ORCID Profile
0000-0002-6613-3661
Current Organisations
Adelaide Univesity
,
University of Adelaide
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Publisher: S. Karger AG
Date: 2018
DOI: 10.1159/000495470
Abstract: b i Background: /i /b The common cytotoxic mechanisms that underpin chemoefficacy and toxicity have h ered 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. b i Objectives: /i /b 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. b i Methods: /i /b Female tumor-bearing Dark Agouti rats ( i n /i = 90) were ided 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. b i Results: /i /b 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 ( i /i = 0.003 vs. vehicle) but did not enhance the efficacy of MTX. b i Conclusions: /i /b 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.
Publisher: Springer Science and Business Media LLC
Date: 26-06-2020
Publisher: MDPI AG
Date: 25-06-2018
DOI: 10.20944/PREPRINTS201806.0390.V1
Abstract: Inflammatory Bowel Disease (IBD) is characterized by chronic remitting and relapsing inflammation of the lower gastrointestinal tract. The etiology underlying IBD remains unknown but is thought to involve a hypersensitive immune response to environmental antigen, including the microbiota. Diagnosis and monitoring of disease 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 PET and SPECT imaging of inflammatory mediators, and how this may be applied to the microbiota.
Publisher: MDPI AG
Date: 05-05-2023
DOI: 10.3390/IJMS24098274
Abstract: Oral mucositis (OM) is a common and impactful toxicity of standard cancer therapy, affecting up to 80% of patients. Its aetiology centres on the initial destruction of epithelial cells and the increase in inflammatory signals. These changes in the oral mucosa create a hostile environment for resident microbes, with oral infections co-occurring with OM, especially at sites of ulceration. Increasing evidence suggests that oral microbiome changes occur beyond opportunistic infection, with a growing appreciation for the potential role of the microbiome in OM development and severity. This review collects the latest articles indexed in the PubMed electronic database which analyse the bacterial shift through 16S rRNA gene sequencing methodology in cancer patients under treatment with oral mucositis. The aims are to assess whether changes in the oral and gut microbiome causally contribute to oral mucositis or if they are simply a consequence of the mucosal injury. Further, we explore the emerging role of a patient’s microbial fingerprint in OM development and prediction. The maintenance of resident bacteria via microbial target therapy is under constant improvement and should be considered in the OM treatment.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2013
Publisher: MDPI AG
Date: 17-10-2022
DOI: 10.3390/MICROORGANISMS10102048
Abstract: The gut microbiota has emerged as a key modulator of cancer treatment responses in terms of both efficacy and toxicity. This effect is clearly mediated by processes impacting the activation and modulation of immune responses. More recently, the ability to regulate chemotherapeutic drug metabolism has also emerged as a key driver of response, although the direct mechanisms have yet to be fully elucidated. Through fermentation, the gut microbiota can produce several types of metabolites, including short-chain fatty acids (SCFAs). SCFAs play an important role in maintaining epithelial barrier functions and intestinal homeostasis, with recent work suggesting that SCFAs can modulate response to cancer treatments and influence both anti-tumor immune response and inflammatory-related side effects. In this review, we will discuss the importance of SCFAs and their implications for cancer treatment response and toxicities.
Publisher: MDPI AG
Date: 21-08-2018
DOI: 10.3390/IJMS19092471
Abstract: 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.
Publisher: MDPI AG
Date: 04-10-2021
DOI: 10.3390/BIOMEDICINES9101389
Abstract: 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.
