Skip to main content

Advertisement

Log in

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

  • Review
  • Published:
Psychopharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

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

References

  • FSANZ (2005) The 21st Australian Total Diet Study. A total diet study of sulphites, benzoates and sorbates. Food Standards Australia New Zealand (FSANZ), Canberra, AU.

  • Aarbakke J, Bakke OM (1972) Localization of microbial L-tyrosine degradation in the intestine of coprophagy-prevented rats. Scand J Gastroenterol 7:417–421

    Article  CAS  PubMed  Google Scholar 

  • Acheson RM, Paul RM, Tomlinson RV (1958) Some constituents of the urine of normal and schizophrenic individuals. Can J Biochem Physiol 36:295–305

    Article  CAS  PubMed  Google Scholar 

  • Almanza-Aguilera E, Urpi-Sarda M, Llorach R, Vazquez-Fresno R, Garcia-Aloy M, Carmona F, Sanchez A, Madrid-Gambin F, Estruch R, Corella D, Andres-Lacueva C (2017) Microbial metabolites are associated with a high adherence to a Mediterranean dietary pattern using a (1)H-NMR-based untargeted metabolomics approach. J Nutr Biochem 48:36–43

    Article  CAS  PubMed  Google Scholar 

  • Altieri L, Neri C, Sacco R, Curatolo P, Benvenuto A, Muratori F, Santocchi E, Bravaccio C, Lenti C, Saccani M, Rigardetto R, Gandione M, Urbani A, Persico AM (2011) Urinary p-cresol is elevated in small children with severe autism spectrum disorder. Biomarkers 16:252–260

    Article  CAS  PubMed  Google Scholar 

  • Aretz I, Meierhofer D (2016) Advantages and Pitfalls of mass spectrometry based metabolome profiling in systems biology. Int J Mol Sci 17

    Article  PubMed Central  CAS  Google Scholar 

  • Armstrong MD, Shaw KN (1957) The occurrence of (-)-beta-m-hydroxyphenyl-hydracrylic acid in human urine. J Biol Chem 225:269–278

    CAS  PubMed  Google Scholar 

  • Armstrong MD, Shaw KN, Wall PE (1956) The phenolic acids of human urine; paper chromatography of phenolic acids. J Biol Chem 218:293–303

    CAS  PubMed  Google Scholar 

  • Asatoor AM (1968) The origin of urinary tyramine. Formation in tissue and by intestinal microorganisms. Clin Chim Acta 22:223–229

    Article  CAS  PubMed  Google Scholar 

  • Asatoor AM, Chamberlain MJ, Emmerson BT, Johnson JR, Levi AJ, Milne MD (1967) Metabolic effects of oral neomycin. Clin Sci 33:111–124

    CAS  PubMed  Google Scholar 

  • Baba S, Furuta T, Horie M, Nakagawa H (1981) Studies on drug metabolism by use of isotopes XXVI: determination of urinary metabolites of rutin in humans. J Pharm Sci 70:780–782

    Article  CAS  PubMed  Google Scholar 

  • Baba S, Furuta T, Fujioka M, Goromaru T (1983) Studies on drug metabolism by use of isotopes XXVII: urinary metabolites of rutin in rats and the role of intestinal microflora in the metabolism of rutin. J Pharm Sci 72:1155–1158

    Article  CAS  PubMed  Google Scholar 

  • Bahr SM, Tyler BC, Wooldridge N, Butcher BD, Burns TL, Teesch LM, Oltman CL, Azcarate-Peril MA, Kirby JR, Calarge CA (2015) Use of the second-generation antipsychotic, risperidone, and secondary weight gain are associated with an altered gut microbiota in children. Transl Psychiatry 5:e652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bai W, Wang C, Ren C (2014) Intakes of total and individual flavonoids by US adults. Int J Food Sci Nutr 65:9–20

    Article  CAS  PubMed  Google Scholar 

  • Beckmann H, Reynolds GP, Sandler M, Waldmeier P, Lauber J, Riederer P, Gattaz WF (1982) Phenylethylamine and phenylacetic acid in CSF of schizophrenics and healthy controls. Arch Psychiatr Nervenkr 232:463–471

    Article  Google Scholar 

  • Bhala A, Bennett MJ, McGowan KL, Hale DE (1993) Limitations of 3-phenylpropionylglycine in early screening for medium-chain acyl-coenzyme A dehydrogenase deficiency. J Pediatr 122:100–103

    Article  CAS  PubMed  Google Scholar 

  • Biedermann L, Zeitz J, Mwinyi J, Sutter-Minder E, Rehman A, Ott SJ, Steurer-Stey C, Frei A, Frei P, Scharl M, Loessner MJ, Vavricka SR, Fried M, Schreiber S, Schuppler M, Rogler G (2013) Smoking cessation induces profound changes in the composition of the intestinal microbiota in humans. PLoS One 8:e59260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bitner BF, Ray JD, Kener KB, Herring JA, Tueller JA, Johnson DK, Tellez Freitas CM, Fausnacht DW, Allen ME, Thomson AH, Weber KS, McMillan RP, Hulver MW, Brown DA, Tessem JS, Neilson AP (2018) Common gut microbial metabolites of dietary flavonoids exert potent protective activities in beta-cells and skeletal muscle cells. J Nutr Biochem 62:95–107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blander JM, Longman RS, Iliev ID, Sonnenberg GF, Artis D (2017) Regulation of inflammation by microbiota interactions with the host. Nat Immunol 18:851–860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bone E, Tamm A, Hill M (1976) The production of urinary phenols by gut bacteria and their possible role in the causation of large bowel cancer. Am J Clin Nutr 29:1448–1454

    Article  CAS  PubMed  Google Scholar 

  • Bongiovanni R, Kirkbride B, Newbould E, Durkalski V, Jaskiw GE (2010) Relationships between large neutral amino acid levels in plasma, cerebrospinal fluid, brain microdialysate and brain tissue in the rat. Brain Res 1334:45–57

    Article  CAS  PubMed  Google Scholar 

  • Bongiovanni R, Leonard S, Jaskiw GE (2013) A simplified method to quantify dysregulated tyrosine transport in schizophrenia. Schizophr Res 150:386–391

    Article  PubMed  Google Scholar 

  • Bongiovanni R, Mchaourab AS, McClellan F, Elsworth J, Double M, Jaskiw GE (2016) Large neutral amino acids levels in primate cerebrospinal fluid do not confirm competitive transport under baseline conditions. Brain Res 1648:372–379

    Article  CAS  PubMed  Google Scholar 

  • Bouatra S, Aziat F, Mandal R, Guo AC, Wilson MR, Knox C, Bjorndahl TC, Krishnamurthy R, Saleem F, Liu P, Dame ZT, Poelzer J, Huynh J, Yallou FS, Psychogios N, Dong E, Bogumil R, Roehring C, Wishart DS (2013) The human urine metabolome. PLoS One 8:e73076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Briggs MH (1962) A comparative study of urinary aromatic compounds from hospitalised mental patients and normal subjects. N Z Med J 61:317–320

    CAS  PubMed  Google Scholar 

  • Briggs MH, Harvey N (1962) Urinary metabolites of aromatic amino acids in schizophrenia. Life Sci 1:61–64

    Article  CAS  Google Scholar 

  • Cassidy A, Minihane AM (2017) The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids. Am J Clin Nutr 105:10–22

    Article  CAS  PubMed  Google Scholar 

  • Chadwick RW, George SE, Claxton LD (1992) Role of the gastrointestinal mucosa and microflora in the bioactivation of dietary and environmental mutagens or carcinogens. Drug Metab Rev 24:425–492

