Advertisement

Psychopharmacology

, 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
Review

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.

Keywords

Schizophrenia Autism Microbiota Gut Polyphenols Phenolic Antipsychotic Brain 

Abbreviations

Chemical names

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

Other abbreviations

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

Notes

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).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 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.Google Scholar
  2. Aarbakke J, Bakke OM (1972) Localization of microbial L-tyrosine degradation in the intestine of coprophagy-prevented rats. Scand J Gastroenterol 7:417–421PubMedCrossRefGoogle Scholar
  3. Acheson RM, Paul RM, Tomlinson RV (1958) Some constituents of the urine of normal and schizophrenic individuals. Can J Biochem Physiol 36:295–305PubMedCrossRefGoogle Scholar
  4. 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 48:36–43PubMedCrossRefGoogle Scholar
  5. 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 16:252–260PubMedCrossRefGoogle Scholar
  6. Aretz I, Meierhofer D (2016) Advantages and Pitfalls of mass spectrometry based metabolome profiling in systems biology. Int J Mol Sci 17PubMedCentralCrossRefPubMedGoogle Scholar
  7. Armstrong MD, Shaw KN (1957) The occurrence of (-)-beta-m-hydroxyphenyl-hydracrylic acid in human urine. J Biol Chem 225:269–278PubMedGoogle Scholar
  8. Armstrong MD, Shaw KN, Wall PE (1956) The phenolic acids of human urine; paper chromatography of phenolic acids. J Biol Chem 218:293–303PubMedGoogle Scholar
  9. Asatoor AM (1968) The origin of urinary tyramine. Formation in tissue and by intestinal microorganisms. Clin Chim Acta 22:223–229PubMedCrossRefGoogle Scholar
  10. Asatoor AM, Chamberlain MJ, Emmerson BT, Johnson JR, Levi AJ, Milne MD (1967) Metabolic effects of oral neomycin. Clin Sci 33:111–124PubMedPubMedCentralGoogle Scholar
  11. 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 70:780–782PubMedCrossRefPubMedCentralGoogle Scholar
  12. 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 72:1155–1158PubMedCrossRefPubMedCentralGoogle Scholar
  13. 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:e652PubMedPubMedCentralCrossRefGoogle Scholar
  14. Bai W, Wang C, Ren C (2014) Intakes of total and individual flavonoids by US adults. Int J Food Sci Nutr 65:9–20PubMedCrossRefPubMedCentralGoogle Scholar
  15. 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 232:463–471CrossRefGoogle Scholar
  16. 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 122:100–103PubMedCrossRefPubMedCentralGoogle Scholar
  17. 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:e59260PubMedPubMedCentralCrossRefGoogle Scholar
  18. 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 62:95–107PubMedCrossRefPubMedCentralGoogle Scholar
  19. Blander JM, Longman RS, Iliev ID, Sonnenberg GF, Artis D (2017) Regulation of inflammation by microbiota interactions with the host. Nat Immunol 18:851–860PubMedPubMedCentralCrossRefGoogle Scholar
  20. 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 29:1448–1454PubMedCrossRefPubMedCentralGoogle Scholar
  21. 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 1334:45–57PubMedCrossRefPubMedCentralGoogle Scholar
  22. Bongiovanni R, Leonard S, Jaskiw GE (2013) A simplified method to quantify dysregulated tyrosine transport in schizophrenia. Schizophr Res 150:386–391PubMedCrossRefPubMedCentralGoogle Scholar
  23. 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 1648:372–379PubMedCrossRefPubMedCentralGoogle Scholar
  24. 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:e73076PubMedPubMedCentralCrossRefGoogle Scholar
  25. Briggs MH (1962) A comparative study of urinary aromatic compounds from hospitalised mental patients and normal subjects. N Z Med J 61:317–320PubMedPubMedCentralGoogle Scholar
  26. Briggs MH, Harvey N (1962) Urinary metabolites of aromatic amino acids in schizophrenia. Life Sci 1:61–64CrossRefGoogle Scholar
  27. Cassidy A, Minihane AM (2017) The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids. Am J Clin Nutr 105:10–22PubMedCrossRefPubMedCentralGoogle Scholar
  28. 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 24:425–492PubMedCrossRefPubMedCentralGoogle Scholar
