Indoxyl sulfate, a gut microbiome-derived uremic toxin, is associated with psychic anxiety and its functional magnetic resonance imaging-based neurologic signature

Christopher R Brydges, Oliver Fiehn, Helen S Mayberg, Henry Schreiber, Siamak Mahmoudian Dehkordi, Sudeepa Bhattacharyya, Jungho Cha, Ki Sueng Choi, W Edward Craighead, Ranga R Krishnan, A John Rush, Boadie W Dunlop, Rima Kaddurah-Daouk, Mood Disorders Precision Medicine Consortium, Brenda Penninx, Elizabeth Binder, Gabi Kastenmüller, Matthias Arnold, Alejo Nevado-Helgado, Colette Blach, Yuri Milaneschi, Janine Knauer-Arloth, Rich Jansen, Dennis Mook-Kanamori, Xianlin Han, Rebecca Baillie, Piero Rinaldo, Christopher R Brydges, Oliver Fiehn, Helen S Mayberg, Henry Schreiber, Siamak Mahmoudian Dehkordi, Sudeepa Bhattacharyya, Jungho Cha, Ki Sueng Choi, W Edward Craighead, Ranga R Krishnan, A John Rush, Boadie W Dunlop, Rima Kaddurah-Daouk, Mood Disorders Precision Medicine Consortium, Brenda Penninx, Elizabeth Binder, Gabi Kastenmüller, Matthias Arnold, Alejo Nevado-Helgado, Colette Blach, Yuri Milaneschi, Janine Knauer-Arloth, Rich Jansen, Dennis Mook-Kanamori, Xianlin Han, Rebecca Baillie, Piero Rinaldo

Abstract

It is unknown whether indoles, metabolites of tryptophan that are derived entirely from bacterial metabolism in the gut, are associated with symptoms of depression and anxiety. Serum samples (baseline, 12 weeks) were drawn from participants (n = 196) randomized to treatment with cognitive behavioral therapy (CBT), escitalopram, or duloxetine for major depressive disorder. Baseline indoxyl sulfate abundance was positively correlated with severity of psychic anxiety and total anxiety and with resting state functional connectivity to a network that processes aversive stimuli (which includes the subcallosal cingulate cortex (SCC-FC), bilateral anterior insula, right anterior midcingulate cortex, and the right premotor areas). The relation between indoxyl sulfate and psychic anxiety was mediated only through the metabolite's effect on the SCC-FC with the premotor area. Baseline indole abundances were unrelated to post-treatment outcome measures, and changes in symptoms were not correlated with changes in indole concentrations. These results suggest that CBT and antidepressant medications relieve anxiety via mechanisms unrelated to modulation of indoles derived from gut microbiota; it remains possible that treatment-related improvement stems from their impact on other aspects of the gut microbiome. A peripheral gut microbiome-derived metabolite was associated with altered neural processing and with psychiatric symptom (anxiety) in humans, which provides further evidence that gut microbiome disruption can contribute to neuropsychiatric disorders that may require different therapeutic approaches. Given the exploratory nature of this study, findings should be replicated in confirmatory studies.Clinical trial NCT00360399 "Predictors of Antidepressant Treatment Response: The Emory CIDAR" https://ichgcp.net/clinical-trials-registry/NCT00360399 .

Conflict of interest statement

Dr. Dunlop has received research support from Acadia, Compass, Aptinyx, NIMH, Sage, and Takeda, and has served as a consultant to Greenwich Biosciences, Myriad Neuroscience, Otsuka, Sage, and Sophren Therapeutics. Dr. Rush has received consulting fees from Compass Inc., Curbstone Consultant LLC, Emmes Corp., Holmusk, Johnson and Johnson (Janssen), Liva-Nova, Neurocrine Biosciences Inc., Otsuka-US, Sunovion; speaking fees from Liva-Nova, Johnson and Johnson (Janssen); and royalties from Guilford Press and the University of Texas Southwestern Medical Center, Dallas, TX (for the Inventory of Depressive Symptoms and its derivatives). He is also named co-inventor on two patents: U.S. Patent No. 7,795,033: Methods to Predict the Outcome of Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S, Wilson AS; and U.S. Patent No. 7,906,283: Methods to Identify Patients at Risk of Developing Adverse Events During Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S. Dr. Mayberg receives consulting and intellectual property licensing fees from Abbott Neuromodulation. Dr. Krishnan is a holder of number of patents in the metabolomic and brain computer interface space some of which have been licensed to Chymia LLC and sublicensed to Psyprotalix. Dr. Kaddurah-Daouk in an inventor on a series of patents on use of metabolomics for the diagnosis and treatment of CNS diseases and holds equity in Metabolon Inc. The other authors declare no competing interests.