    Article  CAS  PubMed  Google Scholar 

  • Collins SM, Surette M, Bercik P (2012) The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol 10:735–742

    Article  CAS  PubMed  Google Scholar 

  • Coretti L, Paparo L, Riccio MP, Amato F, Cuomo M, Natale A, Borrelli L, Corrado G, Comegna M, Buommino E, Castaldo G, Bravaccio C, Chiariotti L, Berni Canani R, Lembo F (2018) Gut microbiota features in young children with autism spectrum disorders. Front Microbiol 9:3146

    Article  PubMed  PubMed Central  Google Scholar 

  • Crozier A, Jaganath IB, Clifford MN (2006) Phenols, polyphenols and tannins: an overview. In: Crozier A, Clifford MN, Ashihara H (eds) Plant secondary metabolites: occurrence, structure and role in the human diet. Blackwell Publishing, Oxford, pp 1–24

    Chapter  Google Scholar 

  • Cummings JH, Hill MJ, Bone ES, Branch WJ, Jenkins DJ (1979) The effect of meat protein and dietary fiber on colonic function and metabolism. II. Bacterial metabolites in feces and urine. Am J Clin Nutr 32:2094–2101

    Article  CAS  PubMed  Google Scholar 

  • Cunha BA (2001) Antibiotic side effects. Med Clin North Am 85:149–185

    Article  CAS  PubMed  Google Scholar 

  • Curtius HC, Mettler M, Ettlinger L (1976a) Study of the intestinal tyrosine metabolism using stable isotopes and gas chromatography-mass spectrometry. J Chromatogr 126:569–580

    Article  CAS  PubMed  Google Scholar 

  • Curtius HC, Redweik U, Steinmann B, Leimbacher W, Wegmann H (1976b) Use of deuterated tyrosine and phenylalanine in the study of catecholamine and aromatic amino acid metabolism. In: Klein ER, Klein PD (eds) Proceedings of the Second International Conference on Stable Isotopes, October 20-23, 1975, Oak Brook, Illinois. U.S. Energy Research and Development Administration, Washington, DC, pp 385–391

    Google Scholar 

  • Dai ZL, Wu G, Zhu WY (2011) Amino acid metabolism in intestinal bacteria: links between gut ecology and host health. Front Biosci 16:1768–1786

    Article  CAS  Google Scholar 

  • Das NP (1974) Studies on flavonoid metabolism. Excretion of m-hydroxyphenylhydracrylic acid from (plus)-catechin in the monkey (Macaca iris sp.). Drug Metab Dispos 2:209–213

    CAS  PubMed  Google Scholar 

  • Dastur DK, Mann JD, Pollin W (1963) Hippuric acid excretion coffee, and schizophremia. Arch Gen Psychiatry 9:79–82

    Article  CAS  PubMed  Google Scholar 

  • David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA, Biddinger SB, Dutton RJ, Turnbaugh PJ (2014) Diet rapidly and reproducibly alters the human gut microbiome. Nature 505:559–563

    Article  CAS  PubMed  Google Scholar 

  • Davis BA, Yu PH, Carlson K, O'Sullivan K, Boulton AA (1982) Plasma levels of phenylacetic acid, m- and p-hydroxyphenylacetic acid, and platelet monoamine oxidase activity in schizophrenic and other patients. Psychiatry Res 6:97–105

    Article  CAS  PubMed  Google Scholar 

  • Davis BA, Shrikhande S, Paralikar VP, Hirsch SR, Durden DA, Boulton AA (1991) Phenylacetic acid in CSF and serum in Indian schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 15:41–47

    Article  CAS  PubMed  Google Scholar 

  • Dayman J, Jepson JB (1969) The metabolism of caffeic acid in humans: the dehydroxylating action of intestinal bacteria. Biochem J 113:11P

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Angelis M, Piccolo M, Vannini L, Siragusa S, De Giacomo A, Serrazzanetti DI, Cristofori F, Guerzoni ME, Gobbetti M, Francavilla R (2013) Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One 8:e76993

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • De Hert M, Hudyana H, Dockx L, Bernagie C, Sweers K, Tack J, Leucht S, Peuskens J (2011) Second-generation antipsychotics and constipation: a review of the literature. Eur Psychiatry 26:34–44

    Article  PubMed  Google Scholar 

  • DeQuattro VL, Sjoerdsma A (1967) Origin of urinary tyramine and tryptamine. Clin Chim Acta 16:227–233

    Article  CAS  PubMed  Google Scholar 

  • Dieme B, Mavel S, Blasco H, Tripi G, Bonnet-Brilhault F, Malvy J, Bocca C, Andres CR, Nadal-Desbarats L, Emond P (2015) Metabolomics study of urine in autism spectrum disorders using a multiplatform analytical methodology. J Proteome Res 14:5273–5282

    Article  CAS  PubMed  Google Scholar 

  • DiLalla LF, McCrary M, Diaz E (2017) A review of endophenotypes in schizophrenia and autism: the next phase for understanding genetic etiologies. Am J Med Genet C Semin Med Genet 175:354–361

    Article  PubMed  Google Scholar 

  • Dinan TG, Cryan JF (2018) Schizophrenia and the microbiome: time to focus on the impact of antipsychotic treatment on the gut microbiota. World J Biol Psychiatry 19:568–570

    Article  PubMed  Google Scholar 

  • Dodd D, Spitzer MH, Van Treuren W, Merrill BD, Hryckowian AJ, Higginbottom SK, Le A, Cowan TM, Nolan GP, Fischbach MA, Sonnenburg JL (2017) A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Nature 551:648–652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dragsted LO, Gao Q, Pratico G, Manach C, Wishart DS, Scalbert A, Feskens EJM (2017) Dietary and health biomarkers-time for an update. Genes Nutr 12:24

    Article  PubMed  PubMed Central  Google Scholar 

  • Elsden SR, Hilton MG, Waller JM (1976) The end products of the metabolism of aromatic amino acids by Clostridia. Arch Microbiol 107:283–288

    Article  CAS  PubMed  Google Scholar 

  • Epps HM (1944) Studies on bacterial amino-acid decarboxylases: 2. l(-)-tyrosine decarboxylase from Streptococcus faecalis. Biochem J 38:242–249

    CAS  PubMed  PubMed Central  Google Scholar 

  • Erlund I, Meririnne E, Alfthan G, Aro A (2001) Plasma kinetics and urinary excretion of the flavanones naringenin and hesperetin in humans after ingestion of orange juice and grapefruit juice. J Nutr 131:235–241

    Article  CAS  PubMed  Google Scholar 

  • Faull KF, King RJ, Barchas JD, Csernansky JG (1989) CSF phenylacetic acid and hostility in paranoid schizophrenia. Psychiatry Res 30:111–118

    Article  CAS  PubMed  Google Scholar 

  • Fernell E, Karagiannakis A, Edman G, Bjerkenstedt L, Wiesel FA, Venizelos N (2007) Aberrant amino acid transport in fibroblasts from children with autism. Neurosci Lett 418:82–86

    Article  CAS  PubMed  Google Scholar 

  • Finegold SM, Dowd SE, Gontcharova V, Liu C, Henley KE, Wolcott RD, Youn E, Summanen PH, Granpeesheh D, Dixon D, Liu M, Molitoris DR, Green JA 3rd (2010) Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe 16:444–453