Publisher: BMJ
Date: 09-01-2017
Publisher: Elsevier BV
Date: 2023
Publisher: Wiley
Date: 30-07-2020
DOI: 10.1002/JCP.29976
Publisher: Springer Science and Business Media LLC
Date: 20-04-2021
DOI: 10.1007/S00280-021-04273-7
Abstract: Conditioning therapy with high-dose melphalan (HDM) is associated with a high risk of gut toxicity, fever and infections in haematopoietic stem cell transplant (HSCT) recipients. However, validated preclinical models that adequately reflect clinical features of melphalan-induced toxicity are not available. We therefore aimed to develop a novel preclinical model of melphalan-induced toxicity that reflected well-defined clinical dynamics, as well as to identify targetable mechanisms that drive intestinal injury. Male Wistar rats were treated with 4–8 mg/kg melphalan intravenously. The primary endpoint was plasma citrulline. Secondary endpoints included survival, weight loss, diarrhea, food/water intake, histopathology, body temperature, microbiota composition (16S sequencing) and bacterial translocation. Melphalan 5 mg/kg caused self-limiting intestinal injury, severe neutropenia and fever while impairing the microbial metabolome, prompting expansion of enteric pathogens. Intestinal inflammation was characterized by infiltration of polymorphic nuclear cells in the acute phases of mucosal injury, driving derangement of intestinal architecture. Ileal atrophy prevented bile acid reabsorption, exacerbating colonic injury via microbiota-dependent mechanisms. We developed a novel translational model of melphalan-induced toxicity, which has excellent homology with the well-known clinical features of HDM transplantation. Application of this model will accelerate fundamental and translational study of melphalan-induced toxicity, with the clinical parallels of this model ensuring a greater likelihood of clinical success.
Publisher: Research Square Platform LLC
Date: 14-10-2020
DOI: 10.21203/RS.3.RS-89422/V1
Abstract: Background: Mucosal barrier injury (MBI) is a recognized risk factor for blood stream infection (BSI) in people undergoing chemotherapy, permitting expansion and translocation of enteric pathobionts a phenomenon now clinically referred to as MBI-associated laboratory-confirmed BSI. Although recognized to originate from endogenous gastrointestinal sources, MBI-associated BSI continue to be treated with antibiotics a counterintuitive approach that may increase infection risk by depletion of the host microbiome. While this point has been argued in numerous clinical studies and opinion pieces, there are few data describing mechanistic strategies to decrease MBI-associated BSI, reflecting a lack of translationally robust preclinical models. Here, we report on a new translational model of MBI caused by the chemotherapeutic drug, melphalan. We aimed to identify candidate pathways to strengthen the mucosal barrier and prevent infection, prompting new antibiotic stewardship initiatives. Results: Melphalan caused dose-dependent, systemic toxicity characterized by severe neutropenia, self-limiting intestinal injury, inflammation and biphasic fever, all of which were clinically and molecularly consistent with the dynamics of melphalan conditioning. The fecal microbiome following melphalan was depleted in richness and commensal taxa, impairing colonization resistance and the microbial metabolome and prompting expansion of enteric pathogens. Breakdown of the intestinal barrier was initiated by melphalan and exacerbated by mucotoxic bile acids.Conclusions: MBI-associated BSI is simply a form of collateral damage resulting from breakdown of the gastrointestinal microenvironment and self-perpetuating injury. Efforts to intervene early in these sequelae are therefore of great clinical significance to restrict antibiotic use and mitigate their detrimental consequences on treatment outcomes and antibiotic resistance. Our data support interventions targeting the host microbiome and metabolome due to its ubiquitous control of inflammation, mucosal injury, bile acid transformation all of which contribute to infection risk in cancer.
Publisher: MDPI AG
Date: 29-12-2020
DOI: 10.3390/BIOM11010034
Abstract: 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 s les 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.
Publisher: MDPI AG
Date: 25-03-2022
DOI: 10.3390/MICROORGANISMS10040713
Abstract: Despite significant advances in the treatment of Chronic Myeloid and Acute Lymphoblastic Leukaemia (CML and ALL, respectively), disease progression and relapse remain a major problem. Growing evidence indicates the loss of immune surveillance of residual leukaemic cells as one of the main contributors to disease recurrence and relapse. More recently, there was an appreciation for how the host’s gut microbiota predisposes to relapse given its potent immunomodulatory capacity. This is especially compelling in haematological malignancies where changes in the gut microbiota have been identified after treatment, persisting in some patients for years after the completion of treatment. In this hypothesis-generating review, we discuss the interaction between the gut microbiota and treatment responses, and its capacity to influence the risk of relapse in both CML and ALL We hypothesize that the gut microbiota contributes to the creation of an immunosuppressive microenvironment, which promotes tumour progression and relapse.
