Modulation of a Circulating Uremic Solute via Rational Genetic Manipulation of the Gut Microbiota

• Published in: Cell host & microbe 2016-12, Vol.20 (6), p.709-715
• Main Authors: Devlin, A. Sloan, Marcobal, Angela, Dodd, Dylan, Nayfach, Stephen, Plummer, Natalie, Meyer, Tim, Pollard, Katherine S., Sonnenburg, Justin L., Fischbach, Michael A.
• Format: Article
• Language: English
• Subjects: Animal Feed; Animals; Bacteria - drug effects; Bacteria - enzymology; Bacteria - genetics; Bacteria - metabolism; Bacteroides; Bacteroides - enzymology; Bacteroides - genetics; chronic kidney disease; Diet; Disease Models, Animal; Disease Progression; Gastrointestinal Microbiome - genetics; Gastrointestinal Microbiome - physiology; Gastrointestinal Tract - microbiology; Genetic Engineering; Germ-Free Life - drug effects; human microbiome; Humans; Indican - metabolism; Indican - toxicity; Indoles - metabolism; indoxyl sulfate; Metagenome; Mice; Microbiota - genetics; Renal Insufficiency, Chronic; Toxins, Biological - biosynthesis; Toxins, Biological - urine; Tryptophan - metabolism; tryptophanase; Tryptophanase - metabolism
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2016.10.021

Renal disease is growing in prevalence and has striking co-morbidities with metabolic and cardiovascular disease. Indoxyl sulfate (IS) is a toxin that accumulates in plasma when kidney function declines and contributes to the progression of chronic kidney disease. IS derives exclusively from the gut microbiota. Bacterial tryptophanases convert tryptophan to indole, which is absorbed and modified by the host to produce IS. Here, we identify a widely distributed family of tryptophanases in the gut commensal Bacteroides and find that deleting this gene eliminates the production of indole in vitro. By altering the status or abundance of the Bacteroides tryptophanase, we can modulate IS levels in gnotobiotic mice and in the background of a conventional murine gut community. Our results demonstrate that it is possible to control host IS levels by targeting the microbiota and suggest a possible strategy for treating renal disease. [Display omitted] •Indole-producing tryptophanases (Tnases) in Bacteroides are identified computationally•Tnase activity and its control of indoxyl sulfate (IS) levels in vivo are established•Rational diet alteration in gnotobiotic mice with a synthetic community controls IS level•Colonization with Tnase-deficient Bacteroides lowers IS in conventional mice Devlin et al. identify a widely distributed family of indole-producing tryptophanases in commensal gut bacteria. Using this information, they engineer bacteria to control in vivo production of the downstream product, the uremic toxin indoxyl sulfate. These results suggest a new strategy for treating chronic kidney disease by targeting the microbiome.