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Published October 25, 2021 | Published + Submitted + Supplemental Material
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Indoxyl sulfate, a gut microbiome-derived uremic toxin, is associated with psychic anxiety and its functional magnetic resonance imaging-based neurologic signature


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.

Additional Information

© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Received 06 May 2021; Accepted 15 September 2021; Published 25 October 2021. We acknowledge the editorial services of Mr. Jon Kilner, MS, MA (Pittsburgh) and the assistance of Ms. Lisa Howerton (Duke). This work was funded by grant support to Dr. Rima Kaddurah-Daouk (PI) through NIH grants R01MH108348, R01AG046171 and U01AG061359. Dr. Boadie Dunlop has support from NIH grants P50-MH077083 (PI Mayberg), R01-MH080880 (PI Craighead), UL1-RR025008 (PI Stevens), M01-RR0039 (PI Stevens) and the Fuqua Family Foundations. A preprint of this manuscript is available on bioRxiv (https://doi.org/10.1101/2020.12.08.388942.). Author Contributions: C.R.B. did analysis of data and helped write the manuscript; O.F. and his team generated biochemical data and wrote its methods and helped with interpretation of findings; H.S.M., W.E.C., J.C., K.S.C. and B.W.D. did analysis connecting metabolomics data to imaging data and helped with writing of manuscript; S.M.D., S.B. and H.S. helped with background literature searches and with interpretation of findings; R.R.K., B.W.D. and A.J.R. helped with interpretation of findings and clinical relevance; R.K.D. is P.I. for project helped with concept development, study design, data interpretation and connecting biochemical and clinical data, and with writing of manuscript. Competing interests: 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.

Attached Files

Published - s41598-021-99845-1.pdf

Submitted - 2020.12.08.388942v1.full.pdf

Supplemental Material - 41598_2021_99845_MOESM1_ESM.tiff

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August 22, 2023
October 23, 2023