20 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
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
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
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
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
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
Updated perspectives on the contribution of the microbiome to the pathogenesis of mucositis using the MASCC/ISOO framework
No full textAdvances in the treatment of cancer have significantly improved mortality rates; however, this has come at a cost, with many treatments still limited by their toxic side effects. Mucositis in both the mouth and gastrointestinal tract is common following many anti-cancer agents, manifesting as ulcerative lesions and associated symptoms throughout the alimentary tract. The pathogenesis of mucositis was first defined in 2004 by Sonis, and almost 20 years on, the model continues to be updated reflecting ongoing research initiatives and more sophisticated analytical techniques. The most recent update, published by the Multinational Association for Supportive Care in Cancer and the International Society for Oral Oncology (MASCC/ISOO), highlights the numerous co-occurring events that underpin mucositis development. Most notably, a role for the ecosystem of microorganisms that reside throughout the alimentary tract (the oral and gut microbiota) was explored, building on initial concepts proposed by Sonis. However, many questions remain regarding the true causal contribution of the microbiota and associated metabolome. This review aims to provide an overview of this rapidly evolving area, synthesizing current evidence on the microbiota’s contribution to mucositis development and progression, highlighting (i) components of the 5-phase model where the microbiome may be involved, (ii) methodological challenges that have hindered advances in this area, and (iii) opportunities for intervention.</p
SCFA biotherapy delays diabetes in humanized gnotobiotic mice by remodeling mucosal homeostasis and metabolome
No full textType 1 diabetes (T1D) is linked to an altered gut microbiota characterized by reduced short-chain fatty acid (SCFA) production. Oral delivery of a SCFA-yielding biotherapy in adults with T1D was followed by increased SCFAs, altered gut microbiota and immunoregulation, as well as delaying diabetes in preclinical models. Here, we show that SCFA-biotherapy in humans is accompanied by remodeling of the gut proteome and mucosal immune homeostasis. Metabolomics showed arginine, glutamate, nucleotide and tryptophan metabolism were enriched following the SCFA-biotherapy, and found metabolites that correlated with glycemic control. Fecal microbiota transfer demonstrated that the microbiota of SCFA-responders delayed diabetes progression in humanized gnotobiotic mice. The protected mice increased similar metabolite pathways to the humans including producing aryl-hydrocarbon receptor ligands and reducing inflammatory mucosal immunity and increasing IgA production in the gut. These data demonstrate that a potent SCFA immunomodulator promotes multiple beneficial pathways and supports targeting the microbiota as an approach against T1D. Trial registration: Australia New Zealand Clinical Trials Registry ACTRN12618001391268.Bree J. Tillett, Jacky Dwiyanto, Kate R. Secombe, Thomas George, Vivian Zhang, Dovile Anderson, Emily Duggan, Rabina Giri, Dorothy Loo, Thomas Stoll, Mark Morrison, Jakob Begun, Michelle M. Hill, Esteban N. Gurzov, Kirstine J. Bell, Sonia Saad, Christopher K. Barlow, Darren J. Creek, Chun Wie Chong, Eliana Mariño, Emma E. Hamilton-William