  29. Collins SM, Surette M, Bercik P (2012) The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol 10:735–742PubMedPubMedCentralCrossRefGoogle Scholar
  30. 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 9:3146PubMedPubMedCentralCrossRefGoogle Scholar
  31. 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 1–24CrossRefGoogle Scholar
  32. 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 32:2094–2101PubMedCrossRefPubMedCentralGoogle Scholar
  33. Cunha BA (2001) Antibiotic side effects. Med Clin North Am 85:149–185PubMedCrossRefPubMedCentralGoogle Scholar
  34. Curtius HC, Mettler M, Ettlinger L (1976a) Study of the intestinal tyrosine metabolism using stable isotopes and gas chromatography-mass spectrometry. J Chromatogr 126:569–580PubMedCrossRefPubMedCentralGoogle Scholar
  35. 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 385–391Google Scholar
  36. Dai ZL, Wu G, Zhu WY (2011) Amino acid metabolism in intestinal bacteria: links between gut ecology and host health. Front Biosci 16:1768–1786CrossRefGoogle Scholar
  37. Das NP (1974) Studies on flavonoid metabolism. Excretion of m-hydroxyphenylhydracrylic acid from (plus)-catechin in the monkey (Macaca iris sp.). Drug Metab Dispos 2:209–213PubMedPubMedCentralGoogle Scholar
  38. Dastur DK, Mann JD, Pollin W (1963) Hippuric acid excretion coffee, and schizophremia. Arch Gen Psychiatry 9:79–82PubMedCrossRefPubMedCentralGoogle Scholar
  39. 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 505:559–563PubMedPubMedCentralCrossRefGoogle Scholar
  40. 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 6:97–105PubMedCrossRefPubMedCentralGoogle Scholar
  41. 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 15:41–47PubMedCrossRefPubMedCentralGoogle Scholar
  42. Dayman J, Jepson JB (1969) The metabolism of caffeic acid in humans: the dehydroxylating action of intestinal bacteria. Biochem J 113:11PPubMedPubMedCentralCrossRefGoogle Scholar
  43. 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:e76993PubMedPubMedCentralCrossRefGoogle Scholar
  44. 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 26:34–44PubMedCrossRefPubMedCentralGoogle Scholar
  45. DeQuattro VL, Sjoerdsma A (1967) Origin of urinary tyramine and tryptamine. Clin Chim Acta 16:227–233PubMedCrossRefPubMedCentralGoogle Scholar
  46. 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 14:5273–5282PubMedCrossRefPubMedCentralGoogle Scholar
  47. 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 175:354–361PubMedCrossRefPubMedCentralGoogle Scholar
  48. 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 19:568–570PubMedPubMedCentralCrossRefGoogle Scholar
  49. 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 551:648–652PubMedPubMedCentralCrossRefGoogle Scholar
  50. 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 12:24PubMedPubMedCentralCrossRefGoogle Scholar
  51. Elsden SR, Hilton MG, Waller JM (1976) The end products of the metabolism of aromatic amino acids by Clostridia. Arch Microbiol 107:283–288PubMedCrossRefPubMedCentralGoogle Scholar
  52. Epps HM (1944) Studies on bacterial amino-acid decarboxylases: 2. l(-)-tyrosine decarboxylase from Streptococcus faecalis. Biochem J 38:242–249PubMedPubMedCentralGoogle Scholar
  53. 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 131:235–241PubMedCrossRefPubMedCentralGoogle Scholar
  54. Faull KF, King RJ, Barchas JD, Csernansky JG (1989) CSF phenylacetic acid and hostility in paranoid schizophrenia. Psychiatry Res 30:111–118PubMedCrossRefPubMedCentralGoogle Scholar
  55. 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 418:82–86PubMedCrossRefPubMedCentralGoogle Scholar
  56. 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 16:444–453PubMedCrossRefPubMedCentralGoogle Scholar
  57. 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 45:133–137PubMedCrossRefPubMedCentralGoogle Scholar
  58. 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 37:261–267CrossRefGoogle Scholar
  59. 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. PharmacotherapyGoogle Scholar
  60. 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 32:5390–5404PubMedPubMedCentralCrossRefGoogle Scholar
  61. 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 19:463–470PubMedCrossRefGoogle Scholar
  62. 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 9:752–759PubMedCrossRefGoogle Scholar
  63. Gale EF (1953) Amino-acid decarboxylases. Br Med Bull 9:135–138PubMedCrossRefGoogle Scholar
