, Volume 236, Issue 5, pp 1471–1489 | Cite as

The phenolic interactome and gut microbiota: opportunities and challenges in developing applications for schizophrenia and autism

  • George E. JaskiwEmail author
  • Mark E. Obrenovich
  • Curtis J. Donskey


Schizophrenia and autism spectrum disorder have long been associated with elevated levels of various small phenolic molecules (SPMs). In turn, the gut microbiota (GMB) has been implicated in the kinetics of many of these analytes. Unfortunately, research into the possible relevance of GMB-mediated SPMs to neuropsychiatry continues to be limited by heterogeneous study design, numerous sources of variance and technical challenges. Some SPMs have multiple structural isomers and most have conjugates. Without specialized approaches, SPMs can be incorrectly assigned or inaccurately quantified. In addition, SPM levels can be affected by dietary polyphenol or protein consumption and by various medications and diseases. Nonetheless, heterotypical excretion of various SPMs in association with schizophrenia or autism continues to be reported in independent samples. Recent studies in human cerebrospinal fluid demonstrate the presence of many SPMs A large number of these are bioactive in experimental models. Whether such mechanisms are relevant to the human brain in health or disease is not known. Systematic metabolomic and microbiome studies of well-characterized populations, an appreciation of multiple confounds, and implementation of standardized approaches across platforms and sites are needed to delineate the potential utility of the phenolic interactome in neuropsychiatry.


Schizophrenia Autism Microbiota Gut Polyphenols Phenolic Antipsychotic Brain 


Chemical names


2-hydroxycinnamic acid


2-hydroxyphenylacetic acid


2,3-dihydroxyhydrocinnamic acid


2,4-dihydroxyhydrocinnamic acid


2-(4-hydroxyphenyl)propanoic acid


3-phenylpropionic acid


3-hydroxyhippuric acid


3-hydroxybenzoic acid


3-hydroxycinnamic acid


3-hydroxyhippuric acid


3-hydroxyphenylacetic acid


3-(2-hydroxyphenyl) propionic acid


3-hydroxy-3-(3-hydroxyphenyl)propanoic acid


3-(3-hydroxyphenyl) propionic acid


3,4-dhydroxycinnamic acid


3,4-dihydroxyhydrocinnamic acid


3,4-dihydroxyphenylacetic acid


3-(3-hydroxy-4-methoxyphenyl) hydracrylic acid


3-(4-hydroxyphenyl) propionic acid


3,5-dihydroxyhydrocinnamic acid


4-hydroxyhippuric acid


4-hydroxybenzoic acid


4-hydroxycinnamic acid


4-hydroxyphenylacetic acid


4-hydroxyphenyllactic acid


4-hydroxyphenylpyruvic acid


Benzoic acid


Ferulic acid


Hippuric acid


Hydroxymandelic acid


Homovanillic acid






Phenylacetic acid




Vanillylmandelic acid

Other abbreviations


Autism Diagnostic Observation Scale


Antipsychotic drug


Blood brain barrier


Bipolar disorder


Cerebrospinal fluid


Diagnostic and Statistical Manual


First episode psychosis


Gut microbiota


High risk


International Classification of Diseases


Liquid chromatography


Mass spectrometry


Not provided


Neurotypical siblings


Not significantly different


Pervasive developmental disorder


Present state examination






Research Diagnostic Criteria




Second-generation antipsychotic


Small phenolic molecule


Unrelated control


Ultra high risk



This works was supported by the Louis Stokes Cleveland DVAMC Research Service and by a grant from the VISN 10 Research Initiative Program (to CJD and GEJ).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019

Authors and Affiliations

  1. 1.Louis Stokes Cleveland Veterans Affairs Medical CenterClevelandUSA
  2. 2.School of MedicineCase Western Reserve UniversityClevelandUSA
  3. 3.Department of ChemistryCase Western Reserve UniversityClevelandUSA
  4. 4.Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical SciencesUniversity of ToledoToledoUSA
  5. 5.Department of ChemistryCleveland State UniversityClevelandUSA

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