title: Modulation of a Circulating Uremic Solute via Rational Genetic Manipulation of the Gut Microbiota.
abstract: 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.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: A Sloan
authors.initials: AS
authors.lastname: Devlin
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Marcobal
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Dylan
authors.initials: D
authors.lastname: Dodd
authors.affiliation: Integrative Program in Quantitative Biology, Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Biostatistics, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Nayfach
authors.affiliation: Department of Medicine, VA Palo Alto HCS and Stanford University, Palo Alto, CA 94304, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Plummer
authors.affiliation: Department of Medicine, VA Palo Alto HCS and Stanford University, Palo Alto, CA 94304, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Meyer
authors.affiliation: Integrative Program in Quantitative Biology, Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Biostatistics, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Pollard
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: jsonnenburg@stanford.edu.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Sonnenburg
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: fischbach@fischbachgroup.org.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Fischbach
mesh_terms: D000821:Animal Feed; D000818:Animals; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D001439:Bacteroides / Q000201:enzymology / Q000235:genetics; D004032:Diet; D004195:Disease Models, Animal; D018450:Disease Progression; D000069196:Gastrointestinal Microbiome / Q000235:genetics / Q000502:physiology*; D041981:Gastrointestinal Tract / Q000382:microbiology*; D005818:Genetic Engineering; D005856:Germ-Free Life / Q000187:drug effects; D006801:Humans; D007200:Indican / Q000378:metabolism* / Q000633:toxicity*; D007211:Indoles / Q000378:metabolism; D054892:Metagenome; D051379:Mice; D064307:Microbiota / Q000235:genetics; D051436:Renal Insufficiency, Chronic; D014118:Toxins, Biological / Q000096:biosynthesis / Q000652:urine; D014364:Tryptophan / Q000378:metabolism; D014368:Tryptophanase / Q000378:metabolism
chemical_list: D007211:Indoles; D014118:Toxins, Biological; C026865:uremia middle molecule toxins; C030374:indole; D014364:Tryptophan; D014368:Tryptophanase; D007200:Indican
keywords: Bacteroides; chronic kidney disease; genetic engineering; human microbiome; indoxyl sulfate; tryptophanase