  64. 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 359:693–697PubMedPubMedCentralCrossRefGoogle Scholar
  65. 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 12:34PubMedPubMedCentralCrossRefGoogle Scholar
  66. 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 6:1341–1352PubMedCrossRefPubMedCentralGoogle Scholar
  67. Gattaz WF, Gasser T, Beckmann H (1985) Multidimensional analysis of the concentrations of 17 substances in the CSF of schizophrenics and controls. Biol Psychiatry 20:360–366PubMedCrossRefPubMedCentralGoogle Scholar
  68. Gerhauser C (2018) Impact of dietary gut microbial metabolites on the epigenome. Philos Trans R Soc Lond B Biol Sci 373.CrossRefGoogle Scholar
  69. 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 5:419–427PubMedCrossRefPubMedCentralGoogle Scholar
  70. 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 39:1680–1688PubMedCrossRefGoogle Scholar
  71. 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 51:73–77PubMedCrossRefGoogle Scholar
  72. 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 93PubMedPubMedCentralCrossRefGoogle Scholar
  73. Group BDW (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95CrossRefGoogle Scholar
  74. 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–S242PubMedGoogle Scholar
  75. Hafiz S, Oakley CL (1976) Clostridium difficile: isolation and characteristics. J Med Microbiol 9:129–136PubMedCrossRefGoogle Scholar
  76. Hagenfeldt L, Venizelos N, Bjerkenstedt L, Wiesel FA (1987) Decreased tyrosine transport in fibroblasts from schizophrenic patients. Life Sci 41:2749–2757PubMedCrossRefGoogle Scholar
  77. 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 179:9–14PubMedCrossRefGoogle Scholar
  78. 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 53:37–45PubMedPubMedCentralCrossRefGoogle Scholar
  79. Hervert-Hernandez D, Goni I (2011) Dietary polyphenols and human gut microbiota: a review. Food Rev Int 27:154–169CrossRefGoogle Scholar
  80. Hicks JM, Young DS, Wootton ID (1964) The effect of uraeic blood constituents on certain cerebral enzymes. Clin Chim Acta 9:228–235PubMedCrossRefGoogle Scholar
  81. 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 64:170–181PubMedCrossRefGoogle Scholar
  82. 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 11:24–36PubMedCrossRefGoogle Scholar
  83. Hughes HK, Ashwood P (2018) Anti-Candida albicans IgG antibodies in children with autism spectrum disorders. Front Psychiatry 9:627PubMedPubMedCentralCrossRefGoogle Scholar
  84. Hyland NP, Cryan JF (2016) Microbe-host interactions: Influence of the gut microbiota on the enteric nervous system. Dev Biol 417:182–187PubMedCrossRefGoogle Scholar
  85. 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 182:349–363PubMedCrossRefGoogle Scholar
  86. 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 40:1035–1046PubMedCrossRefGoogle Scholar
  87. 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 71:115–123PubMedCrossRefGoogle Scholar
  88. 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 1:15067PubMedCrossRefGoogle Scholar
  89. 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–D361CrossRefGoogle Scholar
  90. 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:e68322PubMedPubMedCentralCrossRefGoogle Scholar
  91. 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 49:121–131PubMedCrossRefGoogle Scholar
  92. 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 181:1–7PubMedCrossRefGoogle Scholar
  93. 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 19:165–178PubMedGoogle Scholar
  94. Kawabata M, Kobayashi K, Shohmori T (1986) Determination of phenylacetic acid in cerebrospinal fluid by gas chromatography-mass spectrometry. Acta Med Okayama 40:271–276PubMedGoogle Scholar
  95. 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 35:101–109PubMedCrossRefGoogle Scholar
  96. 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–D1213PubMedCrossRefGoogle Scholar
  97. Kuhnau J (1976) The flavonoids. A class of semi-essential food components: their role in human nutrition. World Rev Nutr Diet 24:117–191PubMedCrossRefGoogle Scholar
  98. 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 262:380–385PubMedCrossRefGoogle Scholar
  99. Lally J, MacCabe JH (2015) Antipsychotic medication in schizophrenia: a review. Br Med Bull 114:169–179PubMedCrossRefGoogle Scholar
  100. 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 47:332–345PubMedCrossRefPubMedCentralGoogle Scholar
