Objective:


 The role of chronic inflammation in obesity, metabolic and cardiovascular diseases is increasingly recognised. Bile acids (BA), synthesised in the liver and modified by the intestinal flora, facilitate the absorption of lipids in the intestine. BAs modulate lipid and glucose homeostasis by activating the FXR nuclear receptor and the TGR5 GPCR. Interestingly, peripheral BA concentrations are elevated in type 2 diabetes (T2D) and FXR mediates the beneficial metabolic response to gastric bypass surgery in mice. The immune system plays an important role in the dialogue with metabolic tissues, such as liver, intestine and adipose tissue. However, it is not known whether the BA modulates immune cell function. Our unpublished results identifying FXR and TGR5 expression in lymphoid cells prompt us to investigate their role in regulating glucose and lipid metabolism through modulation of immune cells. Using reporter mice and specific ligands, we will characterise immune cells expressing active FXR and TGR5.We will determine their role in metabolism and inflammation by inactivation of immune cell-specific genes in models of obesity, T2D and elevated peripheral blood BA concentrations. Mass cytometry, cell sorting and single cell transcriptomic analysis will identify BA-regulated gene networks and their receptors. As microbiota generate biologically active secondary BA, we will assess the impact of microbiota depletion and subsequent changes in the BA acid pool on immune cell populations. Translational studies in humans with altered BA metabolism and pharmacological treatment with anti-diabetic BA sequestrants will assess alterations in immune function. This project aims to identify a hitherto unexplored role of BA through modulation of the immune system on T2D, NAFLD and dyslipidaemia.The success of the project depends critically on an integrative approach undertaken uniquely in my laboratory thanks to its unique multidisciplinary expertise in basic and translational biology.