Research summary
Investigating the relationship between nutrition, inflammation and health outcomes using a comparative medicine approach
Current research interests
My research investigates the factors involved in the initiation and resolution of inflammation. My work aims to advance understanding on how an inflammatory response develops and is restrained in companion, farm and wild animals. This research programme is underpinned by mechanistic studies in experimental murine models and clinical trials in companion animals.
My research falls into two main programmes of work :
1) Nutrition, inflammation and health outcomes
My main research programme explores the relationship between nutrition, inflammation and health outcomes in companion, farm and wild animals. These studies run alongside mechanistic investigations in murine experimental disease models. This diverse, multi-species approach allows me to address key nutritional research questions which would not be possible using a single species system.
I am currently a Wellcome Trust Intermediate Clinical Fellow examining the factors which antigen presenting cells (APCs) have to provide in order to drive an autopathogenic T cell response. A central theme of this work focusses on how vitamin D modulates the host immune response. I have demonstrated that vitamin D supplementation ameliorates the development of experimental autoimmune encephalomyelitis (EAE) when induced by the administration of an adjuvant and myelin autoantigens. In contrast, I have found that administration of vitamin D does not alter the development of active EAE which arises following the administration of ex-vivo activated myelin responsive T cells. Consequently, my work focusses on exploring how vitamin D modulates the initial priming of T cells. I am particularly interested in how vitamin D modulates myeloid cell phenotype and function. I utilise a wide range of in-vitro assays and in-vivo models which I have developed over the past decade including a novel model of EAE in which central nervous system autoimmunity develops following the transfer of naïve auto-antigen responsive T cells and APCs loaded with a relevant peptide. This programme of work has been supported by three consecutive Wellcome Trust Fellowship Awards.
I am also leading population based epidemiological studies which are examining the relationship between vitamin D, inflammation and health outcomes in numerous animal populations. I am studying vitamin D homeostasis in several well phenotyped sheep flocks and cattle herds based in the UK and overseas from which longitudinal vitamin D metabolite data is available. I am also studying vitamin D metabolism in wild animals, notably an unmanaged Soay sheep flock resident on St Kilda. This programme of work has recently demonstrated a relationship between vitamin D status and fecundity which is the first study to link vitamin D and ecological fitness in wild animals.
I run a parallel translational clinical vitamin D research programme which studies spontaneous vitamin D metabolism disorders in client owned companion animals. This work has resulted in the clinical validation of parathyroid hormone related protein and vitamin D metabolite assays and lead to the description of several novel calcium homeostasis disorders in dogs. I have described a novel syndrome of hypovitaminosis D in dogs with inflammatory bowel disease (IBD). Follow up studies have demonstrated an association with low vitamin D status and gastrointestinal and systemic inflammation and, importantly, with a poor clinical outcome. This programme of work has expanded into a broader investigation of the relationship between vitamin D biology and a wide range of infectious, neoplastic and allergic disorders in companion animals. A key finding of this work has been the demonstration that low vitamin D status is highly predictive of all-cause mortality in hospitalised cats. In addition, we have demonstrated that steroid resistance in canine atopic dermatitis is associated with hypovitaminosis D.
2) Inflammatory disorders in companion animals
My second research programme studies the development and resolution of inflammation in gastrointestinal, renal, hepatic and neurological disorders of companion animals. Disorders such as inflammatory bowel disease (IBD), and inflammatory disorders of the liver, for example hepatitis, are major causes of morbidity and mortality in humans and animals. This programme of work aims to understand why inflammation is initiated and persists in companion animals with chronic enteropathies, liver and renal disorders. My research also aims to understand the role of inflammation in the development of systemic complications in patients with liver disease. I have published widely on the pathogenesis of hepatic encephalopathy (HE), which is a highly debilitating neurological complication that commonly occurs in both animals and humans with liver disease. This work has identified that hyperammonemia and inflammation are key drivers of HE in dogs with naturally occurring liver disease. Using longitudinal cohort studies, my work has also established the role of sodium and manganese in the development of HE in dogs with spontaneous liver disorders. This programme of work extends into population studies of canine infectious diseases which aim to understand how best to prevent the development of important zoonotic diseases.
