contribute to both side effects. We therefore aimed to determine if genetic deletion of TLR4 improves chemotherapy-induced gut toxicity and pain. Forty-two female wild-type (WT) and 42 Tlr4 null (-/-) BALB/c mice weighing between 18 and 25 g (10-13 weeks) received a single 270 mg/kg (i.p.) dose of irinotecan hydrochloride or vehicle control and were killed at 6, 24, 48, 72, and 96 hours. Bacterial sequencing was conducted on cecal samples of control animals to determine the gut microbiome profile. Gut toxicity was assessed using validated clinical and histopathologic markers, permeability assays, and inflammatory markers. Chemotherapy-induced pain was assessed using the validated rodent facial grimace criteria, as well as immunologic markers of glial activation in the lumbar spinal cord. TLR4 deletion attenuated irinotecan-induced gut toxicity, with improvements in weight loss (P = 0.0003) and diarrhea (P < 0.0001). Crypt apoptosis was significantly decreased in BALB/c-Tlr4(-/-billy) mice (P < 0.0001), correlating with lower mucosal injury scores (P < 0.005). Intestinal permeability to FITC-dextran (4 kDa) and LPS translocation was greater in WT mice than in BALB/c-Tlr4(-/-billy) (P = 0.01 and P < 0.0001, respectively). GFAP staining in the lumbar spinal cord, indicative of astrocytic activation, was increased at 6 and 72 hours in WT mice compared with BALB/c-Tlr4(-/-billy) mice (P = 0.008, P = 0.01). These data indicate that TLR4 is uniquely positioned to mediate irinotecan-induced gut toxicity and pain, highlighting the possibility of a targetable gut/CNS axis for improved toxicity outcomes. Mol Cancer Ther; 15(6); 1376-86. ©2016 AACR.
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http://dx.doi.org/10.1158/1535-7163.MCT-15-0990DOI Listing
June 2016

A novel in vitro platform for the study of SN38-induced mucosal damage and the development of Toll-like receptor 4-targeted therapeutic options.

Exp Biol Med (Maywood) 2016 07 31;241(13):1386-94. Epub 2016 Mar 31.

Discipline of Physiology, School of Medicine, University of Adelaide, South Australia 5005, Australia.

Tight junction and epithelial barrier disruption is a common trait of many gastrointestinal pathologies, including chemotherapy-induced gut toxicity. Currently, there are no validated in vitro models suitable for the study of chemotherapy-induced mucosal damage that allow paralleled functional and structural analyses of tight junction integrity. We therefore aimed to determine if a transparent, polyester membrane insert supports a polarized T84 monolayer with the phenotypically normal tight junctions. T84 cells (passage 5-15) were seeded into either 0.6 cm(2), 0.4 µm pore mixed-cellulose transwell hanging inserts or 1.12 cm(2), 0.4 µm pore polyester transwell inserts at varying densities. Transepithelial electrical resistance was measured daily to assess barrier formation. Immunofluoresence for key tight junction proteins (occludin, zonular occludens-1, claudin-1) and transmission electron microscopy were performed to assess tight junction integrity, organelle distribution, and polarity. Reverse transcription-polymerase chain reaction was performed to determine expression of toll-like receptor 4 (TLR4). Liquid chromatography was also conducted to assess SN38 degradation in this model. Polyester membrane inserts support a polarized T84 phenotype with functional tight junctions in vitro. Transmission electron microscopy indicated polarity, with apico-laterally located tight junctions. Immunofluorescence showed membranous staining for all tight junction proteins. No internalization was evident. T84 cells expressed TLR4, although this was significantly lower than levels seen in HT29 cells (P = .0377). SN38 underwent more rapid degradation in the presence of cells (-76.04 ± 1.86%) compared to blank membrane (-48.39 ± 4.01%), indicating metabolic processes. Polyester membrane inserts provide a novel platform for paralleled functional and structural analysis of tight junction integrity in T84 monolayers. T84 cells exhibit the unique ability to metabolize SN38 as well as expressing TLR4, making this an excellent platform to study clinically relevant therapeutic interventions for SN38-induced mucosal damage by targeting TLR4.
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http://dx.doi.org/10.1177/1535370216640932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994924PMC
July 2016

Gastrointestinal toxicities of first and second-generation small molecule human epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer.

Curr Opin Support Palliat Care 2016 06;10(2):152-6

aSchool of Medicine, University of Adelaide bDivision of Health Sciences, University of South Australia, Adelaide, Australia.

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http://dx.doi.org/10.1097/SPC.0000000000000210DOI Listing
June 2016

Chemotherapy-induced gut toxicity and pain: involvement of TLRs.

Support Care Cancer 2016 May 19;24(5):2251-2258. Epub 2015 Nov 19.

Discipline of Physiology, School of Medicine, University of Adelaide, Adelaide, Australia.

Purpose: Chemotherapy-induced gut toxicity is associated with significant pain, and pain influences gut function. Toll-like receptors (TLRs) that regulate gut homeostasis are activated by tissue damage and microbes, and their altered expression following chemotherapy may change cellular responses. This study examined the interaction between chemotherapy-induced gut toxicity and pain and related these to gut TLR and glial fibrillary acidic protein (GFAP) expression.

Methods: Female tumor bearing Dark Agouti rats received irinotecan (175 mg/kg, n = 34) or vehicle (n = 5) and were assessed over 120 h for gut toxicity (diarrhea, weight loss), pain (facial), and GFAP, TLR2, 4, 5, and 9 gut expression.

Results: Irinotecan caused diarrhea (72 % of animals grade ≥ 1), weight loss (11.1 ± 6.6 %, P < 0.0001), and pain (5 (0-5), P < 0.0001) all peaking at 72 h. Higher pain scores were observed in rats with diarrhea versus those without: median (range) of 2.0 (0-5) versus 0 (0-5), P = 0.01. Irinotecan also caused a decrease in TLR4 and 5, and an increase in GFAP expression in jejuna crypt at 96 and 120 h (all P < 0.05); with lower TLR4 expression associated with lower pain (P = 0.012).

Conclusions: The association between gut toxicity and pain suggests these toxicities are linked, possibly via TLR-mediated inflammatory pathways. Further, as TLR4 and 5 expression was absent during recovery in the jejuna and GFAP expression was increased in the jejuna, this implies expression of these may be critical in the healing phase following chemotherapy. Detailed studies of gut TLRs and GFAP are now warranted.
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http://dx.doi.org/10.1007/s00520-015-3020-2DOI Listing
May 2016
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