Microbial-Derived Tryptophan Metabolites and Their Role in Neurological Disease: Anthranilic Acid and Anthranilic Acid Derivatives

The gut microbiome provides the host access to otherwise indigestible nutrients, which are often further metabolized by the microbiome into bioactive components. The gut microbiome can also shift the balance of host-produced compounds, which may alter host health. One precursor to bioactive metabolites is the essential aromatic amino acid tryptophan. Tryptophan is mostly shunted into the kynurenine pathway but is also the primary metabolite for serotonin production and the bacterial indole pathway. Balance between tryptophan-derived bioactive metabolites is crucial for neurological homeostasis and metabolic imbalance can trigger or exacerbate neurological diseases. Alzheimer’s, depression, and schizophrenia have been linked to diverging levels of tryptophan-derived anthranilic, kynurenic, and quinolinic acid. Anthranilic acid from collective microbiome metabolism plays a complex but important role in systemic host health. Although anthranilic acid and its metabolic products are of great importance for host–microbe interaction in neurological health, literature examining the mechanistic relationships between microbial production, host regulation, and neurological diseases is scarce and at times conflicting. This narrative review provides an overview of the current understanding of anthranilic acid’s role in neurological health and disease, with particular focus on the contribution of the gut microbiome, the gut–brain axis, and the involvement of the three major tryptophan pathways.

[1]  Gun-Hwa Kim,et al.  Natural Product Skatole Ameliorates Lipotoxicity-Induced Multiple Hepatic Damage under Hyperlipidemic Conditions in Hepatocytes , 2023, Nutrients.

[2]  F. Turroni,et al.  The human gut microbiome of athletes: metagenomic and metabolic insights , 2023, Microbiome.

[3]  M. Wargo,et al.  Lactobacillus reuteri tryptophan metabolism promotes host susceptibility to CNS autoimmunity , 2022, Microbiome.

[4]  Nandita R. Garud,et al.  Community diversity is associated with intra-species genetic diversity and gene loss in the human gut microbiome , 2022, bioRxiv.

[5]  J. Savitz,et al.  The association of kynurenine pathway metabolites with symptom severity and clinical features of bipolar disorder: An overview , 2022, European Psychiatry.

[6]  S. Mande,et al.  Host-microbiome interactions: Gut-Liver axis and its connection with other organs , 2022, npj Biofilms and Microbiomes.

[7]  A. Klegeris,et al.  Dynamic changes in metabolites of the kynurenine pathway in Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease: A systematic Review and meta-analysis , 2022, Frontiers in Immunology.

[8]  M. Sheu,et al.  Modulation of Aryl Hydrocarbon Receptor Expression Alleviated Neuropathic Pain in a Chronic Constriction Nerve Injury Animal Model , 2022, International journal of molecular sciences.

[9]  A. Kraneveld,et al.  The Autism Spectrum Disorder-Associated Bacterial Metabolite p-Cresol Derails the Neuroimmune Response of Microglial Cells Partially via Reduction of ADAM17 and ADAM10 , 2022, International journal of molecular sciences.

[10]  J. Chojnacki,et al.  Altered Tryptophan Metabolism on the Kynurenine Pathway in Depressive Patients with Small Intestinal Bacterial Overgrowth , 2022, Nutrients.

[11]  Haiyang Li,et al.  Dual Role of Indoles Derived From Intestinal Microbiota on Human Health , 2022, Frontiers in Immunology.

[12]  M. Nieuwdorp,et al.  Interactions between Tryptophan Metabolism, the Gut Microbiome and the Immune System as Potential Drivers of Non-Alcoholic Fatty Liver Disease (NAFLD) and Metabolic Diseases , 2022, Metabolites.

[13]  Yibin Zhao,et al.  Factors influencing the blood-brain barrier permeability , 2022, Brain Research.

[14]  F. Blachier,et al.  Production of Indole and Indole-Related Compounds by the Intestinal Microbiota and Consequences for the Host: The Good, the Bad, and the Ugly , 2022, Microorganisms.

[15]  E. Hatano,et al.  Propionic Acid, Induced in Gut by an Inulin Diet, Suppresses Inflammation and Ameliorates Liver Ischemia and Reperfusion Injury in Mice , 2022, Frontiers in Immunology.

[16]  Nuno Empadinhas,et al.  Enzyme Promiscuity in Serotonin Biosynthesis, From Bacteria to Plants and Humans , 2022, Frontiers in Microbiology.

[17]  Yinbao Wu,et al.  Porcine gut microbiota in mediating host metabolic adaptation to cold stress , 2022, NPJ biofilms and microbiomes.

