^{Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.}

^{School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.}

^{Division of Child Development, Rehabilitation and Metabolic Disease, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.}

Address correspondence to: Gary D. Wu, 915 BRB II/III, 421 Curie Blvd., Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. Phone: 215.898.0158; E-mail: ude.nnepu.dem.liam@uwdg.

Authorship note: Ting-Chin David Shen and Lindsey Albenberg contributed equally to this work.

Received 2014 Sep 29; Accepted 2015 May 14.

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.

Abstract

Acknowledgments

This work was supported by grants from the NIH (RO1-{"type":"entrez-nucleotide","attrs":{"text":"DK089472","term_id":"187583730"}}DK089472, to G.D. Wu; UH2/3-{"type":"entrez-nucleotide","attrs":{"text":"DK083981","term_id":"187462119"}}DK083981, to G.D. Wu, F.D. Bushman, and J.D. Lewis; and HD26979, to M. Yudkoff); the Molecular Biology Core and the Molecular Pathology Imaging Core of the Penn Center for Molecular Studies in Digestive and Liver Diseases (P30 DK050306); and the Joint Penn-CHOP Center for Digestive, Liver, and Pancreatic Medicine and the Metabolomic Core at the Children’s Hospital of Philadelphia. Neurobehavior testing was conducted in collaboration with the Neurobehavior Testing Core at the University of Pennsylvania.

Acknowledgments

Footnotes

Conflict of interest: F.D. Bushman, J.D. Lewis, and G.D. Wu are cofounders of Microbiota Therapeutics LLC. No funds from this company were used to generate data for this manuscript.

Reference information:J Clin Invest. 2015;125(7):2841–2850. doi:10.1172/JCI79214.

Footnotes

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