© 2021. The Author(s).

Figures

Figure 1
Figure 1
Tryptophan human gut bacterial co-metabolism leading to production of indoles including IPA, IAA, ILA and IS. 3-HAA 3-hydroxyanthranilic acid, 3H-KYN 3-Hyroxykynurenine, 5-HTP 5-hydroxytryptophan, AAAD aromatic amino acid decarboxylase, AANAT aralkylamine N-acetyltransferase, acdA acyl-CoA dehydrogenase, AraT aromatic amino acid aminotransferase, ASMT Acetylserotonin O-methyltransferase, fldBC phenyllactate dehydratase, fldH phenyllactate dehydrogenase, IA indole acrylic acid, IAA indole acetic acid, IAAld indole-3-acetaldehyde, IAld indole-3-aldehyde, IAM indole-3-acetamide, IDO indolamine 2,3-dioxygenase, ILA indole-3-lactic acid, IPA indole-3-propionic acid, IPYA indole-3-pyruvate, KAT Kynurenine aminotransferase, KMO kynurenine 3-monooxygenase, KYNU kynureninase, MAO monoamine oxidase, NAD nicotinamide adenine dinucleotide, porB C: pyruvate : ferredoxin oxidoreductase B and C, TDO tryptophan 2,3-dioxygenase, TMO tryptophan 2-monooxygenase, TNA tryptophanase, TpH tryptophan hydroxylase, TrD tryptophan decarboxylase.
Figure 2
Figure 2
Heat map of Holm-corrected partial Spearman rank correlations between baseline indole abundance/ratio and Hamilton Anxiety scores and Hamilton Depression scores, after accounting for age, sex, and BMI.
Figure 3
Figure 3
Heat map of Holm-corrected partial Spearman rank correlations between baseline indole abundance/ratio and QIDS-SR items and total score, after accounting for age, sex, and BMI. QIDS-SR 16-item Quick Inventory of Depressive Symptomatology-Self-Rated.
Figure 4
Figure 4
Resting state functional connectivity of subcallosal cingulate cortex (SCC) associations with peripheral indoxyl sulfate abundances and psychic anxiety scores. (A) SCC functionally connected regions showing a significant correlation with indoxyl sulfate abundances. Orange circles identify regions incorporated into the mediation models. (B) SCC functionally connected regions showing a significant correlation with psychic anxiety scores. Green circle identifies right premotor region. (C) Conjunction analysis: SCC functionally connected region showing a significant correlation with both indoxyl sulfate abundances and psychic anxiety scores. The red circle indicates the only region to emerge in this analysis, the right premotor region. HAMPSY Psychic anxiety subscore of the Hamilton Anxiety Rating Scale. SCC-FC subcallosal cingulate cortex functional connectivity.
Figure 5
Figure 5
The impact of indoxyl sulfate on psychic anxiety scores is mediated by its effects on the resting state functional connectivity between the subcallosal cingulate cortex and the right premotor region. (A) Association between indoxyl sulfate and psychic anxiety scores. (B) Mediation model incorporating the overlapping area, right premotor region, indicating that the effect of indoxyl sulfate on psychic anxiety is mediated via its effects on the functional connectivity between the SCC and right premotor region. (C) Significant SCC-FC correlations between the right anterior insula, right anterior midcingulate cortex, and right premotor region, which were included in the mediation model shown in (D). (D) Full mediation model incorporating the three regions showing significant SCC-FC correlations with indoxyl sulfate abundances. Although indoxyl sulfate is significantly correlated with all three regions, only the pathway through the right premotor region significantly mediates indoxyl sulfate’s effect on psychic anxiety. Black lines indicate significant associations within the model; grey lines are insignificant associations. Red line indicates significant mediation of indoxyl sulfate on psychic anxiety through the indirect pathway of right premotor SCC-FC. HAMPSY Psychic anxiety subscore of the Hamilton Anxiety Rating Scale. SCC-FC subcallosal cingulate cortex functional connectivity.

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