[18]  Yunke Li,et al.  Tryptophan and the innate intestinal immunity: Crosstalk between metabolites, host innate immune cells, and microbiota , 2022, European journal of immunology.

[19]  D. Rodionov,et al.  Genomics-Based Reconstruction and Predictive Profiling of Amino Acid Biosynthesis in the Human Gut Microbiome , 2022, Microorganisms.

[20]  P. Zamorano,et al.  The metabolite p‐cresol impairs dendritic development, synaptogenesis, and synapse function in hippocampal neurons: Implications for autism spectrum disorder , 2022, Journal of neurochemistry.

[21]  D. Fuchs,et al.  Gender-specific elevation of plasma anthranilic acid in schizophrenia: Protection against glutamatergic hypofunction? , 2022, Schizophrenia Research.

[22]  V. Cassone,et al.  Transcriptional effects of melatonin on the gut commensal bacterium Klebsiella aerogenes. , 2022, Genomics.

[23]  I. Mogilnicka,et al.  Biological Effects of Indole-3-Propionic Acid, a Gut Microbiota-Derived Metabolite, and Its Precursor Tryptophan in Mammals’ Health and Disease , 2022, International journal of molecular sciences.

[24]  Xiaotong Xie,et al.  Melatonin biosynthesis pathways in nature and its production in engineered microorganisms , 2022, Synthetic and systems biotechnology.

[25]  S. Liberles,et al.  Internal senses of the vagus nerve , 2022, Neuron.

[26]  Jindong Zhang,et al.  Roseburia hominis Increases Intestinal Melatonin Level by Activating p-CREB-AANAT Pathway , 2021, Nutrients.

[27]  L. Lv,et al.  Associations between expression of indoleamine 2, 3-dioxygenase enzyme and inflammatory cytokines in patients with first-episode drug-naive Schizophrenia , 2021, Translational Psychiatry.

[28]  A. Danser,et al.  The Function of the Kynurenine Pathway in the Placenta: A Novel Pharmacotherapeutic Target? , 2021, International journal of environmental research and public health.

[29]  Kun Lu,et al.  High-coverage metabolomics uncovers microbiota-driven biochemical landscape of interorgan transport and gut-brain communication in mice , 2021, Nature Communications.

[30]  N. Braidy,et al.  The kynurenine pathway in chronic diseases: a compensatory mechanism or a driving force? , 2021, Trends in molecular medicine.

[31]  Huanchun Chen,et al.  Meningitic Escherichia coli α-hemolysin aggravates blood–brain barrier disruption via targeting TGFβ1-triggered hedgehog signaling , 2021, Molecular Brain.

[32]  P. Manghi,et al.  Genomic diversity and ecology of human-associated Akkermansia species in the gut microbiome revealed by extensive metagenomic assembly , 2021, Genome biology.

[33]  Jie Chen,et al.  Alterations in Gut Vitamin and Amino Acid Metabolism are Associated with Symptoms and Neurodevelopment in Children with Autism Spectrum Disorder , 2021, Journal of Autism and Developmental Disorders.

[34]  P. Matthews,et al.  Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor , 2021, Proceedings of the National Academy of Sciences.

[35]  Yixiao Zhu,et al.  Glutamine supplementation affected the gut bacterial community and fermentation leading to improved nutrient digestibility in growth-retarded yaks. , 2021, FEMS microbiology ecology.

[36]  Chunhui Bao,et al.  Tryptophan-kynurenine metabolism: a link between the gut and brain for depression in inflammatory bowel disease , 2021, Journal of neuroinflammation.

[37]  P. Prasher,et al.  Medicinal chemistry of anthranilic acid derivatives: A mini review , 2021, Drug development research.

[38]  B. Poeggeler,et al.  Indoles as essential mediators in the gut-brain axis. Their role in Alzheimer's disease , 2021, Neurobiology of Disease.

[39]  Jinying Xu,et al.  Regulation of Neurotransmitters by the Gut Microbiota and Effects on Cognition in Neurological Disorders , 2021, Nutrients.

[40]  E. Fors,et al.  Kynurenine metabolites and ratios differ between Chronic Fatigue Syndrome, Fibromyalgia, and healthy controls , 2021, Psychoneuroendocrinology.

[41]  K. Newell,et al.  The kynurenine pathway in major depression: What we know and where to next , 2021, Neuroscience & Biobehavioral Reviews.

[42]  D. Fuchs,et al.  Plasma Anthranilic Acid and Leptin Levels Predict HAM-D Scores in Depressed Women , 2021, International journal of tryptophan research : IJTR.