  101. Lee HC, Jenner AM, Low CS, Lee YK (2006) Effect of tea phenolics and their aromatic fecal bacterial metabolites on intestinal microbiota. Res Microbiol 157:876–884PubMedCrossRefPubMedCentralGoogle Scholar
  102. Lewis SJ, Heaton KW (1997) Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol 32:920–924PubMedCrossRefPubMedCentralGoogle Scholar
  103. 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 32:834–841PubMedCrossRefPubMedCentralGoogle Scholar
  104. 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 22:1528–1532PubMedPubMedCentralGoogle Scholar
  105. 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 59:2107–2118PubMedPubMedCentralCrossRefGoogle Scholar
  106. 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 25:1483–1490CrossRefGoogle Scholar
  107. 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 19:185–212PubMedCrossRefPubMedCentralGoogle Scholar
  108. 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.Google Scholar
  109. 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 9:40PubMedPubMedCentralCrossRefGoogle Scholar
  110. 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 51–92Google Scholar
  111. 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 555:623–628PubMedPubMedCentralCrossRefGoogle Scholar
  112. Mann JD, Labrosse EH (1959) Urinary excretion of phenolic acids by normal and schizophrenic male patients. AMA Arch Gen Psychiatry 1:547–551PubMedCrossRefPubMedCentralGoogle Scholar
  113. Marshall DD, Powers R (2017) Beyond the paradigm: combining mass spectrometry and nuclear magnetic resonance for metabolomics. Prog Nucl Magn Reson Spectrosc 100:1–16PubMedPubMedCentralCrossRefGoogle Scholar
  114. 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 114:95–102PubMedCrossRefPubMedCentralGoogle Scholar
  115. Mazzoli R, Pessione E (2016) The neuro-endocrinological role of microbial glutamate and GABA signaling. Front Microbiol 7:1934PubMedPubMedCentralCrossRefGoogle Scholar
  116. McGeer PL, McGeer EG, Boulding JE (1956) Relation of aromatic amino acids to excretory pattern of schizophrenics. Science 123:1078–1080PubMedCrossRefPubMedCentralGoogle Scholar
  117. Mead GC (1971) The amino acid-fermenting clostridia. J Gen Microbiol 67:47–56PubMedCrossRefPubMedCentralGoogle Scholar
  118. Ming X, Stein TP, Barnes V, Rhodes N, Guo L (2012) Metabolic perturbance in autism spectrum disorders: a metabolomics study. J Proteome Res 11:5856–5862PubMedCrossRefPubMedCentralGoogle Scholar
  119. 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 102:201–206PubMedCrossRefPubMedCentralGoogle Scholar
  120. Mrochek JE, Dinsmore SR, Ohrt DW (1973) Monitoring phenylalanine-tyrosine metabolism by high-resolution liquid chromatography of urine. Clin Chem 19:927–936PubMedPubMedCentralGoogle Scholar
  121. Murota K, Nakamura Y, Uehara M (2018) Flavonoid metabolism: the interaction of metabolites and gut microbiota. Biosci Biotechnol Biochem 82:600–610PubMedCrossRefPubMedCentralGoogle Scholar
  122. 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 26:1093–1103PubMedPubMedCentralCrossRefGoogle Scholar
  123. Nakagawa Y, Shetlar MR, Wender SH (1965) Urinary products from quercetin in neomycin-treated rats. Biochim Biophys Acta 97:233–241PubMedCrossRefPubMedCentralGoogle Scholar
  124. 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 204:23–29PubMedCrossRefPubMedCentralGoogle Scholar
  125. 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):46–52PubMedCrossRefPubMedCentralGoogle Scholar
  126. 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 17:382–385PubMedPubMedCentralGoogle Scholar
  127. Obrenovich MEM (2018) Leaky gut, leaky brain? Microorganisms 6PubMedCentralCrossRefGoogle Scholar
  128. 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 9:21–30CrossRefGoogle Scholar
  129. 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 10:1591–1608PubMedCrossRefPubMedCentralGoogle Scholar
  130. 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 70:2560–2563PubMedCrossRefPubMedCentralGoogle Scholar
  131. 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 8:96PubMedPubMedCentralCrossRefGoogle Scholar
  132. 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 133:1806–1814PubMedCrossRefPubMedCentralGoogle Scholar
  133. 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 6:29034PubMedPubMedCentralCrossRefGoogle Scholar