    Article  CAS  PubMed  Google Scholar 

  • Finegold SM, Summanen PH, Downes J, Corbett K, Komoriya T (2017) Detection of Clostridium perfringens toxin genes in the gut microbiota of autistic children. Anaerobe 45:133–137

    Article  CAS  PubMed  Google Scholar 

  • Flowers SA, Evans SJ, Ward KM, McInnis MG, Ellingrod VL (2017) Interaction between atypical antipsychotics and the gut microbiome in a bipolar disease cohort. Pharmacotherapy 37:261–267

    Article  CAS  PubMed  Google Scholar 

  • Flowers SA, Baxter NT, Ward KM, Kraal AZ, McInnis MG, Schmidt TM, Ellingrod VL (2019) Effects of atypical antipsychotic treatment and resistant starch supplementation on gut microbiome composition in a cohort of patients with bipolar disorder or schizophrenia. Pharmacotherapy

  • Frolinger T, Smith C, Cobo CF, Sims S, Brathwaite J, de Boer S, Huang J, Pasinetti GM (2018) Dietary polyphenols promote resilience against sleep deprivation-induced cognitive impairment by activating protein translation. FASEB J 32:5390–5404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gabriele S, Sacco R, Cerullo S, Neri C, Urbani A, Tripi G, Malvy J, Barthelemy C, Bonnet-Brihault F, Persico AM (2014) Urinary p-cresol is elevated in young French children with autism spectrum disorder: a replication study. Biomarkers 19:463–470

    Article  CAS  PubMed  Google Scholar 

  • Gabriele S, Sacco R, Altieri L, Neri C, Urbani A, Bravaccio C, Riccio MP, Iovene MR, Bombace F, De Magistris L, Persico AM (2016) Slow intestinal transit contributes to elevate urinary p-cresol level in Italian autistic children. Autism Res 9:752–759

    Article  PubMed  Google Scholar 

  • Gale EF (1953) Amino-acid decarboxylases. Br Med Bull 9:135–138

    Article  CAS  PubMed  Google Scholar 

  • Gandal MJ, Haney JR, Parikshak NN, Leppa V, Ramaswami G, Hartl C, Schork AJ, Appadurai V, Buil A, Werge TM, Liu C, White KP, Horvath S, Geschwind DH (2018) Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science 359:693–697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao Q, Pratico G, Scalbert A, Vergeres G, Kolehmainen M, Manach C, Brennan L, Afman LA, Wishart DS, Andres-Lacueva C, Garcia-Aloy M, Verhagen H, Feskens EJM, Dragsted LO (2017) A scheme for a flexible classification of dietary and health biomarkers. Genes Nutr 12:34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gasperotti M, Passamonti S, Tramer F, Masuero D, Guella G, Mattivi F, Vrhovsek U (2015) Fate of microbial metabolites of dietary polyphenols in rats: is the brain their target destination? ACS Chem Neurosci 6:1341–1352

    Article  CAS  PubMed  Google Scholar 

  • Gattaz WF, Gasser T, Beckmann H (1985) Multidimensional analysis of the concentrations of 17 substances in the CSF of schizophrenics and controls. Biol Psychiatry 20:360–366

    Article  CAS  PubMed  Google Scholar 

  • Gerhauser C (2018) Impact of dietary gut microbial metabolites on the epigenome. Philos Trans R Soc Lond B Biol Sci 373.

    Article  CAS  Google Scholar 

  • Gondalia SV, Palombo EA, Knowles SR, Cox SB, Meyer D, Austin DW (2012) Molecular characterisation of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings. Autism Res 5:419–427

    Article  PubMed  Google Scholar 

  • Gonzalez-Barrio R, Edwards CA, Crozier A (2011) Colonic catabolism of ellagitannins, ellagic acid, and raspberry anthocyanins: in vivo and in vitro studies. Drug Metab Dispos 39:1680–1688

    Article  CAS  PubMed  Google Scholar 

  • Gora B, Gofron Z, Grosiak M, Aptekorz M, Kazek B, Kocelak P, Radosz-Komoniewska H, Chudek J, Martirosian G (2018) Toxin profile of fecal Clostridium perfringens strains isolated from children with autism spectrum disorders. Anaerobe 51:73–77

    Article  CAS  PubMed  Google Scholar 

  • Grimaldi R, Cela D, Swann JR, Vulevic J, Gibson GR, Tzortzis G, Costabile A (2017) In vitro fermentation of B-GOS: impact on faecal bacterial populations and metabolic activity in autistic and non-autistic children. FEMS Microbiol Ecol 93

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Group BDW (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95

    Article  Google Scholar 

  • Gulyassy PF, Bottini AT, Jarrard EA, Stanfel LA (1983) Isolation of inhibitors of ligand: albumin-binding from uremic body fluids and normal urine. Kidney Int Suppl 16:S238–S242

    CAS  PubMed  Google Scholar 

  • Hafiz S, Oakley CL (1976) Clostridium difficile: isolation and characteristics. J Med Microbiol 9:129–136

    Article  CAS  PubMed  Google Scholar 

  • Hagenfeldt L, Venizelos N, Bjerkenstedt L, Wiesel FA (1987) Decreased tyrosine transport in fibroblasts from schizophrenic patients. Life Sci 41:2749–2757

    Article  CAS  PubMed  Google Scholar 

  • Hassanzadeh P, Arbabi E, Atyabi F, Dinarvand R (2017) Ferulic acid exhibits antiepileptogenic effect and prevents oxidative stress and cognitive impairment in the kindling model of epilepsy. Life Sci 179:9–14

    Article  CAS  PubMed  Google Scholar 

  • He Y, Kosciolek T, Tang J, Zhou Y, Li Z, Ma X, Zhu Q, Yuan N, Yuan L, Li C, Jin K, Knight R, Tsuang MT, Chen X (2018) Gut microbiome and magnetic resonance spectroscopy study of subjects at ultra-high risk for psychosis may support the membrane hypothesis. Eur Psychiatry 53:37–45

    Article  PubMed  Google Scholar 

  • Hervert-Hernandez D, Goni I (2011) Dietary polyphenols and human gut microbiota: a review. Food Rev Int 27:154–169

    Article  CAS  Google Scholar 

  • Hicks JM, Young DS, Wootton ID (1964) The effect of uraeic blood constituents on certain cerebral enzymes. Clin Chim Acta 9:228–235

    Article  CAS  PubMed  Google Scholar 

  • Ho L, Zhao D, Ono K, Ruan K, Mogno I, Tsuji M, Carry E, Brathwaite J, Sims S, Frolinger T, Westfall S, Mazzola P, Wu Q, Hao K, Lloyd TE, Simon JE, Faith J, Pasinetti GM (2019) Heterogeneity in gut microbiota drive polyphenol metabolism that influences alpha-synuclein misfolding and toxicity. J Nutr Biochem 64:170–181

    Article  CAS  PubMed  Google Scholar 

  • Holingue C, Newill C, Lee LC, Pasricha PJ, Daniele Fallin M (2018) Gastrointestinal symptoms in autism spectrum disorder: a review of the literature on ascertainment and prevalence. Autism Res 11:24–36

    Article  PubMed  Google Scholar 

  • Hughes HK, Ashwood P (2018) Anti-Candida albicans IgG antibodies in children with autism spectrum disorders. Front Psychiatry 9:627

    Article  PubMed  PubMed Central  Google Scholar 

  • Hyland NP, Cryan JF (2016) Microbe-host interactions: Influence of the gut microbiota on the enteric nervous system. Dev Biol 417:182–187