[43]  Matthew P. Shaughnessy,et al.  Serotonin as a Mitogen in the Gastrointestinal Tract: Revisiting a Familiar Molecule in a New Role , 2021, Cellular and molecular gastroenterology and hepatology.

[44]  T. Perera,et al.  Early Life Stress and the Fate of Kynurenine Pathway Metabolites , 2021, Frontiers in Human Neuroscience.

[45]  Chang H. Kim Control of lymphocyte functions by gut microbiota-derived short-chain fatty acids , 2021, Cellular & Molecular Immunology.

[46]  Hong Wei,et al.  Fecal Microbiome Transplantation from Children with Autism Spectrum Disorder Modulates Tryptophan and Serotonergic Synapse Metabolism and Induces Altered Behaviors in Germ-Free Mice , 2021, mSystems.

[47]  M. Mohamadzadeh,et al.  Tryptophan Metabolism and Gut-Brain Homeostasis , 2021, International journal of molecular sciences.

[48]  I. Chiu,et al.  The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes , 2021, Mucosal Immunology.

[49]  W. Dai,et al.  Aryl Hydrocarbon Receptor: Its Roles in Physiology. , 2021, Biochemical pharmacology.

[50]  P. Greengard,et al.  Serotonin receptor 4 in the hippocampus modulates mood and anxiety , 2021, Molecular Psychiatry.

[51]  Keiko Umeda,et al.  Indole-3-acetic acid synthesized through the indole-3-pyruvate pathway promotes Candida tropicalis biofilm formation , 2020, PloS one.

[52]  Evgeny M. Zdobnov,et al.  OrthoDB in 2020: evolutionary and functional annotations of orthologs , 2020, Nucleic Acids Res..

[53]  G. Perdew,et al.  The aryl hydrocarbon receptor as a mediator of host-microbiota interplay , 2020, Gut microbes.

[54]  A. Szulc,et al.  Gut microbiota, kynurenine pathway and mental disorders – Review , 2020, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[55]  J. Savitz,et al.  The kynurenine pathway in bipolar disorder: a meta-analysis on the peripheral blood levels of tryptophan and related metabolites , 2020, Molecular Psychiatry.

[56]  Chongming Wu,et al.  The Gut Microbiota-Produced Indole-3-Propionic Acid Confers the Antihyperlipidemic Effect of Mulberry-Derived 1-Deoxynojirimycin , 2020, mSystems.

[57]  V. Salomaa,et al.  Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort , 2020, Nature Genetics.

[58]  B. Vellingiri,et al.  Kynurenine pathway in Parkinson's disease—An update , 2020, eNeurologicalSci.

[59]  Elizabeth A. Scoville,et al.  Succinate Produced by Intestinal Microbes Promotes Specification of Tuft Cells to Suppress Ileal Inflammation. , 2020, Gastroenterology.

[60]  D. Kalman,et al.  Indoles from the commensal microbiota act via the AHR and IL-10 to tune the cellular composition of the colonic epithelium during aging , 2020, Proceedings of the National Academy of Sciences.

[61]  E. de Vita,et al.  Kynurenine pathway metabolites in cerebrospinal fluid and blood as potential biomarkers in Huntington's disease , 2020, medRxiv.

[62]  Therese Limbana,et al.  Gut Microbiome and Depression: How Microbes Affect the Way We Think , 2020, Cureus.

[63]  Edward W. Davis,et al.  Ancient co-option of an amino acid ABC transporter locus in Pseudomonas syringae for host signal-dependent virulence gene regulation , 2020, PLoS pathogens.

[64]  Natta Tansila,et al.  Indole signaling decreases biofilm formation and related virulence of Listeria monocytogenes. , 2020, FEMS microbiology letters.

[65]  J. Clardy,et al.  Enteroendocrine cells sense bacterial tryptophan catabolites to activate enteric and vagal neuronal pathways , 2020, bioRxiv.

[66]  A. Baj,et al.  Tryptophan Metabolites Along the Microbiota-Gut-Brain Axis: An Interkingdom Communication System Influencing the Gut in Health and Disease , 2020, International journal of tryptophan research : IJTR.

[67]  N. Glaichenhaus,et al.  The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota , 2020, bioRxiv.

[68]  Rui B Chang,et al.  Vagal sensory neurons and gut-brain signaling , 2020, Current Opinion in Neurobiology.

[69]  R. P. Ross,et al.  Glucagon-Like Peptide-1 Secreting L-Cells Coupled to Sensory Nerves Translate Microbial Signals to the Host Rat Nervous System , 2020, Frontiers in Cellular Neuroscience.

[70]  Y. Eguchi,et al.  The Signaling Molecule Indole Inhibits Induction of the AR2 Acid Resistance System in Escherichia coli , 2020, Frontiers in Microbiology.