Publisher: Elsevier BV
Date: 08-2021
DOI: 10.1016/J.EJCA.2021.05.015
Abstract: 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. 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. 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.
Publisher: Springer Science and Business Media LLC
Date: 23-05-2023
DOI: 10.1038/S41419-023-05850-9
Abstract: 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 sychological 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 (cm 3 /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 ersity 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.
Publisher: S. Karger AG
Date: 2021
DOI: 10.1159/000519200
Abstract: b i Introduction: /i /b Toll-like receptor 4 (TLR4) is a highly conserved immunosurveillance protein of innate immunity, displaying well-established roles in homeostasis and intestinal inflammation. Current evidence shows complex relationships between TLR4 activation, maintenance of health, and disease progression however, it commonly overlooks the importance of site-specific TLR4 expression. This omission has the potential to influence translation of results as previous evidence shows the differing and distinct roles that TLR4 exhibits are dependent on its spatiotemporal expression. b i Methods: /i /b An intestinal epithelial TLR4 conditional knockout (KO) mouse line ( i Tlr4 /i sup i ΔIEC /i /sup , i n /i = 6–8) was utilized to dissect the contribution of epithelial TLR4 expression to intestinal homeostasis with comparisons to wild-type (WT) ( i n /i = 5–7) counterparts. Functions of the intestinal barrier in the ileum and colon were assessed with tissue resistance in Ussing chambers. Molecular and structural comparisons in the ileum and colon were assessed via histological staining, expression of tight junction proteins (occludin and zonular occludin 1 [ZO-1]), and presence of CD11b-positive immune cells. b i Results: /i /b There was no impact of the intestinal epithelial TLR4 KO, with no differences in (1) tissue resistance–ileum (mean ± standard error of mean [SEM]): WT 22 ± 7.2 versus i Tlr4 /i sup i ΔIEC /i /sup 20 ± 5.6 (Ω × cm sup /sup ) i /i = 0.831, colon WT 30.8 ± 3.6 versus i Tlr4 /i sup i ΔIEC /i /sup 45.1 ± 9.5 i /i = 0.191 (2) histological staining (overall tissue structure) and (3) tight junction protein expression (% area stain, mean ± SEM)–ZO-1: ileum–WT 1.49 ± 0.155 versus i Tlr4 /i sup i ΔIEC /i /sup 1.17 ± 0.07, i /i = 0.09 colon–WT 1.36 ± 0.26 versus i Tlr4 /i sup i ΔIEC /i /sup 1.12 ± 0.18 i /i = 0.47 occludin: ileum–WT 1.07 ± 0.12 versus i Tlr4 /i sup i ΔIEC /i /sup 0.95 ± 0.13, i /i = 0.53 colon–WT 1.26 ± 0.26 versus i Tlr4 /i sup i ΔIEC /i /sup 1.02 ± 0.16 i /i = 0.45. CD11b-positive immune cells (% area stain, mean ± SEM) in the ileum were mildly decreased in WT mice: WT 0.14 ± 0.02 versus i Tlr4 /i sup i ΔIEC /i /sup 0.09 ± 0.01 i /i = 0.04. However, in the colon, there was no difference in CD11b-positive immune cells between strains: WT 0.53 ± 0.08 versus i Tlr4 /i sup i ΔIEC /i /sup 0.49 ± 0.08 i /i = 0.73. b i Conclusions: /i /b These data have 2 important implications. First, these data refute the assumption that epithelial TLR4 exerts physiological control of intestinal physiology and immunity in health. Second, and most importantly, these data support the use of the i Tlr4 /i sup i ΔIEC /i /sup line in future models interrogating health and disease, confirming no confounding effects of genetic manipulation.
Publisher: Springer Science and Business Media LLC
Date: 26-10-2023
No related grants have been discovered for Hannah Wardill.