Engineering the Gut Microbiota to Treat Hyperammonemia

Engineering the gut microbiota for therapeutic modulation of host metabolism is an emerging goal of microbiome research. In the intestine, bacterial urease converts host-derived urea to ammonia and carbon dioxide, contributing to hyperammonemia-associated neurotoxicity and encephalopathy in patients with liver disease. Here we report engineering the gut microbiota in mice for therapeutic reduction of urease activity. Depletion of the pre-existing gut microbiota followed by inoculation with Altered Schaedler's Flora (ASF), a defined consortium of 8 bacteria with minimal urease gene content, established a persistent new community that exhibited long-term reduction in fecal urease activity and ammonia production. ASF transplantation was associated with decreased morbidity and mortality in a murine model of hepatic injury. These results provide proof-of-concept that inoculation of a prepared host with a defined gut microbiota can lead to durable metabolic changes with therapeutic utility.