1 Vol.:(0123456789) Scientifc Reports | (2021) 11:21011 | https://doi.org/10.1038/s41598-021-99845-1 www.nature.com/scientificreports 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 1 , Oliver Fiehn 1 , Helen S. Mayberg 2,3 , Henry Schreiber 4 , Siamak Mahmoudian Dehkordi 5 , Sudeepa Bhattacharyya 6 , Jungho Cha 2,3 , Ki Sueng Choi 2,3 , W. Edward Craighead 7,8 , Ranga R. Krishnan 9 , A. John Rush 5,10,11 , Boadie W. Dunlop 3,15* , Rima Kaddurah‑Daouk 5,12,13,14* & the Mood Disorders Precision Medicine Consortium * 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 efect 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 OPEN 1 West Coast Metabolomics Center, University of California, Davis, CA, USA. 2 Department of Neurology and Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 3 Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA. 4 Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA, USA. 5 Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA. 6 Department of Biological Sciences, Arkansas Biosciences Institute, Arkansas State University, Jonesboro, AR, USA. 7 Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30329, USA. 8 Department of Psychology, Emory University, Atlanta, GA, USA. 9 Department of Psychiatry, Rush Medical College, Chicago, IL, USA. 10 Department of Psychiatry, Health Sciences Center, Texas Tech University, Permian Basin, TX, USA. 11 Duke-National University of Singapore, Singapore, Singapore. 12 Department of Medicine, Duke University, Durham, NC, USA. 13 Duke Institute of Brain Sciences, Duke University, Durham, NC, USA. 14 Duke University Medical Center, DUMC 3903, Blue Zone South, Durham, NC, USA. 15 Emory University College of Medicine, 12 Executive Park Dr. NE, Room 347, Atlanta, GA 30329, USA. * A list of authors and their afliations appears at the end of the paper. * email: bdunlop@ emory.edu; kaddu001@mc.duke.edu