Engineering the gut microbiota to treat hyperammonemia
Ting-Chin David Shen, Lindsey Albenberg, Kyle Bittinger, Christel Chehoud, Ying-Yu Chen, Colleen A. Judge, Lillian Chau, Josephine Ni, Michael Sheng, Andrew Lin, Benjamin J. Wilkins, Elizabeth L. Buza, James D. Lewis, Yevgeny Daikhin, Ilana Nissim, Marc Yudkoff, Frederic D. Bushman, Gary D. Wu
Ting-Chin David Shen, Lindsey Albenberg, Kyle Bittinger, Christel Chehoud, Ying-Yu Chen, Colleen A. Judge, Lillian Chau, Josephine Ni, Michael Sheng, Andrew Lin, Benjamin J. Wilkins, Elizabeth L. Buza, James D. Lewis, Yevgeny Daikhin, Ilana Nissim, Marc Yudkoff, Frederic D. Bushman, Gary D. Wu
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Research Article Gastroenterology

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

Ting-Chin David Shen, Lindsey Albenberg, Kyle Bittinger, Christel Chehoud, Ying-Yu Chen, Colleen A. Judge, Lillian Chau, Josephine Ni, Michael Sheng, Andrew Lin, Benjamin J. Wilkins, Elizabeth L. Buza, James D. Lewis, Yevgeny Daikhin, Ilana Nissim, Marc Yudkoff, Frederic D. Bushman, Gary D. Wu

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Figure 3

Development of a stable gut microbial community nucleated by inoculation with ASF.

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Development of a stable gut microbial community nucleated by inoculation...
(A) Segmented regression analysis of communities in mice that were either germ-free or prepared conventional mice subjected to ASF gavage. The y axis shows the proportion of ASF lineages inferred from 16S rRNA gene tag pyrosequencing data. The x axis shows the number of days after transfer. Segmented regression analysis showed 2 phases, indicating a slow decline in the ASF proportion up to about day 30, followed by establishment of a new steady state consisting of approximately 40% ASF lineages. (B) Principal coordinates analysis (PCoA) ordination over time. Changes in community membership over time were analyzed using unweighted Unifrac (61). Progression of time is indicated by a gray arrow. (C) Shannon diversity of gut microbiota over time in the 4 hosts described in Figure 2. n = 5 per group for Conventional + ASF gavage, Germ-free + ASF gavage, and Prepared + ASF gavage. n = 10 for ASF-colonized.