    Article  CAS  PubMed  Google Scholar 

  • Iovene MR, Bombace F, Maresca R, Sapone A, Iardino P, Picardi A, Marotta R, Schiraldi C, Siniscalco D, Serra N, de Magistris L, Bravaccio C (2017) Intestinal dysbiosis and yeast isolation in stool of subjects with autism spectrum disorders. Mycopathologia 182:349–363

    Article  PubMed  Google Scholar 

  • Jaganath IB, Mullen W, Edwards CA, Crozier A (2006) The relative contribution of the small and large intestine to the absorption and metabolism of rutin in man. Free Radic Res 40:1035–1046

    Article  CAS  PubMed  Google Scholar 

  • Kageyama Y, Kasahara T, Morishita H, Mataga N, Deguchi Y, Tani M, Kuroda K, Hattori K, Yoshida S, Inoue K, Kato T (2017) Search for plasma biomarkers in drug-free patients with bipolar disorder and schizophrenia using metabolome analysis. Psychiatry Clin Neurosci 71:115–123

    Article  CAS  PubMed  Google Scholar 

  • Kahn RS, Sommer IE, Murray RM, Meyer-Lindenberg A, Weinberger DR, Cannon TD, O'Donovan M, Correll CU, Kane JM, van Os J, Insel TR (2015) Schizophrenia. Nat Rev Dis Primers 1:15067

    Article  PubMed  Google Scholar 

  • Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K (2017) KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res 45:D353–D361

    Article  CAS  PubMed  Google Scholar 

  • Kang DW, Park JG, Ilhan ZE, Wallstrom G, Labaer J, Adams JB, Krajmalnik-Brown R (2013) Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS One 8:e68322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kang DW, Ilhan ZE, Isern NG, Hoyt DW, Howsmon DP, Shaffer M, Lozupone CA, Hahn J, Adams JB, Krajmalnik-Brown R (2018) Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders. Anaerobe 49:121–131

    Article  CAS  PubMed  Google Scholar 

  • Kantarcioglu AS, Kiraz N, Aydin A (2016) Microbiota-gut-brain axis: yeast species isolated from stool samples of children with suspected or diagnosed autism spectrum disorders and in vitro susceptibility against nystatin and fluconazole. Mycopathologia 181:1–7

    Article  CAS  PubMed  Google Scholar 

  • Karoum F, Potkin S, Chuang LW, Murphy DL, Liebowitz MR, Wyatt RJ (1984) Phenylacetic acid excretion in schizophrenia and depression: the origins of PAA in man. Biol Psychiatry 19:165–178

    CAS  PubMed  Google Scholar 

  • Kawabata M, Kobayashi K, Shohmori T (1986) Determination of phenylacetic acid in cerebrospinal fluid by gas chromatography-mass spectrometry. Acta Med Okayama 40:271–276

    CAS  PubMed  Google Scholar 

  • Kesli R, Gokcen C, Bulug U, Terzi Y (2014) Investigation of the relation between anaerobic bacteria genus clostridium and late-onset autism etiology in children. J Immunoassay Immunochem 35:101–109

    Article  CAS  PubMed  Google Scholar 

  • Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, Han L, He J, He S, Shoemaker BA, Wang J, Yu B, Zhang J, Bryant SH (2016) PubChem substance and compound databases. Nucleic Acids Res 44:D1202–D1213

    Article  CAS  PubMed  Google Scholar 

  • Kuhnau J (1976) The flavonoids. A class of semi-essential food components: their role in human nutrition. World Rev Nutr Diet 24:117–191

    Article  CAS  PubMed  Google Scholar 

  • Kunin CM, Chalmers TC, Leevy CM, Sebastyen SC, Lieber CS, Finland M (1960) Absorption of orally administered neomycin and kanamycin with special reference to patients with severe hepatic and renal disease. N Engl J Med 262:380–385

    Article  CAS  PubMed  Google Scholar 

  • Lally J, MacCabe JH (2015) Antipsychotic medication in schizophrenia: a review. Br Med Bull 114:169–179

    Article  CAS  PubMed  Google Scholar 

  • Le Bastard Q, Al-Ghalith GA, Gregoire M, Chapelet G, Javaudin F, Dailly E, Batard E, Knights D, Montassier E (2018) Systematic review: human gut dysbiosis induced by non-antibiotic prescription medications. Aliment Pharmacol Ther 47:332–345

    Article  PubMed  Google Scholar 

  • Lee HC, Jenner AM, Low CS, Lee YK (2006) Effect of tea phenolics and their aromatic fecal bacterial metabolites on intestinal microbiota. Res Microbiol 157:876–884

    Article  CAS  PubMed  Google Scholar 

  • Lewis SJ, Heaton KW (1997) Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol 32:920–924

    Article  CAS  PubMed  Google Scholar 

  • Li J, Jia H, Cai X, Zhong H, Feng Q, Sunagawa S, Arumugam M, Kultima JR, Prifti E, Nielsen T, Juncker AS, Manichanh C, Chen B, Zhang W, Levenez F, Wang J, Xu X, Xiao L, Liang S, Zhang D, Zhang Z, Chen W, Zhao H, Al-Aama JY, Edris S, Yang H, Wang J, Hansen T, Nielsen HB, Brunak S, Kristiansen K, Guarner F, Pedersen O, Dore J, Ehrlich SD, Meta HITC, Bork P, Wang J, Meta HITC (2014) An integrated catalog of reference genes in the human gut microbiome. Nat Biotechnol 32:834–841

    Article  CAS  PubMed  Google Scholar 

  • Lis AW, McLaughlin I, Mpclaughlin RK, Lis EW, Stubbs EG (1976) Profiles of ultraviolet-absorbing components of urine from autistic children, as obtained by high-resolution ion-exchange chromatography. Clin Chem 22:1528–1532

    CAS  PubMed  Google Scholar 

  • Liu H, Garrett TJ, Tayyari F, Gu L (2015) Profiling the metabolome changes caused by cranberry procyanidins in plasma of female rats using (1) H NMR and UHPLC-Q-Orbitrap-HRMS global metabolomics approaches. Mol Nutr Food Res 59:2107–2118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Loftfield E, Vogtmann E, Sampson JN, Moore SC, Nelson H, Knight R, Chia N, Sinha R (2016) Comparison of collection methods for fecal samples for discovery metabolomics in epidemiologic studies. Cancer Epidemiol Biomark Prev 25:1483–1490

    Article  Google Scholar 

  • Lord C, Rutter M, Goode S, Heemsbergen J, Jordan H, Mawhood L, Schopler E (1989) Autism diagnostic observation schedule: a standardized observation of communicative and social behavior. J Autism Dev Disord 19:185–212

    Article  CAS  PubMed  Google Scholar 

  • Luca SV, Macovei I, Bujor A, Miron A, Skalicka-Wozniak K, Aprotosoaie AC, Trifan A (2019) Bioactivity of dietary polyphenols: the role of metabolites. Crit Rev Food Sci Nutr 1–34.

