Engineering the gut microbiota to treat hyperammonemia

J Clin Invest. 2015 Jul 1;125(7):2841-50. doi: 10.1172/JCI79214. Epub 2015 Jun 22.


Increasing evidence indicates that the gut microbiota can be altered to ameliorate or prevent disease states, and engineering the gut microbiota to therapeutically modulate 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 engineered murine gut microbiota to reduce urease activity. Animals were depleted of their preexisting gut microbiota and then inoculated with altered Schaedler flora (ASF), a defined consortium of 8 bacteria with minimal urease gene content. This protocol resulted in establishment of a persistent new community that promoted a long-term reduction in fecal urease activity and ammonia production. Moreover, in a murine model of hepatic injury, ASF transplantation was associated with decreased morbidity and mortality. 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Ammonia / metabolism
  • Animals
  • Bacteria / enzymology
  • Bacteria / genetics
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Bioengineering
  • Biological Therapy / methods*
  • Chemical and Drug Induced Liver Injury / therapy
  • Digestive System / metabolism
  • Digestive System / microbiology*
  • Disease Models, Animal
  • Feces / microbiology
  • Female
  • Genes, Bacterial
  • Hyperammonemia / metabolism
  • Hyperammonemia / microbiology*
  • Hyperammonemia / therapy*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, SCID
  • Microbiota* / physiology
  • Time Factors
  • Urease / genetics
  • Urease / metabolism


  • Bacterial Proteins
  • Ammonia
  • Urease