  134. 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:e0158568PubMedPubMedCentralCrossRefGoogle Scholar
  135. 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 7:982–988PubMedPubMedCentralCrossRefGoogle Scholar
  136. 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 100:1378–1384PubMedCrossRefPubMedCentralGoogle Scholar
  137. 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 31:181–186PubMedCrossRefPubMedCentralGoogle Scholar
  138. 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 11Google Scholar
  139. 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 92:126–132PubMedCrossRefPubMedCentralGoogle Scholar
  140. Potkin SG, Wyatt RJ, Karoum F (1980) Phenylethylamine (PEA) and phenylacetic acid (PAA) in the urine of chronic schizophrenic patients and controls. Psychopharmacol Bull 16:52–54PubMedPubMedCentralGoogle Scholar
  141. 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 14:179PubMedPubMedCentralCrossRefGoogle Scholar
  142. 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 76:1102–1114PubMedCrossRefPubMedCentralGoogle Scholar
  143. Quastel JHW (1938) Faulty detoxification in schizophrenia. Lancet 232:301–305CrossRefGoogle Scholar
  144. 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 8:704–709PubMedCrossRefPubMedCentralGoogle Scholar
  145. 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–S84PubMedCrossRefPubMedCentralGoogle Scholar
  146. 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 42:268–276PubMedCrossRefPubMedCentralGoogle Scholar
  147. 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 555:210–215CrossRefPubMedGoogle Scholar
  148. 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 57:523–535PubMedCrossRefPubMedCentralGoogle Scholar
  149. 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 2:199–202PubMedPubMedCentralGoogle Scholar
  150. 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 15:429–435PubMedCrossRefPubMedCentralGoogle Scholar
  151. 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 59:429–435Google Scholar
  152. Savin Z, Kivity S, Yonath H, Yehuda S (2018) Smoking and the intestinal microbiome. Arch Microbiol 200:677–684PubMedCrossRefPubMedCentralGoogle Scholar
  153. Scalbert A, Williamson G (2000) Dietary intake and bioavailability of polyphenols. J Nutr 130:2073S–2085SPubMedCrossRefGoogle Scholar
  154. Schantz M, Erk T, Richling E (2010) Metabolism of green tea catechins by the human small intestine. Biotechnol J 5:1050–1059PubMedCrossRefPubMedCentralGoogle Scholar
  155. Scheline RR (1973) Metabolism of foreign compounds by gastrointestinal microorganisms. Pharmacol Rev 25:451–523PubMedGoogle Scholar
  156. 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 102:1518–1526PubMedPubMedCentralCrossRefGoogle Scholar
  157. 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 17:406–428PubMedCrossRefPubMedCentralGoogle Scholar
  158. 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 18:330–356PubMedCrossRefGoogle Scholar
  159. 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 192:398–403CrossRefGoogle Scholar
  160. 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 268:1363–1372PubMedCrossRefGoogle Scholar
  161. Severance EG, Yolken RH (2019) From infection to the microbiome: an evolving role of microbes in schizophrenia. Curr Top Behav NeurosciGoogle Scholar
  162. 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 2:16018PubMedPubMedCentralCrossRefGoogle Scholar
  163. Shangari N, Chan TS, O'Brien PJ (2005) Sulfation and glucuronidation of phenols: implications in coenyzme Q metabolism. Methods Enzymol 400:342–359PubMedCrossRefPubMedCentralGoogle Scholar
  164. 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 91:293–298PubMedCrossRefPubMedCentralGoogle Scholar
  165. 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 13:135–143PubMedCrossRefPubMedCentralGoogle Scholar
  166. 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 31–48Google Scholar
  167. 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) 16:50–57Google Scholar
  168. Shaw KN, Trevarthen J (1958) Exogenous sources of urinary phenol and indole acids. Nature 182:797–798PubMedCrossRefPubMedCentralGoogle Scholar
  169. 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 427Google Scholar
  170. 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 1:15–26Google Scholar
  171. 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 ResGoogle Scholar
