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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

Brydges, Christopher R. and Fiehn, Oliver and Mayberg, Helen S. and Schreiber, Henry and Dehkordi, Siamak Mahmoudian and Bhattacharyya, Sudeepa and Cha, Jungho and Choi, Ki Sueng and Craighead, W. Edward and Krishnan, Ranga R. and Rush, A. John and Dunlop, Boadie W. and Kaddurah-Daouk, Rima (2020) Indoxyl sulfate, a gut microbiome-derived uremic toxin, is associated with psychic anxiety and its functional magnetic resonance imaging-based neurologic signature. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20201210-122853319

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Abstract

Background: 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. Methods: 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. Results: 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, which suggests that CBT and antidepressant medications relieve anxiety via mechanisms unrelated to gut microbiota. Conclusions: 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.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2020.12.08.388942DOIDiscussion Paper
ORCID:
AuthorORCID
Brydges, Christopher R.0000-0001-5901-638X
Fiehn, Oliver0000-0002-6261-8928
Mayberg, Helen S.0000-0002-1672-2716
Schreiber, Henry0000-0002-4501-9886
Dunlop, Boadie W.0000-0002-4653-0483
Kaddurah-Daouk, Rima0000-0003-1858-5732
Alternate Title:Indoxyl sulfate associated with psychic anxiety
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. This version posted December 9, 2020. 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. Author Contributions: CRB did analysis of data and helped write the manuscript; OF and his team generated biochemical data and wrote its methods and helped with interpretation of findings; HSM, WEC, JC, KSC and BWD did analysis connecting metabolomics data to imaging data and helped with writing of manuscript; SMD, SB and HS helped with background literature searches and with interpretation of findings; RRK, BWD and AJR helped with interpretation of findings and clinical relevance; RKD is PI for project helped with concept development, study design, data interpretation and connecting biochemical and clinical data, and with writing of manuscript. Competing 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. 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.
Funders:
Funding AgencyGrant Number
NIHR01MH108348
NIHR01AG046171
NIHU01AG061359
NIHP50-MH077083
NIHR01-MH080880
NIHUL1-RR025008
NIHM01-RR0039
Fuqua Family FoundationsUNSPECIFIED
Subject Keywords:Metabolomics, gut microbiome, indoles, indoxyl sulfate, anxiety, depression, major depressive disorder
Record Number:CaltechAUTHORS:20201210-122853319
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20201210-122853319
Official Citation: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. bioRxiv 2020.12.08.388942; doi: https://doi.org/10.1101/2020.12.08.388942
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:107012
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:10 Dec 2020 21:11
Last Modified:10 Dec 2020 21:11

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