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

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Abstract

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.

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Abbreviations

2-HCA :

2-hydroxycinnamic acid

2-HPAA:

2-hydroxyphenylacetic acid

2,3-DHHCA:

2,3-dihydroxyhydrocinnamic acid

2,4-DHHCA:

2,4-dihydroxyhydrocinnamic acid

2,4-HPPA :

2-(4-hydroxyphenyl)propanoic acid

3-PPA:

3-phenylpropionic acid

3-HHA:

3-hydroxyhippuric acid

3-HBA:

3-hydroxybenzoic acid

3-HCA:

3-hydroxycinnamic acid

3-HHA :

3-hydroxyhippuric acid

3-HPAA :

3-hydroxyphenylacetic acid

3,2-HPPA:

3-(2-hydroxyphenyl) propionic acid

3,3-HPHPA:

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

3,3-HPPA :

3-(3-hydroxyphenyl) propionic acid

3,4-DHCA:

3,4-dhydroxycinnamic acid

3,4-DHHCA:

3,4-dihydroxyhydrocinnamic acid

3,4-DOPAC:

3,4-dihydroxyphenylacetic acid

3,4-HMPHA:

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

3,4-HPPA:

3-(4-hydroxyphenyl) propionic acid

3,5-DHHCA:

3,5-dihydroxyhydrocinnamic acid

4-HHA:

4-hydroxyhippuric acid

4-HBA:

4-hydroxybenzoic acid

4-HCA:

4-hydroxycinnamic acid

4-HPAA:

4-hydroxyphenylacetic acid

4-HPLA:

4-hydroxyphenyllactic acid

4-HPPU:

4-hydroxyphenylpyruvic acid

BA:

Benzoic acid

FA:

Ferulic acid

HA:

Hippuric acid

HMA:

Hydroxymandelic acid

HVA:

Homovanillic acid

L-PHE:

l-Phenylalanine

L-TYR:

l-Tyrosine

PAA:

Phenylacetic acid

PPG:

Phenylpropionylglycine

VMA:

Vanillylmandelic acid

ADOS:

Autism Diagnostic Observation Scale

APD:

Antipsychotic drug

BBB:

Blood brain barrier

BPD:

Bipolar disorder

CSF:

Cerebrospinal fluid

DSM:

Diagnostic and Statistical Manual

FEP:

First episode psychosis

GMB:

Gut microbiota

HR:

High risk

ICD:

International Classification of Diseases

LC:

Liquid chromatography

MS:

Mass spectrometry

np:

Not provided

NSIB:

Neurotypical siblings

nsd:

Not significantly different

PDD:

Pervasive developmental disorder

PSE:

Present state examination

quaL:

Qualitative

quaN:

Quantitative

RDC:

Research Diagnostic Criteria

RIS:

Risperidone

SGA:

Second-generation antipsychotic

SPM:

Small phenolic molecule

UC:

Unrelated control

UHR:

Ultra high risk

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Acknowledgements

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).

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Authors and Affiliations

  1. Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, USA

    George E. Jaskiw, Mark E. Obrenovich & Curtis J. Donskey

  2. School of Medicine, Case Western Reserve University, Cleveland, OH, USA

    George E. Jaskiw & Curtis J. Donskey

  3. Department of Chemistry, Case Western Reserve University, Cleveland, OH, USA

    Mark E. Obrenovich

  4. Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, USA

    Mark E. Obrenovich

  5. Department of Chemistry, Cleveland State University, Cleveland, OH, USA

    Mark E. Obrenovich

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  1. George E. Jaskiw
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Jaskiw, G.E., Obrenovich, M.E. & Donskey, C.J. The phenolic interactome and gut microbiota: opportunities and challenges in developing applications for schizophrenia and autism. Psychopharmacology 236, 1471–1489 (2019). https://doi.org/10.1007/s00213-019-05267-3

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