  172. 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 1420:5–25CrossRefPubMedGoogle Scholar
  173. 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 15:73PubMedPubMedCentralCrossRefGoogle Scholar
  174. Stalmach A, Edwards CA, Wightman JD, Crozier A (2013) Colonic catabolism of dietary phenolic and polyphenolic compounds from concord grape juice. Food Funct 4:52–62PubMedCrossRefPubMedCentralGoogle Scholar
  175. 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 5:24PubMedPubMedCentralCrossRefGoogle Scholar
  176. Tanaka T (1964) The decomposition of L-tyrosine and its derivatives by Proteus vulgaris. Bull Pharm Res Inst 50:1–7PubMedGoogle Scholar
  177. 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 74:1–10PubMedGoogle Scholar
  178. Theriot CM, Young VB (2015) Interactions between the gastrointestinal microbiome and Clostridium difficile. Annu Rev Microbiol 69:445–461PubMedPubMedCentralCrossRefGoogle Scholar
  179. 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 16:280–290PubMedCrossRefGoogle Scholar
  180. 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 138:179–187PubMedPubMedCentralCrossRefGoogle Scholar
  181. 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 112:108–128PubMedCrossRefGoogle Scholar
  182. 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 63:1800384CrossRefGoogle Scholar
  183. 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 23:733–740PubMedCrossRefGoogle Scholar
  184. 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 9:402–404PubMedGoogle Scholar
  185. Vonstudnitz W, Engelman K, Sjoerdsma A (1964) Urinary excretion of phenolic acids in human subjects on a glucose diet. Clin Chim Acta 9:224–227PubMedCrossRefGoogle Scholar
  186. 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 4:42PubMedPubMedCentralCrossRefGoogle Scholar
  187. 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 59:1025–1040PubMedPubMedCentralCrossRefGoogle Scholar
  188. 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 9:477PubMedPubMedCentralCrossRefGoogle Scholar
  189. 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 4Google Scholar
  190. Westphal JF, Vetter D, Brogard JM (1994) Hepatic side-effects of antibiotics. J Antimicrob Chemother 33:387–401PubMedCrossRefGoogle Scholar
  191. 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:e24585PubMedPubMedCentralCrossRefGoogle Scholar
  192. 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 3Google Scholar
  193. Williamson G, Clifford MN (2017) Role of the small intestine, colon and microbiota in determining the metabolic fate of polyphenols. Biochem Pharmacol 139:24–39PubMedCrossRefGoogle Scholar
  194. 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 11:143–149PubMedGoogle Scholar
  195. 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–D617PubMedCrossRefGoogle Scholar
  196. 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 2016:9485412PubMedPubMedCentralGoogle Scholar
  197. 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 9:2996–3004PubMedCrossRefGoogle Scholar
  198. 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 41:1153–1161PubMedPubMedCentralCrossRefGoogle Scholar
  199. 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 21:229–236PubMedCrossRefGoogle Scholar
  200. 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 189–197Google Scholar
  201. 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 201:299–306PubMedPubMedCentralCrossRefGoogle Scholar
  202. 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 679:68–74PubMedCrossRefPubMedCentralGoogle Scholar
  203. Zeni ALB, Camargo A, Dalmagro AP (2017) Ferulic acid reverses depression-like behavior and oxidative stress induced by chronic corticosterone treatment in mice. Steroids 125:131–136PubMedCrossRefPubMedCentralGoogle Scholar
  204. 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 171:501–509PubMedCrossRefPubMedCentralGoogle Scholar
  205. Zheng W, Chodobski A (2005) The blood-cerebrospinal barrier. Taylor and Francis, New YorkGoogle Scholar
  206. 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:eaau8317PubMedPubMedCentralCrossRefGoogle Scholar
  207. 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 352:565–569PubMedPubMedCentralCrossRefGoogle Scholar
  208. 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 10:1691–1715PubMedCrossRefPubMedCentralGoogle Scholar

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

Personalised recommendations