HNF4-Alpha as an Early Integration Point for Environmental Risk Factors in IBD Development
Abstract
Inflammatory bowel disease (IBD) is a medically disqualifying factor for active military duty and enlistment, significantly impacting the ability of the Armed Forces to recruit and maintain active-duty personnel. The peak age of IBD onset is the same as a significant percentage of active-duty Soldiers, and the incidence of disease has more than doubled over the past 15 years in military populations. The combination of an early age of disease development and the chronic nature of this disease makes it a significant medical and economic challenge for people with IBD. Strategies to prevent IBD development or block disease flares would have significant benefits for maintaining military readiness through decreased disease-associated loss of military personnel. Several factors have been linked to an increased risk of developing IBD, but no single risk factor is enough to cause disease. Family history (genetics), intestinal microbes (microbiome), how an individual fights infection (immune response), as well as where you live, what you eat, or what you touch (environment) are all IBD risk factors. What is unclear is how these multiple IBD risk factors combine to cause a person to develop IBD. In this study, we propose the new idea that a receptor called hepatocyte nuclear factor 4 alpha (HNF4a) found inside epithelial cells that line the intestine is a central target for environmental risk factors that are linked to IBD development. This is based on reports that link HNF4a activity to maintaining gut health and descriptions of how HNF4a levels are lower in the intestines of IBD patients, as well as how artificially changing the amounts of HNF4a subtypes (P1 or P2 isoforms) alter disease activity in experimental IBD models. Other studies show that environmental IBD risk factors, such as smoking, early life antibiotic use, eating a high-fat diet or processed foods, all cause the loss of a specific cell type in the intestine; the same cells that HNF4a acts to keep healthy. Plastics are widely used for food packaging, storage, in healthcare products, and clothing. These plastic items shed huge numbers of plastic microparticles in a variety of shapes and sizes into the environment, especially when heated or damaged. Active-duty military need to easily carry food in compact, lightweight packages that maintain food integrity and freshness; these meals-ready-to-eat (MREs) are packaged and heated in plastic lined pouches, potentially exposing military personnel to high levels of microplastics over time. Based primarily on animal studies, microplastics are proposed to be an environmental risk factor for IBD. This study tests the hypothesis that environmental risk factors, such as microplastics, integrate at a common functional node controlled by the ratio of HNF4a isoform expression, driving intestinal epithelial dysfunction and accelerating IBD onset. The study takes the innovative approach to define the actual microplastics present in our local environment and determine the microplastic types associated with poor clinical outcomes of IBD patients treated in the same area (Aim 1). Next, a panel of microplastics found in our local area will be directly tested for their ability to change levels of HNF4a isoforms in intestinal epithelial cells from healthy and IBD donors and promote injury in this cutting-edge cell culture system (Aim 2), as well as determine if these microplastics accelerate disease onset in a murine model of IBD (Aim 3). Finally, a new paradigm for how environmental risk factors impact IBD development by targeting not just the total expression level of HNF4a, but rather the ratio of HNF4a isoform levels will be tested in experiments that artificially change HNF4a isoform ratios to directly determine if this blocks or amplifies injury caused by microplastics. The results of these studies will provide new insights into a potential common target for environmental risk factors that promote the onset of IBD pathogenesis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310243
Entities
People
- Christine McDonald
Organizations
- Cleveland Clinic
- United States Army