Human inflammatory bowel disease
Human inflammatory bowel diseases (IBD) that includes Crohn's disease (CD) and ulcerative colitis are a set of clinically and microscopically heterogeneous diseases of the gastrointestinal tract. The aetilogy of IBD is complex and is characterised by homeostatic breakdown that is influenced by the interactions between host genetics and envrionental factors that includes the gut microbiome. The complexity and heterogeneity in IBD results in difficulty in defining effective treatments for all patients. We aim to better define the complex molecular, cellular and microbal networks that are involved in IBD pathogenesis with the goal of defining new treatment targets that are based around underlyng immune proccesses.
1. The liver-gut axis in health and primary sclerosing cholangitis-associated inflammatory bowel disease
We are currently investigating the interactions between the liver and the intestine and how these can be modulated by members of the microbiome. We believe that alterations to the abundance of liver-derived factors in healthy ageing and diseases such as primary sclerosing cholangitis will shape microbiota-mediated intestinal function and inflammation. Alterations to the liver-gut functional network may increase risk of further intestinal pathology such as colorectal cancer.
To achieve this we are using transcriptomics across multiple tissue sites to interrogate inter-organ co-expression networks, 16S amplicon sequencing in PSC-UC cohorts to assess microbial associations in a disease setting, as well as microbiological techniques to determine members of the microbiome that may be involved in liver-gut modulation.
2. Understanding the impact of regulatory T cell subtypes on response to anti-TNF therapy in inflammatory bowel disease
Regulatory T (Treg) cells are critical for immune homeostasis and prevention of immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel diseases (IBD). Evidence suggests that changes in the composition and function of Treg subsets may drive disease. Furthermore, previous reports indicate that the tumour necrosis factor-alpha neutralization (anti-TNF), which is currently the most effective biologic therapy for IBD, promotes impact on Treg responses and this may contribute to its anti-inflammatory effects. However, up to 40% of IBD patients exhibit primary non-responsiveness to anti-TNF therapy, and the molecular/cellular mechanisms associated with anti-TNF resistance, particularly the role of the Treg cells in this context, are not fully understood. In this research project, we have characterized Treg subsets from blood and tissue of IBD patients recruited pre and post anti-TNF therapy. Based on findings from the Tregs characterisation, functional experiments are now ongoing to clarify the effects and immunological events associated with anti-TNF administration in terms of phenotypic and functional features of certain Treg subsets. More importantly, these experiments will also provide insights to understand whether Treg responses have a role indeed for the anti-TNF resistance in IBD.
3. Leukocyte-stromal interaction in IBD
We aim to understand the function of stromal cells in IBD and how these cells interact with immune cells to sustain chronic inflammation. We are dissecting the cellular and molecular landscape of inflamed tissue from IBD patients with gene expression profiling, quantitative in situ analyses, multiplexed image fluorescence and functional ex vivo assays. We are also using in vivo models of IBD to interrogate key pathways involved in IBD pathophysiology and identify new therapeutic targets.
4. Investigating the lymphatic vasculature in intestinal inflammation
Our research aims to understand the lymphatic vasculature of the intestine and consider how manipulation may play a therapeutic role for patients who do not respond to existing inflammatory bowel disease therapies.
Much work has focused on the way immune cells enter and cause inflammation in the intestinal mucosa. We believe it will be fruitful to also consider how cells exit sites of inflammation and whether impairment of this process prevents the resolution of inflammation. The lymphatic system plays a key role in the exit of cells and fluid from tissues to the lymph node and the role of the lymphatic vasculature in IBD remains to be precisely understood, which forms the basis of this research.