  • Ma B, Liang J, Dai M, Wang J, Luo J, Zhang Z, Jing J (2019) Altered gut microbiota in Chinese children with autism spectrum disorders. Front Cell Infect Microbiol 9:40

    Article  PubMed  PubMed Central  Google Scholar 

  • Macfarlane GT, Cummings JH (1991) The colonic flora, fermentation and large bowel digestive function. In: Phillips SF, Pemberton JH, Shorter RG (eds) The large intestine: physiology, pathophysiology and disease. Raven Press, New York, pp 51–92

    Google Scholar 

  • Maier L, Pruteanu M, Kuhn M, Zeller G, Telzerow A, Anderson EE, Brochado AR, Fernandez KC, Dose H, Mori H, Patil KR, Bork P, Typas A (2018) Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 555:623–628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mann JD, Labrosse EH (1959) Urinary excretion of phenolic acids by normal and schizophrenic male patients. AMA Arch Gen Psychiatry 1:547–551

    Article  CAS  PubMed  Google Scholar 

  • Marshall DD, Powers R (2017) Beyond the paradigm: combining mass spectrometry and nuclear magnetic resonance for metabolomics. Prog Nucl Magn Reson Spectrosc 100:1–16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mavel S, Nadal-Desbarats L, Blasco H, Bonnet-Brilhault F, Barthelemy C, Montigny F, Sarda P, Laumonnier F, Vourc'h P, Andres CR, Emond P (2013) 1H-13C NMR-based urine metabolic profiling in autism spectrum disorders. Talanta 114:95–102

    Article  CAS  PubMed  Google Scholar 

  • Mazzoli R, Pessione E (2016) The neuro-endocrinological role of microbial glutamate and GABA signaling. Front Microbiol 7:1934

    Article  PubMed  PubMed Central  Google Scholar 

  • McGeer PL, McGeer EG, Boulding JE (1956) Relation of aromatic amino acids to excretory pattern of schizophrenics. Science 123:1078–1080

    Article  CAS  PubMed  Google Scholar 

  • Mead GC (1971) The amino acid-fermenting clostridia. J Gen Microbiol 67:47–56

    Article  CAS  PubMed  Google Scholar 

  • Ming X, Stein TP, Barnes V, Rhodes N, Guo L (2012) Metabolic perturbance in autism spectrum disorders: a metabolomics study. J Proteome Res 11:5856–5862

    Article  CAS  PubMed  Google Scholar 

  • Monagas M, Khan N, Andres-Lacueva C, Urpi-Sarda M, Vazquez-Agell M, Lamuela-Raventos RM, Estruch R (2009) Dihydroxylated phenolic acids derived from microbial metabolism reduce lipopolysaccharide-stimulated cytokine secretion by human peripheral blood mononuclear cells. Br J Nutr 102:201–206

    Article  CAS  PubMed  Google Scholar 

  • Mrochek JE, Dinsmore SR, Ohrt DW (1973) Monitoring phenylalanine-tyrosine metabolism by high-resolution liquid chromatography of urine. Clin Chem 19:927–936

    CAS  PubMed  Google Scholar 

  • Murota K, Nakamura Y, Uehara M (2018) Flavonoid metabolism: the interaction of metabolites and gut microbiota. Biosci Biotechnol Biochem 82:600–610

    Article  CAS  PubMed  Google Scholar 

  • Muskens JB, Velders FP, Staal WG (2017) Medical comorbidities in children and adolescents with autism spectrum disorders and attention deficit hyperactivity disorders: a systematic review. Eur Child Adolesc Psychiatry 26:1093–1103

    Article  PubMed  PubMed Central  Google Scholar 

  • Nakagawa Y, Shetlar MR, Wender SH (1965) Urinary products from quercetin in neomycin-treated rats. Biochim Biophys Acta 97:233–241

    Article  CAS  PubMed  Google Scholar 

  • Nguyen TT, Kosciolek T, Maldonado Y, Daly RE, Martin AS, McDonald D, Knight R, Jeste DV (2019) Differences in gut microbiome composition between persons with chronic schizophrenia and healthy comparison subjects. Schizophr Res 204:23–29

    Article  PubMed  Google Scholar 

  • Noto A, Fanos V, Barberini L, Grapov D, Fattuoni C, Zaffanello M, Casanova A, Fenu G, De Giacomo A, De Angelis M, Moretti C, Papoff P, Ditonno R, Francavilla R (2014) The urinary metabolomics profile of an Italian autistic children population and their unaffected siblings. J Matern Fetal Neonatal Med 27(Suppl 2):46–52

    Article  CAS  PubMed  Google Scholar 

  • Nunez-Montiel OL, Thompson FS, Dowell VR Jr (1983) Norleucine-tyrosine broth for rapid identification of Clostridium difficile by gas-liquid chromatography. J Clin Microbiol 17:382–385

    CAS  PubMed  PubMed Central  Google Scholar 

  • Obrenovich MEM (2018) Leaky gut, leaky brain? Microorganisms 6

    Article  PubMed Central  Google Scholar 

  • Obrenovich M, Mana TSC, Rai H, Shola D, Sass C, McCloskey B, Levison BS (2017) Recent findings within the microbiota–gut–brain–endocrine metabolic interactome. Pathol Lab Med Int 9:21–30

    Article  Google Scholar 

  • Obrenovich ME, Donskey CJ, Schiefer IT, Bongiovanni R, Li L, Jaskiw GE (2018) Quantification of phenolic acid metabolites in humans by LC-MS: a structural and targeted metabolomics approach. Bioanalysis 10:1591–1608

    Article  CAS  PubMed  Google Scholar 

  • Ohnishi R, Ito H, Iguchi A, Shinomiya K, Kamei C, Hatano T, Yoshida T (2006) Effects of chlorogenic acid and its metabolites on spontaneous locomotor activity in mice. Biosci Biotechnol Biochem 70:2560–2563

    Article  CAS  PubMed  Google Scholar 

  • Olde Loohuis LM, Mangul S, Ori APS, Jospin G, Koslicki D, Yang HT, Wu T, Boks MP, Lomen-Hoerth C, Wiedau-Pazos M, Cantor RM, de Vos WM, Kahn RS, Eskin E, Ophoff RA (2018) Transcriptome analysis in whole blood reveals increased microbial diversity in schizophrenia. Transl Psychiatry 8:96

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Olthof MR, Hollman PC, Buijsman MN, van Amelsvoort JM, Katan MB (2003) Chlorogenic acid, quercetin-3-rutinoside and black tea phenols are extensively metabolized in humans. J Nutr 133:1806–1814

    Article  CAS  PubMed  Google Scholar 

  • Ottaviani JI, Borges G, Momma TY, Spencer JP, Keen CL, Crozier A, Schroeter H (2016) The metabolome of [2-(14)C](-)-epicatechin in humans: implications for the assessment of efficacy, safety, and mechanisms of action of polyphenolic bioactives. Sci Rep 6:29034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pallister T, Jennings A, Mohney RP, Yarand D, Mangino M, Cassidy A, MacGregor A, Spector TD, Menni C (2016) Characterizing blood metabolomics profiles associated with self-reported food intakes in female twins. PLoS One 11:e0158568

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Patel KP, Luo FJ, Plummer NS, Hostetter TH, Meyer TW (2012) The production of p-cresol sulfate and indoxyl sulfate in vegetarians versus omnivores. Clin J Am Soc Nephrol 7:982–988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pereira-Caro G, Borges G, van der Hooft J, Clifford MN, Del Rio D, Lean ME, Roberts SA, Kellerhals MB, Crozier A (2014) Orange juice (poly)phenols are highly bioavailable in humans. Am J Clin Nutr 100:1378–1384

    Article  CAS  PubMed  Google Scholar 

  • Perry TL, Hansen S, Diamond S, Melancon SB, Lesk D (1971) Acetic and benzoic acids in the urine of patients with chronic schizophrenia. Clin Chim Acta 31:181–186

