27 research outputs found
GRAFT checklist
No full textA fillable checklist to enable easy use of the GRAFT recommendations for carrying out preclinical fecal microbiota transplant studiesSupplement to: Kate R. Secombe, Ghanyah H. Al-Qadami, Courtney B. Subramaniam,
Joanne M. Bowen, Jacqui Scott, Ysabella Z.A. Van Sebille, Matthew Snelson, Caitlin Cowan,
Gerard Clarke, Cassandra E. Gheorghe, John F. Cryan & Hannah R. Wardill (2021) Guidelines
for reporting on animal fecal transplantation (GRAFT) studies: recommendations from a
systematic review of murine transplantation protocols, Gut Microbes, 13:1, 1979878, DOI:
10.1080/19490976.2021.1979878<br
Irinotecan-induced gastrointestinal dysfunction and pain are mediated by common TLR4-dependent mechanisms
No full textPublished Online First March 29, 2016Abstract not availableHannah R. Wardill, Rachel J. Gibson, Ysabella Z.A. Van Sebille, Kate R. Secombe, Janet K. Coller, Imogen A. White, Jim Manavis, Mark R. Hutchinson, Vasiliki Staikopoulos, Richard M. Logan, and Joanne M. Bowe
TLR4-dependent claudin-1 internalization and secretagogue-mediated chloride secretion regulate irinotecan-induced diarrhea
No full textPublished OnlineFirst August 22, 2016Abstract not availableHannah R.Wardill, Joanne M. Bowen, Ysabella Z.A. Van Sebille, Kate R. Secombe, Janet K. Coller, Imogen A. Ball, Richard M. Logan, and Rachel J Gibso
GRAFT systematic review data
No full textData collected from systematic review used to generate GRAFT recommendation
Exploration of the gut microbiome as a predictive factor for cancer treatment-induced gastrointestinal toxicity
No full textGastrointestinal toxicity is a significant side effect of many cancer treatments. Characterised by diarrhoea, abdominal pain and bleeding, this toxicity can affect up to 80% of patients, depending on treatment regimen. Currently, there are no highly effective intervention strategies for the vast majority of people affected, thus more evidence is required to improve future management. This thesis focussed primarily on gastrointestinal toxicity stemming from two major types of cancer treatment. These are chemotherapy, the most common form of cancer treatment, and small molecule tyrosine kinase inhibitors (SM-TKIs), a class of targeted therapies, often used in combination with chemotherapy. There is a clear gap in knowledge in understanding how these different cancer treatments cause gastrointestinal toxicity, and how the population of microorganisms in the intestine, the gut microbiome, links to these responses. This thesis therefore aimed to investigate the role of the gut microbiome in influencing the development and exacerbation of gastrointestinal toxicity stemming from cancer treatment. This was investigated in three main sections. Firstly, I aimed to examine the interaction between the gut microbiome and the innate immune system (chiefly the innate immune receptor Toll-like receptor 4 (TLR4)), and determine how this interaction could be involved in the development of gastrointestinal toxicity following chemotherapy. In order to achieve this aim, I characterised the microbial composition of a TLR4 conditional knockout mouse model and assessed changes due to chemotherapy treatment. There were no clear differences in the microbiome of wild type and TLR4 conditional knockout mice. Secondly, I aimed to characterise the role of the gut microbiome in diarrhoea stemming from the SM-TKI treatment neratinib, which causes high levels of diarrhoea. I found that, in a pre-clinical model, neratinib treatment does cause changes to microbial composition, however it was unclear if these changes were a key driver of diarrhoea development or simply a side effect of this diarrhoea. Therefore I analysed diarrhoea development following an initial, antibiotic-induced perturbation, showing that addition of narrow-spectrum antibiotics caused a significant decrease in diarrhoea severity and timespan. Finally, I clinically appraised the use of the gut microbiome in predicting risk of cancer treatment-induced gastrointestinal toxicity in two defined patient cohorts. A retrospective cohort showed that participants who went on to develop diarrhoea had significantly lower amounts of the bacterial genera Blautia and significantly higher amounts of the genera Collinsella. A longitudinal study was then developed. Pilot results did not show clear microbial clustering based on diarrhoea status. The results of my thesis demonstrate the emerging role gut microbiome composition has on the development of diarrhoea following cancer treatment. However I was unable to definitively identify any particular bacterial type that is a key mediator of this effect. The results presented here however provide strong rationale for further research in this area using specific machine learning and metabolomic techniques to identify compositional features that may be important in accurately predicting diarrhoea development following cancer treatment.Thesis (Ph.D.) -- University of Adelaide, School of Biomedicine, 202
Diarrhea Induced by Small Molecule Tyrosine Kinase Inhibitors Compared With Chemotherapy: Potential Role of the Microbiome.
