Gut ammonia production and its modulation

Abstract

Systemic hyperammonemia has been largely found in patients with cirrhosis and hepatic encephalopathy, and ammonia plays a major role in the pathogenesis of hepatic encephalopathy. However, controversial points remain: a) the correlation between plasma ammonia levels and neurophysiological impairment. The lack of correlation between ammonia levels and grade of hepatic encephalopathy in some cases has been considered a weakness of the ammonia hypothesis, but new methods for ammonia measurements and the implication of systemic inflammation in the modulation of ammonia neurotoxicity could explain this gap; b) the source of ammonia production. Hyperammonemia has been considered as derived from urea breakdown by intestinal bacteria and the majority of treatments were targeted against bacteria-derived ammonia from the colon. However, some data suggest an important role for small intestine ammonia production: 1) the hyperammonemia after porto-caval shunted rats has been found similar in germ-free than in non-germ-free animals. 2) In cirrhotic patients the greatest hyperammonemia was found in portal drained viscera and derived mainly from glutamine deamination. 3) The amount of time required to increase of ammonia (less than one hour) after oral glutamine challenge supports a small intestine origin of the hyperammonemia. As the main source of ammonia in cirrhotics derives from portal drained viscera owing to glutamine deamidation, increased glutaminase activity in the intestine seems to be responsible for systemic hyperammonemia. Lastly, some genetic alterations in the glutaminase gene such as the haplotype TACC could modulate intestinal ammonia production and the risk of overt hepatic encephalopathy in cirrhotics.

Gut microbiome and liver diseases

“…Ammonia has long been thought to be produced primarily by urease producing gut microbiota (figure 3), but more recent evidence implicates an important role of the viscera (in particular small intestine and kidneys) as well 85 86. In addition to such increased generation of ammonia, the compromised clearance of portal venous ammonia by the cirrhotic liver and increased uptake of ammonia by astrocytes in the brain are thought to play important roles in development of neurological symptoms (figure 3).…”

Gut Microbiota: Its Role in Hepatic Encephalopathy

“…38 Since hyperammonemia in cirrhosishas been thought to be derived predominantly from urea breakdown by urease producing bacteria, most of the treatments for HE have targeted these ammonia producing colonic bacteria. 39,40 However, lately, focus is shifting from the large to the small intestine and kidneys as the major sources of…”

“…Glutamine deamidation by glutaminase seems to be the main source of ammonia generation in patients with cirrhosis. 40 …”

Glyphosate’s Suppression of Cytochrome P450 Enzymes and Amino Acid Biosynthesis by the Gut Microbiome: Pathways to Modern Diseases

“…Ammonia plays an important role in the etiology of hepatic encephalopathy associated with both acute and chronic liver dysfunction [56,57]. The source of the ammonia is believed to be intestinal bacteria, including those in both the small and large intestine [58]. Impaired liver function prevents detoxification of ammonia via the urea pathway.…”