Gut Microbial Urease Activity Drives Hyperammonemia and Predicts Overt Hepatic Encephalopathy in Cirrhosis

Hyperammonemia is a key factor in genesis and outcome of overt hepatic encephalopathy (OHE). It is caused by both reduced hepatic ammonia clearance and increased production in the gut by the bacterial urease enzyme. We studied relationship of microbial urease activity in gut and stool with ammonia metabolism and levels, and assessed the relative effectiveness of stool urease activity (SUA) in predicting OHE in cirrhosis.

In experimental cirrhosis, the expression of whole-body ammonia metabolic enzymes, ammonia clearance, plasma ammonia levels, and SUA were studied in rats. Live and pasteurized urease-positive bacteria, Klebsiella pneumonia (Kp), were gavaged in bowel-cleansed controls and cirrhotic rats for 7 days. Baseline SUA and normalized plasma ammonia (AMM-ULN) were analyzed in 50 hospitalized cirrhosis patients without any baseline hepatic encephalopathy (HE) and 30 healthy controls. The performance of SUA as a predictor of OHE was studied in patients after a 3-month follow-up.

In cirrhotic rat models, there was a significant elevation of gut and SUA along with plasma ammonia levels as compared to healthy animals. Live Kp gavage substantially increased SUA and plasma ammonia in cirrhotic models but not in control animals. As compared to controls, both SUA and AMM-ULN were significantly increased in patients with cirrhosis. During follow-up, 40% of patients developed OHE. SUA (area under the receiver operating characteristic curve [AUROC]: 0.78; P = 0.003) emerged as a significant and better predictor of OHE than AMM-ULN (AUROC: 0.71; P = 0.02).

Our study underscores a direct contribution of gut urease activity to plasma ammonia levels and proposes increased SUA as a promising biomarker for predicting new-onset OHE in patients with cirrhosis.