[71]  S. Puglisi‐Allegra,et al.  P-cresol Alters Brain Dopamine Metabolism and Exacerbates Autism-Like Behaviors in the BTBR Mouse , 2020, Brain sciences.

[72]  A. Zivkovic,et al.  Human gut microbiome composition and tryptophan metabolites were changed differently by fast food and Mediterranean diet in 4 days: a pilot study. , 2020, Nutrition research.

[73]  Weiling Hu,et al.  Deoxycholic Acid-Induced Gut Dysbiosis Disrupts Bile Acid Enterohepatic Circulation and Promotes Intestinal Inflammation , 2020, Digestive Diseases and Sciences.

[74]  C. Cervellati,et al.  Inflammation in neurological disorders: the thin boundary between brain and periphery. , 2020, Antioxidants & redox signaling.

[75]  Richard O. Williams,et al.  IDO and Kynurenine Metabolites in Peripheral and CNS Disorders , 2020, Frontiers in Immunology.

[76]  A. de Gottardi,et al.  The gut-liver axis in liver disease: pathophysiological basis for therapy. , 2020, Journal of hepatology.

[77]  M. Inglot,et al.  The role of anthranilic acid in the increase of depressive symptoms and major depressive disorder during treatment for hepatitis C with pegylated interferon-α2a and oral ribavirin , 2020, Journal of psychiatry & neuroscience : JPN.

[78]  C. Mu,et al.  Tryptophan Metabolism: A Link Between the Gut Microbiota and Brain. , 2019, Advances in nutrition.

[79]  P. Chanson,et al.  Peripheral tryptophan, serotonin, kynurenine, and their metabolites in major depression: A case–control study , 2019, Psychiatry and clinical neurosciences.

[80]  P. Naudé,et al.  Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target , 2019, Front. Immunol..

[81]  Kieran Rea,et al.  The Microbiota-Gut-Brain Axis. , 2019, Physiological reviews.

[82]  G. Guillemin,et al.  Kynurenine Pathway Metabolites as Biomarkers for Amyotrophic Lateral Sclerosis , 2019, Front. Neurosci..

[83]  M. Akagawa,et al.  Propionate suppresses hepatic gluconeogenesis via GPR43/AMPK signaling pathway. , 2019, Archives of biochemistry and biophysics.

[84]  D. Aarsland,et al.  Kynurenines, Neuropsychiatric Symptoms, and Cognitive Prognosis in Patients with Mild Dementia , 2019, International journal of tryptophan research : IJTR.

[85]  Hongyi Yang,et al.  Factors affecting the composition of the gut microbiota, and its modulation , 2019, PeerJ.

[86]  Jacob M. Luber,et al.  The Landscape of Genetic Content in the Gut and Oral Human Microbiome. , 2019, Cell host & microbe.

[87]  L. Albenberg,et al.  The Structure and Function of the Human Small Intestinal Microbiota: Current Understanding and Future Directions , 2019, Cellular and molecular gastroenterology and hepatology.

[88]  E. Allen-Vercoe,et al.  Macronutrient metabolism by the human gut microbiome: major fermentation by-products and their impact on host health , 2019, Microbiome.

[89]  V. Sperandio,et al.  Indole Signaling at the Host-Microbiota-Pathogen Interface , 2019, mBio.

[90]  S. Banskota,et al.  Serotonin in the gut: Blessing or a curse. , 2019, Biochimie.

[91]  Hamed Kazemi Shariat Panahi,et al.  Microorganisms, Tryptophan Metabolism, and Kynurenine Pathway: A Complex Interconnected Loop Influencing Human Health Status , 2019, International journal of tryptophan research : IJTR.

[92]  Jae Sung Cho,et al.  Microbial production of methyl anthranilate, a grape flavor compound , 2019, Proceedings of the National Academy of Sciences.

[93]  J. Savitz The Kynurenine Pathway: A Finger in Every Pie , 2019, Molecular Psychiatry.

[94]  T. Spector,et al.  Interplay between the human gut microbiome and host metabolism , 2019, Nature Communications.

[95]  Ahmed A. Metwally,et al.  Serotonin Transporter Deficiency is Associated with Dysbiosis and Changes in Metabolic Function of the Mouse Intestinal Microbiome , 2019, Scientific Reports.

[96]  P. Pirina,et al.  Circulating serotonin levels in COPD patients: a pilot study , 2018, BMC Pulmonary Medicine.

[97]  R. Gibbs,et al.  Temporal development of the gut microbiome in early childhood from the TEDDY study , 2018, Nature.