    Article  CAS  PubMed  Google Scholar 

  • Plaza-Diaz J, Gomez-Fernandez A, Chueca N, Torre-Aguilar MJ, Gil A, Perez-Navero JL, Flores-Rojas K, Martin-Borreguero P, Solis-Urra P, Ruiz-Ojeda FJ, Garcia F, Gil-Campos M (2019) Autism spectrum disorder (ASD) with and without mental regression is associated with changes in the fecal microbiota. Nutrients 11

  • Postorino V, Sanges V, Giovagnoli G, Fatta LM, De Peppo L, Armando M, Vicari S, Mazzone L (2015) Clinical differences in children with autism spectrum disorder with and without food selectivity. Appetite 92:126–132

    Article  PubMed  Google Scholar 

  • Potkin SG, Wyatt RJ, Karoum F (1980) Phenylethylamine (PEA) and phenylacetic acid (PAA) in the urine of chronic schizophrenic patients and controls. Psychopharmacol Bull 16:52–54

    CAS  PubMed  Google Scholar 

  • Prata J, Santos SG, Almeida MI, Coelho R, Barbosa MA (2017) Bridging autism spectrum disorders and schizophrenia through inflammation and biomarkers - pre-clinical and clinical investigations. J Neuroinflammation 14:179

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pulikkan J, Maji A, Dhakan DB, Saxena R, Mohan B, Anto MM, Agarwal N, Grace T, Sharma VK (2018) Gut microbial dysbiosis in Indian children with autism spectrum disorders. Microb Ecol 76:1102–1114

    Article  CAS  PubMed  Google Scholar 

  • Quastel JHW (1938) Faulty detoxification in schizophrenia. Lancet 232:301–305

    Article  Google Scholar 

  • Rampini S, Vollmin JA, Bosshard HR, Muller M, Curtius HC (1974) Aromatic acids in urine of healthy infants, persistent hyperphenylalaninemia, and phenylketonuria, before and after phenylalanine load. Pediatr Res 8:704–709

    Article  CAS  PubMed  Google Scholar 

  • Rashid MU, Zaura E, Buijs MJ, Keijser BJ, Crielaard W, Nord CE, Weintraub A (2015) Determining the long-term effect of antibiotic administration on the human normal intestinal microbiota using culture and pyrosequencing methods. Clin Infect Dis 60(Suppl 2):S77–S84

    Article  CAS  PubMed  Google Scholar 

  • Roick C, Fritz-Wieacker A, Matschinger H, Heider D, Schindler J, Riedel-Heller S, Angermeyer MC (2007) Health habits of patients with schizophrenia. Soc Psychiatry Psychiatr Epidemiol 42:268–276

    Article  PubMed  Google Scholar 

  • Rothschild D, Weissbrod O, Barkan E, Kurilshikov A, Korem T, Zeevi D, Costea PI, Godneva A, Kalka IN, Bar N, Shilo S, Lador D, Vila AV, Zmora N, Pevsner-Fischer M, Israeli D, Kosower N, Malka G, Wolf BC, Avnit-Sagi T, Lotan-Pompan M, Weinberger A, Halpern Z, Carmi S, Fu J, Wijmenga C, Zhernakova A, Elinav E, Segal E (2018) Environment dominates over host genetics in shaping human gut microbiota. Nature 555:210–215

    Article  CAS  PubMed  Google Scholar 

  • Russell WR, Duncan SH, Scobbie L, Duncan G, Cantlay L, Calder AG, Anderson SE, Flint HJ (2013) Major phenylpropanoid-derived metabolites in the human gut can arise from microbial fermentation of protein. Mol Nutr Food Res 57:523–535

    Article  CAS  PubMed  Google Scholar 

  • Sandler M, Ruthven CR, Goodwin BL, King GS, Pettit BR, Reynolds GP, Tyrer SP, Weller MP, Hirsch SR (1978) Raised cerebrospinal fluid phenylacetic acid concentration: preliminary support for the phenylethylamine hypothesis of schizophrenia? Commun Psychopharmacol 2:199–202

    CAS  PubMed  Google Scholar 

  • Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Vaisanen ML, Nelson MN, Wexler HM (2000) Short-term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol 15:429–435

    Article  CAS  PubMed  Google Scholar 

  • Sasaki T (1914) Uber die biochemische Umwandlung primarer Ei wei β-spaltprodukte durch Bakterien. I. Das Verhalten von Tyrosin gegen Bact. coli commune. Eine einfache biochemische Darstellungsmethode von p-Oxyphenylathylamin. Biochem Zeitschr 59:429–435

    CAS  Google Scholar 

  • Savin Z, Kivity S, Yonath H, Yehuda S (2018) Smoking and the intestinal microbiome. Arch Microbiol 200:677–684

    Article  CAS  PubMed  Google Scholar 

  • Scalbert A, Williamson G (2000) Dietary intake and bioavailability of polyphenols. J Nutr 130:2073S–2085S

    Article  CAS  PubMed  Google Scholar 

  • Schantz M, Erk T, Richling E (2010) Metabolism of green tea catechins by the human small intestine. Biotechnol J 5:1050–1059

    Article  CAS  PubMed  Google Scholar 

  • Scheline RR (1973) Metabolism of foreign compounds by gastrointestinal microorganisms. Pharmacol Rev 25:451–523

    CAS  PubMed  Google Scholar 

  • Schmidt JA, Rinaldi S, Ferrari P, Carayol M, Achaintre D, Scalbert A, Cross AJ, Gunter MJ, Fensom GK, Appleby PN, Key TJ, Travis RC (2015) Metabolic profiles of male meat eaters, fish eaters, vegetarians, and vegans from the EPIC-Oxford cohort. Am J Clin Nutr 102:1518–1526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmitt A, Rujescu D, Gawlik M, Hasan A, Hashimoto K, Iceta S, Jarema M, Kambeitz J, Kasper S, Keeser D, Kornhuber J, Koutsouleris N, Lanzenberger R, Malchow B, Saoud M, Spies M, Stober G, Thibaut F, Riederer P, Falkai P (2016) Consensus paper of the WFSBP Task force on biological markers: Criteria for biomarkers and endophenotypes of schizophrenia part II: cognition, neuroimaging and genetics. World J Biol Psychiatry 17:406–428

    Article  PubMed  Google Scholar 

  • Schmitt A, Martins-de-Souza D, Akbarian S, Cassoli JS, Ehrenreich H, Fischer A, Fonteh A, Gattaz WF, Gawlik M, Gerlach M, Grunblatt E, Halene T, Hasan A, Hashimoto K, Kim YK, Kirchner SK, Kornhuber J, Kraus TFJ, Malchow B, Nascimento JM, Rossner M, Schwarz M, Steiner J, Talib L, Thibaut F, Riederer P, Falkai P (2017) Consensus paper of the WFSBP Task Force on biological markers: criteria for biomarkers and endophenotypes of schizophrenia, part III: molecular mechanisms. World J Biol Psychiatry 18:330–356

    Article  PubMed  Google Scholar 

  • Schwarz E, Maukonen J, Hyytiainen T, Kieseppa T, Oresic M, Sabunciyan S, Mantere O, Saarela M, Yolken R, Suvisaari J (2018) Analysis of microbiota in first episode psychosis identifies preliminary associations with symptom severity and treatment response. Schizophr Res 192:398–403

    Article  PubMed  Google Scholar 

  • Selmer T, Andrei PI (2001) p-Hydroxyphenylacetate decarboxylase from Clostridium difficile. A novel glycyl radical enzyme catalysing the formation of p-cresol. Eur J Biochem 268:1363–1372

