A number of diseases affecting the gastrointestinal tract are characterized by the dysregulation of ion and fluid transport resulting in diarrhea or constipation. Over the past fifty years, a plethora of studies have focused on possible mechanisms and treatments for these abnormalities. Ion transport in the colon has been a target of particular interest. It was recognized early on that ammonium (NH4+) in colonic effluent far exceeded that of systemic NH4+ concentration and that, in cases of liver failure, systemic NH4+ levels could exceed toxic concentrations. Although colonic absorption of NH4+ is widely recognized, the possibility of regulated ammonia (NH3) / NH4+ transport in the colon has received little attention, this despite the fact that such transport does occur in a number of epithelia exposed to a high NH4+ environment. Moreover, the effects of relative high and variable NH4+ in the colonic lumen on the balance ion and fluid transport are poorly understood. This proposal will address: 1) Expression pattern and functional role of Rhesus Associated Glycoprotein NH4+ transporters along the colon, 2) The non-RhG mediated mechanisms of secretory transport of NH3 / NH4+ in the colon, 3) Regulation of NH3/NH4+ secretion. This project will focus primarily on NH3/NH4+ transport mechanisms within the colon using the colonic cell line, T84 and mouse distal colon as models. Vectorial NH3/NH4+ transport will be accessed by unidirectional flux assay under a variety of conditions. The physiological importance of NH4+ transport mechanisms and similarity to known renal and fish gill transport mechanisms will be accessed using mouse colon. At present the mechanisms of intestinal NH3/NH4+ transport are ill defined and poorly understood, this despite the well known impact of portal vein NH4+ concentration in the development of hyperammonemia in liver disease. A better understanding of NH4+ transport mechanisms and regulation will be of significant potential in the development of more efficient treatments of secretory dysregulation and hepatic associated hyperammonemia.
Increased levels of blood ammonia can cause brain malfunction, referred to as hyperammonemia induced encephalopathy which if left untreated can become life threatening. Liver disease is often the cause of hyperammonemia, however current treatment regimes which may have uncomfortable or severe side effects are targeted to the intestine in an effort to minimize ammonia absorption. The long term goal of this project is to provide improved treatment for hyperammonemia.
|Engevik, Melinda A; Aihara, Eitaro; Montrose, Marshall H et al. (2013) Loss of NHE3 alters gut microbiota composition and influences Bacteroides thetaiotaomicron growth. Am J Physiol Gastrointest Liver Physiol 305:G697-711|