[98]  P. Bhargava,et al.  Altered tryptophan metabolism is associated with pediatric multiple sclerosis risk and course , 2018, Annals of clinical and translational neurology.

[99]  Xiling Shen,et al.  A gut-brain neural circuit for nutrient sensory transduction , 2018, Science.

[100]  R. Baldessarini,et al.  Tryptophan and Kynurenine Metabolites: Are They Related to Depression? , 2018, Neuropsychobiology.

[101]  Philip Strandwitz Neurotransmitter modulation by the gut microbiota , 2018, Brain Research.

[102]  M. Choudhary,et al.  Anthranilic Acid Derivatives: Novel Inhibitors of Protein Glycation and the Associated Oxidative Stress in the Hepatocytes. , 2018, Medicinal chemistry (Shariqah (United Arab Emirates)).

[103]  F. Bäckhed,et al.  Gut microbiota regulates maturation of the adult enteric nervous system via enteric serotonin networks , 2018, Proceedings of the National Academy of Sciences.

[104]  Harry Sokol,et al.  Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease. , 2018, Cell host & microbe.

[105]  Kyongbum Lee,et al.  Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages , 2018, Cell reports.

[106]  J. Miyoshi,et al.  Small Intestine Microbiota Regulate Host Digestive and Absorptive Adaptive Responses to Dietary Lipids. , 2018, Cell host & microbe.

[107]  N. Pons,et al.  Indole, a Signaling Molecule Produced by the Gut Microbiota, Negatively Impacts Emotional Behaviors in Rats , 2018, Front. Neurosci..

[108]  Micah T. Nelp,et al.  Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form , 2018, Proceedings of the National Academy of Sciences.

[109]  W. B. Church,et al.  Inhibition of human kynurenine aminotransferase isozymes by estrogen and its derivatives , 2017, Scientific Reports.

[110]  S. Poitevin,et al.  Indoxyl Sulfate Upregulates Liver P-Glycoprotein Expression and Activity through Aryl Hydrocarbon Receptor Signaling. , 2017, Journal of the American Society of Nephrology : JASN.

[111]  Eddy J. Bautista,et al.  Community characteristics of the gut microbiomes of competitive cyclists , 2017, Microbiome.

[112]  P. Moughan,et al.  Amino Acid Absorption in the Large Intestine of Humans and Porcine Models. , 2017, The Journal of nutrition.

[113]  C. Bode,et al.  The Effects of Serotonin in Immune Cells , 2017, Front. Cardiovasc. Med..

[114]  Kazufumi Yoshihara,et al.  Regulation of gut luminal serotonin by commensal microbiota in mice , 2017, PloS one.

[115]  David Julius,et al.  Enterochromaffin Cells Are Gut Chemosensors that Couple to Sensory Neural Pathways , 2017, Cell.

[116]  Yonggong Zhai,et al.  Melatonin prevents obesity through modulation of gut microbiota in mice , 2017, Journal of pineal research.

[117]  D. Fuchs,et al.  Increased breakdown of kynurenine towards its neurotoxic branch in bipolar disorder , 2017, PloS one.

[118]  M. Denison,et al.  And Now for Something Completely Different: Diversity in Ligand-Dependent Activation of Ah Receptor Responses. , 2017, Current opinion in toxicology.

[119]  T. Dinan,et al.  Kynurenine pathway metabolism and the microbiota-gut-brain axis , 2017, Neuropharmacology.

[120]  Lizhi Xu,et al.  Antibiotics-induced depletion of mice microbiota induces changes in host serotonin biosynthesis and intestinal motility , 2017, Journal of Translational Medicine.

[121]  J. O'Connor,et al.  Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation , 2016, Translational psychiatry.

[122]  S. Pyo,et al.  Inhibition of LPS-induced inflammatory mediators by 3-hydroxyanthranilic acid in macrophages through suppression of PI3K/NF-κB signaling pathways. , 2016, Food & function.

[123]  F. Bäckhed,et al.  Microbiota-Produced Succinate Improves Glucose Homeostasis via Intestinal Gluconeogenesis. , 2016, Cell metabolism.

[124]  A. Le Gouellec,et al.  Tryptophan catabolism in Pseudomonas aeruginosa and potential for inter-kingdom relationship , 2016, BMC Microbiology.

[125]  Frédéric Leroy,et al.  Bifidobacteria and Butyrate-Producing Colon Bacteria: Importance and Strategies for Their Stimulation in the Human Gut , 2016, Front. Microbiol..

[126]  F. Nicoletti,et al.  Altered kynurenine pathway metabolites in serum of chronic migraine patients , 2016, The Journal of Headache and Pain.

