The Pharmabiotic Approach to Treat Hyperammonemia

Abstract

Ammonia is constantly produced as a metabolic waste from amino acid catabolism in mammals. Ammonia, the toxic waste metabolite, is resolved in the liver where the urea cycle converts free ammonia to urea. Liver malfunctions cause hyperammonemia that leads to central nervous system (CNS) dysfunctions, such as brain edema, convulsions, and coma. The current treatments for hyperammonemia, such as antibiotics or lactulose, are designed to decrease the intestinal production of ammonia and/or its absorption into the body and are not effective, besides being often accompanied by side effects. In recent years, increasing evidence has shown that modifications of the gut microbiota could be used to treat hyperammonemia. Considering the role of the gut microbiota and the physiological characteristics of the intestine, the removal of ammonia from the intestine by modulating the gut microbiota would be an ideal approach to treat hyperammonemia. In this review, we discuss the significance of hyperammonemia and its related diseases and the efficacy of the current management methods for hyperammonemia to understand the mechanism of ammonia transport in the human body. The possibility to use the gut microbiota as pharmabiotics to treat hyperammonemia and its related diseases is also explored.

Keywords: ammonia; gut microbiota; hyperammonemia; pharmabiotics.

Figure 1

Ammonia removal by glutamine synthetase (GS) in astrocytes and the key steps in the “glutamate–glutamine cycle”. Glutamate is released into the synaptic cleft from the presynaptic neuron (PRE), where it acts on the postsynaptic (POST) NMDAR receptor. The excess glutamate is then taken up by the astrocytes via the glutamate receptor EAAT-2.

Figure 2

Ammonia trafficking between the liver and the gut. In the liver, ammonia detoxifies through the urea cycle and produces urea, which is excreted by the kidneys or transported to the intestine. Bacteria residing in the gastrointestinal tract produce urease and hydrolyze urea into carbon dioxide and ammonia. In addition, enterocytes of the small intestine and colon also produce ammonia through the deamination of glutamine by glutaminase. Gut-derived ammonia is then (i) utilized by the gut bacteria for protein synthesis; (ii) reabsorbed into the intestinal blood vessels, which are the main suppliers of the portal vein, to be pooled into the liver for endogenous detoxification; (iii) excreted in the feces.