Ultrasound localisation microscopy as a novel tool to study small intestinal microvasculature in nutrient sensing

Obesity was estimated to affect more than 10% of people worldwide in 2022, and the global prevalence of obesity and associated diseases is expected to rise to 24% by 2035. The importance of this crisis is multiplied by the many comorbidities associated with obesity such as type 2 diabetes (T2D), cardiovascular disease, and dementia. Together, these illnesses are expected to cost 3% of global gross domestic product (GDP) in the next ten years. This crisis has been the focus of extensive biomedical research for the past two decades. While novel therapeutic treatments, such as the new generation of glucagon-like-peptide 1 analogues, are hoped to curb these projected rises, they are unlikely to be useful or accessible to all who would benefit.

Understanding how obesity and related diseases manifest and drive tissue pathology is therefore important. There is thus a need for cutting-edge tools to provide insight into the mechanisms triggering the onset and development of the disease. Contrast enhanced ultrasound (CEUS) imaging and its associated post-processing tools provide high-resolution ultrasound localisation microscopy (ULM) images of the microcirculation in a non-invasive and safe way. Proof of concept studies in this thesis demonstrate that ULM can provide images with a resolution comparable to those found using histological analysis. These tools have the potential to help answer questions about structural and dynamic changes in microvasculature in obesity and diabetes, affecting nutrient sensing and insulin production and secretion.

Building on the well reported nutrient sensing role of the duodenum and the increase blood flow to the small intestine, via the superior mesenteric artery, during a meal, the studies in this thesis aimed to measure changes in microvascular perfusion in response to macronutrients. The effects of these macronutrients were compared between lean mice and diet-induced obese mice to study the effect of obesity on nutrient sensing.