[127]  F. Nicoletti,et al.  Altered serum levels of kynurenine metabolites in patients affected by cluster headache , 2016, The Journal of Headache and Pain.

[128]  C. Bernstein Psychological Stress and Depression: Risk Factors for IBD? , 2016, Digestive Diseases.

[129]  J. Ochoa-Repáraz,et al.  The Second Brain: Is the Gut Microbiota a Link Between Obesity and Central Nervous System Disorders? , 2016, Current Obesity Reports.

[130]  V. Cassone,et al.  Human Gut Bacteria Are Sensitive to Melatonin and Express Endogenous Circadian Rhythmicity , 2016, PloS one.

[131]  T. Wood,et al.  Roles of indole as an interspecies and interkingdom signaling molecule. , 2015, Trends in microbiology.

[132]  C. Sudlow,et al.  Differences in Common Genetic Predisposition to Ischemic Stroke by Age and Sex , 2015, Stroke.

[133]  P. Okhuysen,et al.  A Rapid and Specific Method for the Detection of Indole in Complex Biological Samples , 2015, Applied and Environmental Microbiology.

[134]  William H. Bisson,et al.  Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles , 2015, Scientific Reports.

[135]  M. Zou,et al.  Tryptophan-kynurenine pathway is dysregulated in inflammation, and immune activation. , 2015, Frontiers in bioscience.

[136]  W. Weckwerth,et al.  Iron chelation and redox chemistry of anthranilic acid and 3-hydroxyanthranilic acid: A comparison of two structurally related kynurenine pathway metabolites to obtain improved insights into their potential role in neurological disease development , 2015, Journal of organometallic chemistry.

[137]  Rustem F. Ismagilov,et al.  Indigenous Bacteria from the Gut Microbiota Regulate Host Serotonin Biosynthesis , 2015, Cell.

[138]  C. Dejong,et al.  The Role of Microbial Amino Acid Metabolism in Host Metabolism , 2015, Nutrients.

[139]  Lai Guan Ng,et al.  The gut microbiota influences blood-brain barrier permeability in mice , 2014, Science Translational Medicine.

[140]  R. Knight,et al.  Gut Microbes and the Brain: Paradigm Shift in Neuroscience , 2014, The Journal of Neuroscience.

[141]  Davide Heller,et al.  STRING v10: protein–protein interaction networks, integrated over the tree of life , 2014, Nucleic Acids Res..

[142]  Andrew H. Van Benschoten,et al.  Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. , 2014, Cell host & microbe.

[143]  C. Barthélémy,et al.  Urinary p-cresol is elevated in young French children with autism spectrum disorder: a replication study , 2014, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[144]  A. Le Gouellec,et al.  Scavenging of reactive oxygen species by tryptophan metabolites helps Pseudomonas aeruginosa escape neutrophil killing. , 2014, Free radical biology & medicine.

[145]  A. Santamaría,et al.  The role of melatonin in multiple sclerosis, Huntington's disease and cerebral ischemia. , 2014, CNS & neurological disorders drug targets.

[146]  T. Connor,et al.  Inhibition of stress-induced hepatic tryptophan 2,3-dioxygenase exhibits antidepressant activity in an animal model of depressive behaviour. , 2014, The international journal of neuropsychopharmacology.

[147]  C. Huttenhower,et al.  Relating the metatranscriptome and metagenome of the human gut , 2014, Proceedings of the National Academy of Sciences.

[148]  Kyongbum Lee,et al.  Microbiome-Derived Tryptophan Metabolites and Their Aryl Hydrocarbon Receptor-Dependent Agonist and Antagonist Activities , 2014, Molecular Pharmacology.

[149]  B. Stockinger,et al.  The aryl hydrocarbon receptor: multitasking in the immune system. , 2014, Annual review of immunology.

[150]  R. Phillips Structure and mechanism of kynureninase. , 2014, Archives of biochemistry and biophysics.

[151]  A. von Deimling,et al.  Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR , 2014, Oncotarget.

[152]  R. Schwarcz,et al.  Targeted Deletion of Kynurenine 3-Monooxygenase in Mice , 2013, The Journal of Biological Chemistry.

[153]  M. Seeger,et al.  Genomic and Functional Analyses of the 2-Aminophenol Catabolic Pathway and Partial Conversion of Its Substrate into Picolinic Acid in Burkholderia xenovorans LB400 , 2013, PloS one.

[154]  S. Eussen,et al.  Substrate product ratios of enzymes in the kynurenine pathway measured in plasma as indicators of functional vitamin B-6 status. , 2013, The American journal of clinical nutrition.

