Presently, we are focused on defining the mechanisms that govern gut mucosal defense and the interplay between the host and the intestinal microflora.
Gut development: The mammalian small intestine undergoes a very precise and complex series of morphological and biochemical changes during pre- and post-natal development. Among the most critical factors involved in this process is thyroid hormone. Animals that are hypo-thyroid or lack thyroid hormone receptors exhibit profound abnormalities within the gut mucosa. We are investigating the molecular mechanisms by which thyroid hormone exerts its effects upon gut mucosal homeostasis.
Gut homeostasis: The gut epithelium is a dynamic structure that undergoes a continuous cycle of self-renewal, with pluripotent stem cells located in the crypts giving rise to fully differentiated villus cells. We are studying the differentiation process of the enterocyte, the cell that comprises 95% of all villus cells and is responsible for the nutrient digestion and absorption that is critical to life. The enterocyte marker gene, intestinal alkaline phosphatase (IAP) is being used as a tool to identify and characterize transcription factors that mediate the differentiation process. Among the mechanisms that underlie gut differentiation is a specific alteration in chromatin structure. We have therefore employed novel techniques to examine the role that histone proteins play in enterocyte growth and differentiation.
Gut pathology: Unfortunately, the normal differentiation process goes awry under a variety of conditions, many of which are seen in surgical patients. Perhaps most notable is the gut mucosal failure that occurs with starvation and inflammation. We have identified a specific alteration in the phenotype of the enterocyte (IAP gene silencing) that appears to be a reliable marker for this gut mucosal failure. Recent work from the lab suggests that this loss of IAP expression may be a key factor in the breakdown of gut mucosal defense that is seen in starvation and other diseases.
Microbiotal homeostasis: Over the past millions of years, metazoans have evolved to develop and maintain a mutually beneficial symbiotic relationship with commensal microbiota. Intestinal microbiota plays a pivotal role in maintaining human health and well-being, and dysregulation of the normal homeostasis of the intestinal microbiota has been implicated in the pathogenesis of myriad disease conditions including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colorectal carcinoma, systemic sepsis, antibiotic-associated diarrhea, etc. The human gastrointestinal tract harbors approximately 1014 bacteria that are composed of between 300 and 1,000 different species. Presently, we are attempting to decipher the fundamental mechanisms that govern the normal homeostatic number and composition of the intestinal microbiota.
We are employing IAP knockout and IAP transgenic mice in order to examine the role of this protein in regard to the gut barrier, and to lay the groundwork for IAP-based therapies that could be used clinically to help patients in the settings of severe trauma, sepsis, critical illness, and in the context of a variety of gut diseases such as IBD.