title: Engineering the gut microbiota to treat hyperammonemia.
abstract: 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.
authors.forename: Ting-Chin David
authors.initials: TC
authors.lastname: Shen
authors.forename: Lindsey
authors.initials: L
authors.lastname: Albenberg
authors.forename: Kyle
authors.initials: K
authors.lastname: Bittinger
authors.forename: Christel
authors.initials: C
authors.lastname: Chehoud
authors.forename: Ying-Yu
authors.initials: YY
authors.lastname: Chen
authors.forename: Colleen A
authors.initials: CA
authors.lastname: Judge
authors.forename: Lillian
authors.initials: L
authors.lastname: Chau
authors.forename: Josephine
authors.initials: J
authors.lastname: Ni
authors.forename: Michael
authors.initials: M
authors.lastname: Sheng
authors.forename: Andrew
authors.initials: A
authors.lastname: Lin
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Wilkins
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Buza
authors.forename: James D
authors.initials: JD
authors.lastname: Lewis
authors.forename: Yevgeny
authors.initials: Y
authors.lastname: Daikhin
authors.forename: Ilana
authors.initials: I
authors.lastname: Nissim
authors.forename: Marc
authors.initials: M
authors.lastname: Yudkoff
authors.forename: Frederic D
authors.initials: FD
authors.lastname: Bushman
authors.forename: Gary D
authors.initials: GD
authors.lastname: Wu
mesh_terms: D000641:Ammonia / Q000378:metabolism; D000818:Animals; D001419:Bacteria / Q000201:enzymology / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D057005:Bioengineering; D001691:Biological Therapy / Q000379:methods*; D056486:Chemical and Drug Induced Liver Injury / Q000628:therapy; D004064:Digestive System / Q000378:metabolism / Q000382:microbiology*; D004195:Disease Models, Animal; D005243:Feces / Q000382:microbiology; D005260:Female; D005798:Genes, Bacterial; D022124:Hyperammonemia / Q000378:metabolism / Q000382:microbiology* / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D064307:Microbiota / Q000502:physiology; D013997:Time Factors; D014510:Urease / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D000641:Ammonia; D014510:Urease