No full textSmall molecule receptor tyrosine kinase inhibitors (SM-TKIs) are among a group of targeted cancer therapies, intended to be more specific to cancer cells compared with treatments, such as chemotherapy, hence reducing adverse events. Unfortunately, many patients report high levels of diarrhea, the pathogenesis of which remains under investigation. In this article, we compare the current state of knowledge of the pathogenesis of chemotherapy-induced diarrhea (CID) in comparison to SM-TKI–induced diarrhea, and investigate how a similar research approach in both areas may be beneficial. To this end, we review evidence that both treatment modalities may interact with the gut microbiome, and as such the microbiome should be investigated for its ability to reduce the risk of diarrhea.Kate R. Secombe, Ysabella Z. A. Van Sebille, Bronwen J. Mayo, Janet K. Coller, Rachel J. Gibson, and Joanne M. Bowe
Dacomitinib‐induced diarrhoea is associated with altered gastrointestinal permeability and disruption in ileal histology in rats
No full textLink to a related website: https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ijc.30699, Open Access via UnpaywallDacomitinib-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.Ysabella Z.A. Van Sebille, Rachel J. Gibson, Hannah R. Wardill, Kate R. Secombe, Imogen A. Ball, Dorothy M.K. Keefe, John W. Finnie, Joanne M. Bowe
The GLP-2 Analogue Elsiglutide Reduces Diarrhoea Caused by the Tyrosine Kinase Inhibitor Lapatinib in Rats
No full textPurpose: Lapatinib is a small molecule tyrosine kinase inhibitor used to treat breast cancer, often in combination with chemotherapy. Diarrhoea commonly occurs in up to 78% of patients undertaking lapatinib treatment. The mechanism of this diarrhoea is currently unknown. Elsiglutide is a GLP-2 analogue known to increase cell proliferation and reduce apoptosis in the intestine. Methods: We used a previously developed rat model of lapatinib-induced diarrhoea to determine if co-treatment with elsiglutide was able to reduce diarrhoea caused by lapatinib. Additionally, we analysed the caecal microbiome of these rats to assess changes in the microbiome due to lapatinib. Results: Rats treated with lapatinib and elsiglutide had less severe diarrhoea than rats treated with lapatinib alone. Serum lapatinib levels, blood biochemistry, myeloperoxidase levels and serum limulus amebocyte lysate levels were not significantly different between groups. Rats treated with lapatinib alone had significantly higher histopathological damage in the ileum than vehicle controls. This increase was not seen in rats also receiving elsiglutide. Rats receiving lapatinib alone had lower microbial diversity than rats who also received elsiglutide. Conclusions: Elsiglutide was able to reduce diarrhoea from lapatinib treatment. This does not appear to be via reduction in inflammation or barrier permeability, and may be due to thickening of mucosa, leading to increased surface area for fluid absorption in the distal small intestine. Microbial changes seen in this study require further research to fully elucidate their role in the development of diarrhoea.Bronwen J. Mayo, Kate R. Secombe, Anthony D. Wignall, Emma Bateman, Daniel Thorpe, Claudio Pietra, Dorothy M. Keefe, Joanne M. Bowe
A novel in vitro platform for the study of SN38-induced mucosal damage and the development of Toll-like receptor 4-targeted therapeutic options
No full textData source: Supplemental material, http://journals.sagepub.com/doi/suppl/10.1177/1535370216640932
Link to a related website: http://europepmc.org/articles/pmc4994924?pdf=render, Open Access via UnpaywallTight 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.Hannah R Wardill, Rachel J Gibson, Ysabella ZA Van Sebille, Kate R Secombe, Richard M Logan, and Joanne M Bowe
Exercise and the gut microbiome: implications for supportive care in cancer
No full textPurpose: Growing recognition of the gut microbiome as an infuential modulator of cancer treatment efcacy and toxicity has led to the emergence of clinical interventions targeting the microbiome to enhance cancer and health outcomes. The highly modifable nature of microbiota to endogenous, exogenous, and environmental inputs enables interventions to promote resilience of the gut microbiome that have rapid efects on host health, or response to cancer treatment. While diet, probiotics, and faecal microbiota transplant are primary avenues of therapy focused on restoring or protecting gut function in people undergoing cancer treatment, the role of physical activity and exercise has scarcely been examined in this population. Methods: A narrative review was conducted to explore the nexus between cancer care and the gut microbiome in the context of physical activity and exercise as a widely available and clinically efective supportive care strategy used by cancer survivors. Results: Exercise can facilitate a more diverse gut microbiome and functional metabolome in humans; however, most physical activity and exercise studies have been conducted in healthy or athletic populations, primarily using aerobic exercise modalities. A scarcity of exercise and microbiome studies in cancer exists. Conclusions: Exercise remains an attractive avenue to promote microbiome health in cancer survivors. Future research should elucidate the various infuences of exercise modalities, intensities, frequencies, durations, and volumes to explore doseresponse relationships between exercise and the gut microbiome among cancer survivors, as well as multifaceted approaches (such as diet and probiotics), and examine the influences of exercise on the gut microbiome and associated symptom burden prior to, during, and following cancer treatment.Nicolas H. Hart, Matthew P. Wallen, Morgan J. Farley, Darren Haywood, Alexander N. Boytar, Kate Secombe, Ria Joseph, Raymond J. Chan, Marlou-Floor Kenkhuis, Laurien M. Bufart, Tina L. Skinner, Hannah R. Wardil