    Article  CAS  PubMed  Google Scholar 

  • Severance EG, Yolken RH (2019) From infection to the microbiome: an evolving role of microbes in schizophrenia. Curr Top Behav Neurosci

  • Severance EG, Gressitt KL, Stallings CR, Katsafanas E, Schweinfurth LA, Savage CL, Adamos MB, Sweeney KM, Origoni AE, Khushalani S, Leweke FM, Dickerson FB, Yolken RH (2016) Candida albicans exposures, sex specificity and cognitive deficits in schizophrenia and bipolar disorder. NPJ schizophrenia 2:16018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shangari N, Chan TS, O'Brien PJ (2005) Sulfation and glucuronidation of phenols: implications in coenyzme Q metabolism. Methods Enzymol 400:342–359

    Article  CAS  PubMed  Google Scholar 

  • Sharma RP, Faull K, Javaid JI, Davis JM (1995) Cerebrospinal fluid levels of phenylacetic acid in mental illness: behavioral associations and response to neuroleptic treatment. Acta Psychiatr Scand 91:293–298

    Article  CAS  PubMed  Google Scholar 

  • Shaw W (2010) Increased urinary excretion of a 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia spp. in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia. Nutr Neurosci 13:135–143

    Article  CAS  PubMed  Google Scholar 

  • Shaw W (2016) Clostridia bacteria in the gastrointestinal tract as a major cause of depression and other neuropsychiatric disorders. In: Greenblatt J, Brogan K (eds) Integrative Psychiatry for Depression: Redefining Models for Assessment, Treatment, and Prevention of Mood Disorders. Taylor and Francis, New York, pp 31–48

    Google Scholar 

  • Shaw W (2017) Elevated urinary glyphosate and clostridia metabolites with altered dopamine metabolism in triplets with autistic spectrum disorder or suspected seizure disorder: a case study. Integr Med (Encinitas) 16:50–57

    Google Scholar 

  • Shaw KN, Trevarthen J (1958) Exogenous sources of urinary phenol and indole acids. Nature 182:797–798

    Article  CAS  PubMed  Google Scholar 

  • Shaw KNF, Gutenstein M, Jepson JB (1961) Intestinal flora and diet in relation to m-hydroxyphenyl acids of human urine. In: Sissakian NM (ed) Fifth International Congress of Biochemistry. Pergamon Press, Moscow, p 427

    Google Scholar 

  • Shaw W, Kassen E, Chaves E (2000) Assessment of antifungal drug therapy in autism by measurement of suspected microbial metabolites in urine with gas chromatography-mass spectrometry. Clin Pract Altern Med 1:15–26

    Google Scholar 

  • Shen Y, Xu J, Li Z, Huang Y, Yuan Y, Wang J, Zhang M, Hu S, Liang Y (2018) Analysis of gut microbiota diversity and auxiliary diagnosis as a biomarker in patients with schizophrenia: a cross-sectional study. Schizophr Res

  • Sherwin E, Dinan TG, Cryan JF (2018) Recent developments in understanding the role of the gut microbiota in brain health and disease. Ann N Y Acad Sci 1420:5–25

    Article  PubMed  Google Scholar 

  • Singh RK, Chang HW, Yan D, Lee KM, Ucmak D, Wong K, Abrouk M, Farahnik B, Nakamura M, Zhu TH, Bhutani T, Liao W (2017) Influence of diet on the gut microbiome and implications for human health. J Transl Med 15:73

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Stalmach A, Edwards CA, Wightman JD, Crozier A (2013) Colonic catabolism of dietary phenolic and polyphenolic compounds from concord grape juice. Food Funct 4:52–62

    Article  CAS  PubMed  Google Scholar 

  • Strati F, Cavalieri D, Albanese D, De Felice C, Donati C, Hayek J, Jousson O, Leoncini S, Renzi D, Calabro A, De Filippo C (2017) New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 5:24

    Article  PubMed  PubMed Central  Google Scholar 

  • Tanaka T (1964) The decomposition of L-tyrosine and its derivatives by Proteus vulgaris. Bull Pharm Res Inst 50:1–7

    CAS  PubMed  Google Scholar 

  • Tanaka T (1968) The decomposition of 1-tyrosine and its derivatives by proteus vulgaris. (4) The decomposition pathway of p-hydroxyphenyllactic acid, p-hydroxyphenylacrylic acid and p-hydroxyphenylpropionic acid. Bull Pharm Res Inst 74:1–10

    CAS  PubMed  Google Scholar 

  • Theriot CM, Young VB (2015) Interactions between the gastrointestinal microbiome and Clostridium difficile. Annu Rev Microbiol 69:445–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thibaut F, Boutros NN, Jarema M, Oranje B, Hasan A, Daskalakis ZJ, Wichniak A, Schmitt A, Riederer P, Falkai P (2015) Consensus paper of the WFSBP Task Force on biological markers: criteria for biomarkers and endophenotypes of schizophrenia part I: neurophysiology. World J Biol Psychiatry 16:280–290

    Article  PubMed  Google Scholar 

  • Tomova A, Husarova V, Lakatosova S, Bakos J, Vlkova B, Babinska K, Ostatnikova D (2015) Gastrointestinal microbiota in children with autism in Slovakia. Physiol Behav 138:179–187

    Article  CAS  PubMed  Google Scholar 

  • Trošt K, Ulaszewska MM, Stanstrup J, Albanese D, De Filippo C, Tuohy KM, Natella F, Scaccini C, Mattivi F (2018) Host: microbiome co-metabolic processing of dietary polyphenols – an acute, single blinded, cross-over study with different doses of apple polyphenols in healthy subjects. Food Res Int 112:108–128

    Article  PubMed  CAS  Google Scholar 

  • Ulaszewska MM, Weinert CH, Trimigno A, Portmann R, Andres Lacueva C, Badertscher R, Brennan L, Brunius C, Bub A, Capozzi F, Cialiè Rosso M, Cordero CE, Daniel H, Durand S, Egert B, Ferrario PG, Feskens EJM, Franceschi P, Garcia-Aloy M, Giacomoni F, Giesbertz P, González-Domínguez R, Hanhineva K, Hemeryck LY, Kopka J, Kulling SE, Llorach R, Manach C, Mattivi F, Migné C, Münger LH, Ott B, Picone G, Pimentel G, Pujos-Guillot E, Riccadonna S, Rist MJ, Rombouts C, Rubert J, Skurk T, Sri Harsha PSC, Van Meulebroek L, Vanhaecke L, Vázquez-Fresno R, Wishart D, Vergères G (2019) nutrimetabolomics: an integrative action for metabolomic analyses in human nutritional studies. Mol Nutr Food Res 63:1800384

    Article  CAS  Google Scholar 

  • Vissiennon C, Nieber K, Kelber O, Butterweck V (2012) Route of administration determines the anxiolytic activity of the flavonols kaempferol, quercetin and myricetin--are they prodrugs? J Nutr Biochem 23:733–740

    Article  CAS  PubMed  Google Scholar 

  • Vollmin JA, Bosshard HR, Muller M, Rampini S, Curtius HC (1971) Determination of urinary aromatic acids by gas chromatography. Results from healthy infants and from patients with phenylketonuria. Z Klin Chem Klin Biochem 9:402–404

    CAS  PubMed  Google Scholar 

  • Vonstudnitz W, Engelman K, Sjoerdsma A (1964) Urinary excretion of phenolic acids in human subjects on a glucose diet. Clin Chim Acta 9:224–227

