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

Cell Host Microbe. 2016 Dec 14;20(6):709-715. doi: 10.1016/j.chom.2016.10.021. Epub 2016 Dec 1.


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.

Keywords: Bacteroides; chronic kidney disease; genetic engineering; human microbiome; indoxyl sulfate; tryptophanase.

MeSH terms

  • Animal Feed
  • Animals
  • Bacteria / drug effects
  • Bacteria / enzymology
  • Bacteria / genetics
  • Bacteria / metabolism
  • Bacteroides / enzymology
  • Bacteroides / genetics
  • Diet
  • Disease Models, Animal
  • Disease Progression
  • Gastrointestinal Microbiome / genetics
  • Gastrointestinal Microbiome / physiology*
  • Gastrointestinal Tract / microbiology*
  • Genetic Engineering
  • Germ-Free Life / drug effects
  • Humans
  • Indican / metabolism*
  • Indican / toxicity*
  • Indoles / metabolism
  • Metagenome
  • Mice
  • Microbiota / genetics
  • Renal Insufficiency, Chronic
  • Toxins, Biological / biosynthesis
  • Toxins, Biological / urine
  • Tryptophan / metabolism
  • Tryptophanase / metabolism


  • Indoles
  • Toxins, Biological
  • uremia middle molecule toxins
  • indole
  • Tryptophan
  • Tryptophanase
  • Indican