[155]  J. Collins,et al.  Salmonella typhimurium intercepts Escherichia coli signaling to enhance antibiotic tolerance , 2013, Proceedings of the National Academy of Sciences.

[156]  Ryan D. Hernandez,et al.  Dysbiosis of the Gut Microbiota Is Associated with HIV Disease Progression and Tryptophan Catabolism , 2013, Science Translational Medicine.

[157]  F. Oakley,et al.  Serotonin paracrine signaling in tissue fibrosis☆☆☆ , 2013, Biochimica et biophysica acta.

[158]  S. Denery-Papini,et al.  Perinatal and postweaning exposure to galactooligosaccharides/inulin prebiotics induced biomarkers linked to tolerance mechanism in a mouse model of strong allergic sensitization. , 2013, Journal of agricultural and food chemistry.

[159]  P. Scully,et al.  The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner , 2013, Molecular Psychiatry.

[160]  J. Foster,et al.  SLC6 transporters: structure, function, regulation, disease association and therapeutics. , 2013, Molecular aspects of medicine.

[161]  V. Tremaroli,et al.  Functional interactions between the gut microbiota and host metabolism , 2012, Nature.

[162]  E. Chesler,et al.  Host genetic and environmental effects on mouse intestinal microbiota , 2012, The ISME Journal.

[163]  R. Schwarcz,et al.  Kynurenines in the mammalian brain: when physiology meets pathology , 2012, Nature Reviews Neuroscience.

[164]  Li-ping Zhou,et al.  Indoleamine 2,3-dioxygenase expression in human inflammatory bowel disease , 2012, European journal of gastroenterology & hepatology.

[165]  Peer Bork,et al.  The human small intestinal microbiota is driven by rapid uptake and conversion of simple carbohydrates , 2012, The ISME Journal.

[166]  N. Braidy,et al.  Changes in kynurenine pathway metabolism in the brain, liver and kidney of aged female Wistar rats , 2011, The FEBS journal.

[167]  Sunhee C. Lee,et al.  The tryptophan metabolite 3-hydroxyanthranilic acid plays anti-inflammatory and neuroprotective roles during inflammation: role of hemeoxygenase-1. , 2011, The American journal of pathology.

[168]  N. de Pedro,et al.  Melatonin effects on gut motility are independent of the relaxation mediated by the nitrergic system in the goldfish. , 2011, Comparative biochemistry and physiology. Part A, Molecular & integrative physiology.

[169]  J. Alverdy,et al.  Contributions of intestinal bacteria to nutrition and metabolism in the critically ill. , 2011, The Surgical clinics of North America.

[170]  B. Leonard,et al.  The new ‘5-HT’ hypothesis of depression: Cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression , 2011, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[171]  F. Muratori,et al.  Urinary p-cresol is elevated in small children with severe autism spectrum disorder , 2011, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[172]  M. D’Esposito,et al.  Estrogen Shapes Dopamine-Dependent Cognitive Processes: Implications for Women's Health , 2011, The Journal of Neuroscience.

[173]  Jintae Lee,et al.  Indole as an intercellular signal in microbial communities. , 2010, FEMS microbiology reviews.

[174]  P. Bork,et al.  A human gut microbial gene catalogue established by metagenomic sequencing , 2010, Nature.

[175]  Nicholas Stoy,et al.  On the Biological Importance of the 3-hydroxyanthranilic Acid: Anthranilic Acid Ratio , 2010, International journal of tryptophan research : IJTR.

[176]  A. Jayaraman,et al.  The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates indicators of inflammation , 2009, Proceedings of the National Academy of Sciences.

[177]  B. Brew,et al.  Effect of quinolinic acid on human astrocytes morphology and functions: implications in Alzheimer's disease , 2009, Journal of Neuroinflammation.

[178]  A. Yamaguchi,et al.  Secreted indole serves as a signal for expression of type III secretion system translocators in enterohaemorrhagic Escherichia coli O157:H7. , 2009, Microbiology.

[179]  L. Lix,et al.  The Manitoba IBD Cohort Study: A Population-Based Study of the Prevalence of Lifetime and 12-Month Anxiety and Mood Disorders , 2008, The American Journal of Gastroenterology.

[180]  W. Zgrajka,et al.  Micromolar concentration of kynurenic acid in rat small intestine , 2008, Amino Acids.

[181]  Gilles J Guillemin,et al.  Characterization of the Kynurenine Pathway in Human Neurons , 2007, The Journal of Neuroscience.

[182]  G. M. Mackay,et al.  Altered kynurenine metabolism correlates with infarct volume in stroke , 2007, The European journal of neuroscience.