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT, Conlon MA (2013) Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder. Mol Autism 4:42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang D, Ho L, Faith J, Ono K, Janle EM, Lachcik PJ, Cooper BR, Jannasch AH, D'Arcy BR, Williams BA, Ferruzzi MG, Levine S, Zhao W, Dubner L, Pasinetti GM (2015) Role of intestinal microbiota in the generation of polyphenol-derived phenolic acid mediated attenuation of Alzheimer's disease beta-amyloid oligomerization. Mol Nutr Food Res 59:1025–1040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang J, Hodes GE, Zhang H, Zhang S, Zhao W, Golden SA, Bi W, Menard C, Kana V, Leboeuf M, Xie M, Bregman D, Pfau ML, Flanigan ME, Esteban-Fernandez A, Yemul S, Sharma A, Ho L, Dixon R, Merad M, Han MH, Russo SJ, Pasinetti GM (2018) Epigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice. Nat Commun 9:477

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang M, Wan J, Rong H, He F, Wang H, Zhou J, Cai C, Wang Y, Xu R, Yin Z, Zhou W (2019) Alterations in gut glutamate metabolism associated with changes in gut microbiota composition in children with autism spectrum disorder. mSystems 4

  • Westphal JF, Vetter D, Brogard JM (1994) Hepatic side-effects of antibiotics. J Antimicrob Chemother 33:387–401

    Article  CAS  PubMed  Google Scholar 

  • Williams BL, Hornig M, Buie T, Bauman ML, Cho Paik M, Wick I, Bennett A, Jabado O, Hirschberg DL, Lipkin WI (2011) Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS One 6:e24585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Williams BL, Hornig M, Parekh T, Lipkin WI (2012) Application of novel PCR-based methods for detection, quantitation, and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances. mBio 3

  • Williamson G, Clifford MN (2017) Role of the small intestine, colon and microbiota in determining the metabolic fate of polyphenols. Biochem Pharmacol 139:24–39

    Article  CAS  PubMed  Google Scholar 

  • Willmann PK, Bidzinski A, Jakimow B, Puzynski S (1977) [Psychomimetic compounds in the urine of schizophrenics. I. Study of catechol derivatives: so-called Pink Spot and 3.4-dimethoxyphenylethylamine (DMPEA)]. Psychiatr Pol 11:143–149

    CAS  PubMed  Google Scholar 

  • Wishart DS, Feunang YD, Marcu A, Guo AC, Liang K, Vazquez-Fresno R, Sajed T, Johnson D, Li C, Karu N, Sayeeda Z, Lo E, Assempour N, Berjanskii M, Singhal S, Arndt D, Liang Y, Badran H, Grant J, Serra-Cayuela A, Liu Y, Mandal R, Neveu V, Pon A, Knox C, Wilson M, Manach C, Scalbert A (2018) HMDB 4.0: the human metabolome database for 2018. Nucleic Acids Res 46:D608–D617

    Article  CAS  PubMed  Google Scholar 

  • Xiong X, Liu D, Wang Y, Zeng T, Peng Y (2016) Urinary 3-(3-Hydroxyphenyl)-3-hydroxypropionic acid, 3-hydroxyphenylacetic acid, and 3-hydroxyhippuric acid are elevated in children with autism spectrum disorders. BioMed research international 2016:9485412

    PubMed  PubMed Central  Google Scholar 

  • Yap IK, Angley M, Veselkov KA, Holmes E, Lindon JC, Nicholson JK (2010) Urinary metabolic phenotyping differentiates children with autism from their unaffected siblings and age-matched controls. J Proteome Res 9:2996–3004

    Article  CAS  PubMed  Google Scholar 

  • Yolken RH, Severance EG, Sabunciyan S, Gressitt KL, Chen O, Stallings C, Origoni A, Katsafanas E, Schweinfurth LA, Savage CL, Banis M, Khushalani S, Dickerson FB (2015) Metagenomic sequencing indicates that the oropharyngeal phageome of individuals with schizophrenia differs from that of controls. Schizophr Bull 41:1153–1161

    Article  PubMed  PubMed Central  Google Scholar 

  • Yoshimoto S, Kaku H, Shimogawa S, Watanabe A, Nakagawara M, Takahashi R (1987) Urinary trace amine excretion and platelet monoamine oxidase activity in schizophrenia. Psychiatry Res 21:229–236

    Article  CAS  PubMed  Google Scholar 

  • Young MK Jr, Berry HK, Beerstecher E Jr, Berry JS (1951) Metabolic patterns of schizophrenic and control groups. Biochemical Institute Studies IV: Individual metabolic patterns and human disease: an exploratory study utilizing predominantly paper chromatographic methods. The University of Texas Publication). University of Texas, Austin, pp 189–197

    Google Scholar 

  • Yuan X, Zhang P, Wang Y, Liu Y, Li X, Kumar BU, Hei G, Lv L, Huang XF, Fan X, Song X (2018) Changes in metabolism and microbiota after 24-week risperidone treatment in drug naive, normal weight patients with first episode schizophrenia. Schizophr Res 201:299–306

    Article  PubMed  Google Scholar 

  • Zeni AL, Zomkowski AD, Maraschin M, Rodrigues AL, Tasca CI (2012) Ferulic acid exerts antidepressant-like effect in the tail suspension test in mice: evidence for the involvement of the serotonergic system. Eur J Pharmacol 679:68–74

    Article  CAS  PubMed  Google Scholar 

  • Zeni ALB, Camargo A, Dalmagro AP (2017) Ferulic acid reverses depression-like behavior and oxidative stress induced by chronic corticosterone treatment in mice. Steroids 125:131–136

    Article  CAS  PubMed  Google Scholar 

  • Zhai Q, Cen S, Jiang J, Zhao J, Zhang H, Chen W (2019) Disturbance of trace element and gut microbiota profiles as indicators of autism spectrum disorder: A pilot study of Chinese children. Environ Res 171:501–509

    Article  CAS  PubMed  Google Scholar 

  • Zheng W, Chodobski A (2005) The blood-cerebrospinal barrier. Taylor and Francis, New York

    Google Scholar 

  • Zheng P, Zeng B, Liu M, Chen J, Pan J, Han Y, Liu Y, Cheng K, Zhou C, Wang H, Zhou X, Gui S, Perry SW, Wong ML, Licinio J, Wei H, Xie P (2019) The gut microbiome from patients with schizophrenia modulates the glutamate-glutamine-GABA cycle and schizophrenia-relevant behaviors in mice. Sci Adv 5:eaau8317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhernakova A, Kurilshikov A, Bonder MJ, Tigchelaar EF, Schirmer M, Vatanen T, Mujagic Z, Vila AV, Falony G, Vieira-Silva S, Wang J, Imhann F, Brandsma E, Jankipersadsing SA, Joossens M, Cenit MC, Deelen P, Swertz MA, Weersma RK, Feskens EJ, Netea MG, Gevers D, Jonkers D, Franke L, Aulchenko YS, Huttenhower C, Raes J, Hofker MH, Xavier RJ, Wijmenga C, Fu J (2016) Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science 352:565–569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ziedonis D, Hitsman B, Beckham JC, Zvolensky M, Adler LE, Audrain-McGovern J, Breslau N, Brown RA, George TP, Williams J, Calhoun PS, Riley WT (2008) Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res 10:1691–1715

    Article  PubMed  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to George E. Jaskiw.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article belongs to a Special Issue on Microbiome in Psychiatry & Psychopharmacology.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-019-05267-3

Keywords

Navigation