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Phase I biotransformation reactions are integral to drug metabolism, predominantly involving oxidative, reductive, and hydrolytic transformations. Chief among these are oxidative reactions, which enhance the hydrophilicity of xenobiotics and introduce polar functional groups to facilitate their elimination from the body.
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Many circulating indole and phenol metabolites are host derived.

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Host cells, not just gut bacteria, produce key indole and phenol metabolites. This finding reveals a significant host contribution to these important signaling molecules in circulation.

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Area of Science:

  • Microbiology
  • Metabolomics
  • Human Physiology

Background:

  • Indole and phenol metabolites are primarily attributed to bacterial digestion of amino acids like tryptophan and phenylalanine/tyrosine.
  • These metabolites have significant physiological roles, including AhR signaling (indoles) and association with healthy body weight (phenols).
  • The host's contribution to circulating pools of these metabolites remains undercharacterized.

Purpose of the Study:

  • To investigate the host's role in producing circulating indole and phenol metabolites.
  • To differentiate between host and microbial contributions to these metabolite pools.

Main Methods:

  • Stable isotope tracing was employed in mammalian cell cultures and mouse models.
  • Metabolite levels were analyzed in mice and human patients.
  • The impact of microbiome perturbations on metabolite levels was assessed.

Main Results:

  • Mammalian cells were shown to synthesize aryl-pyruvates, aryl-lactates, aryl-acetates, and aryl-carboxylic acids.
  • Levels of these host-derived metabolites in mice and human patients were largely unaffected by microbiome changes.
  • Bacterial metabolism was essential for producing aryl-propionates, free indole, phenol, and cresol.

Conclusions:

  • Host metabolism is a major source of circulating aryl-pyruvates, -lactates, -acetates, and -carboxylic acids.
  • Bacterial metabolism is crucial for the synthesis of specific indole and phenol derivatives like aryl-propionates and free indoles/phenols.
  • Host contribution to circulating indole and phenol metabolite pools is significant and primary for certain metabolite classes.