[183]  M. Feldmann,et al.  The anti-allergic drug, N-(3',4'-dimethoxycinnamonyl) anthranilic acid, exhibits potent anti-inflammatory and analgesic properties in arthritis. , 2007, Rheumatology.

[184]  John H. Loughrin,et al.  Characterization of skatole-producing microbial populations in enriched swine lagoon slurry. , 2007, FEMS microbiology ecology.

[185]  Rajiv Chopra,et al.  Identification of anthranilic acid derivatives as a novel class of allosteric inhibitors of hepatitis C NS5B polymerase. , 2007, Journal of medicinal chemistry.

[186]  Thomas K. Wood,et al.  YliH (BssR) and YceP (BssS) Regulate Escherichia coli K-12 Biofilm Formation by Influencing Cell Signaling , 2006, Applied and Environmental Microbiology.

[187]  E. Romeo,et al.  Luminal kidney and intestine SLC6 amino acid transporters of B0AT-cluster and their tissue distribution in Mus musculus. , 2006, American journal of physiology. Renal physiology.

[188]  K. Ho,et al.  Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: a randomised, double blind, placebo controlled study , 2005, Gut.

[189]  H. Tilg,et al.  Overexpression of indoleamine 2,3-dioxygenase in human inflammatory bowel disease. , 2004, Clinical Immunology.

[190]  Tadhg P Begley,et al.  NAD biosynthesis: identification of the tryptophan to quinolinate pathway in bacteria. , 2003, Chemistry & biology.

[191]  Pieter Dorrestein,et al.  Aerobic tryptophan degradation pathway in bacteria: novel kynurenine formamidase. , 2003, FEMS microbiology letters.

[192]  A. Caspi,et al.  Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene , 2003, Science.

[193]  B. Brew,et al.  Implications of the kynurenine pathway and quinolinic acid in Alzheimer's disease , 2002, Redox report : communications in free radical research.

[194]  Jacobo Wortsman,et al.  Conversion of L‐tryptophan to serotonin and melatonin in human melanoma cells , 2002, FEBS letters.

[195]  B. Brew,et al.  Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection , 2001, Journal of neurochemistry.

[196]  J. Kountouras,et al.  Reactive oxygen metabolites and upper gastrointestinal diseases. , 2001, Hepato-gastroenterology.

[197]  G. Bentley Unraveling the enigma: The role of melatonin in seasonal processes in birds , 2001, Microscopy research and technique.

[198]  L. Lubbers,et al.  Distribution of mRNAs encoding the arylhydrocarbon receptor, arylhydrocarbon receptor nuclear translocator, and arylhydrocarbon receptor nuclear translocator‐2 in the rat brain and brainstem , 2000, The Journal of comparative neurology.

[199]  A. Brzezinski Melatonin in humans. , 1997, The New England journal of medicine.

[200]  A. M. Castrucci,et al.  Comparative aspects of the pineal/melatonin system of poikilothermic vertebrates , 1996, Journal of pineal research.

[201]  G. Huether Melatonin Synthesis in the Gastrointestinal Tract and the Impact of Nutritional Factors on Circulating Melatonin , 1994, Annals of the New York Academy of Sciences.

[202]  M. Demitrack,et al.  Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. , 1992, Brain : a journal of neurology.

[203]  W. Pardridge,et al.  Transport of Tryptophan into Brain from the Circulating, Albumin‐Bound Pool in Rats and in Rabbits , 1990, Journal of neurochemistry.

[204]  E. Werner,et al.  Characteristics of interferon induced tryptophan metabolism in human cells in vitro. , 1989, Biochimica et biophysica acta.

[205]  C. Hirayama,et al.  Serum indole and skatole in patients with various liver diseases. , 1988, Clinica chimica acta; international journal of clinical chemistry.

[206]  W. C. Purdy,et al.  The Origin of Indoleacetic Acid and Indolepropionic Acid in Rat and Human Cerebrospinal Fluid 1 , 1980, Journal of neurochemistry.

[207]  OUP accepted manuscript , 2022, FEMS Microbiology Ecology.

[208]  G. Oxenkrug,et al.  Anthranilic Acid: A Potential Biomarker and Treatment Target for Schizophrenia. , 2016, Annals of psychiatry and mental health.

[209]  Luying Peng,et al.  Effects of Butyrate on Intestinal Barrier Function in a Caco-2 Cell Monolayer Model of Intestinal Barrier , 2007, Pediatric Research.

[210]  B. Brew,et al.  Expression of the kynurenine pathway enzymes in human microglia and macrophages. , 2003, Advances in experimental medicine and biology.

[211]  G. Macfarlane,et al.  Contribution of the microflora to proteolysis in the human large intestine. , 1988, The Journal of applied bacteriology.