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

Brydges, Christopher; Fiehn, Oliver; Mayberg, Helen S.; Schreiber, Henry L.; Dehkordi, Siamak Mahmoudian; Bhattacharyya, Sudeepa; Cha, Jung-Ho; Choi, Ki Sueng; Craighead, W. Edward; Krishnan, Ranga; Rush, A. John; Dunlop, Boadie W.; Kaddurah‐Daouk, Rima

doi:10.1038/s41598-021-99845-1

Cited by 57 publications

(38 citation statements)

References 84 publications

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“…In our study, we observed elevated levels of the sulfated form of the toxic LCA and GLCA in more severely anxious patients. We have also previously reported increased production of other bacterially-derived sulfates like pcresol sulfate and indoxyl sulfates (Brydges, Fiehn et al 2021) in the PReDICT study participants. Together, these findings suggest that alterations in sulfotransferase activities may occur in the liver of some patients.…”

Section: Gut Metabolites In Depression and Anxietysupporting

confidence: 56%

Gut microbiome-linked metabolites in the pathobiology of depression and anxiety - a role for bile acids

MahmoudianDehkordi

Bhattacharyya

Brydges

et al. 2022

Preprint

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BackgroundThe gut microbiome may play a role in the pathogenesis of neuropsychiatric diseases including major depressive disorder (MDD). Bile acids (BAs) are steroid acids that are synthesized in the liver from cholesterol and further processed by gut-bacterial enzymes, thus requiring both human and gut microbiome enzymatic processes in their metabolism. BAs participate in a range of important host functions such as lipid transport and metabolism, cellular signaling and regulation of energy homeostasis. BAs have recently been implicated in the pathophysiology of Alzheimer’s and several other neuropsychiatric diseases, but the biochemical underpinnings of these gut microbiome-linked metabolites in the pathophysiology of depression and anxiety remains largely unknown.MethodUsing targeted metabolomics, we profiled primary and secondary BAs in the baseline serum samples of 208 untreated outpatients with MDD. We assessed the relationship of BA concentrations and the severity of depressive and anxiety symptoms as defined by the 17-item Hamilton Depression Rating Scale (HRSD17) and the 14-item Hamilton Anxiety Rating Scale (HRSA-Total), respectively. We also evaluated whether the baseline metabolic profile of BA informs about treatment outcomes.ResultsThe concentration of the primary BA chenodeoxycholic acid (CDCA) was significantly lower at baseline in both severely depressed (log2 fold difference (LFD)= -0.48; p=0.021) and highly anxious (LFD= -0.43; p=0.021) participants compared to participants with less severe symptoms. The gut bacteria-derived secondary BAs produced from CDCA such as lithocholic acid (LCA) and several of its metabolites, and their ratios to primary BAs, were significantly higher in the more anxious participants (LFD’s range=[0.23,1.36]; p’s range=[6.85E-6,1.86E-2]). The interaction analysis of HRSD17 and HRSA-Total suggested that the BA concentration differences were more strongly correlated to the symptoms of anxiety than depression. Significant differences in baseline CDCA (LFD= -0.87, p=0.0009), isoLCA (LFD= -1.08, p=0.016) and several BA ratios (LFD’s range [0.46, 1.66], p’s range [0.0003, 0.049]) differentiated treatment failures from remitters.ConclusionIn patients with MDD, BA profiles representing changes in gut microbiome compositions are associated with higher levels of anxiety and increased probability of first-line treatment failure. If confirmed, these findings suggest the possibility of developing gut microbiome-directed therapies for MDD characterized by gut dysbiosis.

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Section: Gut Metabolites In Depression and Anxietysupporting

confidence: 56%

Gut microbiome-linked metabolites in the pathobiology of depression and anxiety - a role for bile acids

MahmoudianDehkordi

Bhattacharyya

Brydges

et al. 2022

Preprint

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“…The 229 identified metabolites were then repositioned into metabolic pathways [ 28 ]. A total of 52 enriched metabolic pathways were identified, and the most enriched ones are shown in Figure 2 b.…”

Section: Resultsmentioning

confidence: 99%

The Human Meconium Metabolome and Its Evolution during the First Days of Life

et al. 2022

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Meconium represents the first newborn stools, formed from the second month of gestation and excreted in the first days after birth. As an accumulative and inert matrix, it accumulates most of the molecules transferred through the placenta from the mother to the fetus during the last 6 months of pregnancy, and those resulting from the metabolic activities of the fetus. To date, only few studies dealing with meconium metabolomics have been published. In this study, we aimed to provide a comprehensive view of the meconium metabolic composition using 33 samples collected longitudinally from 11 healthy newborns and to analyze its evolution during the first 3 days of life. First, a robust and efficient methodology for metabolite extraction was implemented. Data acquisition was performed using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS), using two complementary LC-HRMS conditions. Data preprocessing and treatment were performed using the Workflow4Metabolomics platform and the metabolite annotation was performed using our in-house database by matching accurate masses, retention times, and MS/MS spectra to those of pure standards. We successfully identified up to 229 metabolites at a high confidence level in human meconium, belonging to diverse chemical classes and from different origins. A progressive evolution of the metabolic profile was statistically evidenced, with sugars, amino acids, and some bacteria-derived metabolites being among the most impacted identified compounds. Our implemented analytical workflow allows a unique and comprehensive description of the meconium metabolome, which is related to factors, such as maternal diet and environment.

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“…Title and abstract Title and abstract Of the studies evaluated in our review, 21 evaluated therapeutic approaches [10,13,14,[18][19][20][21]26,29,33,[36][37][38]40,43,[48][49][50]55,56,58]. One study assessed arms with bupropion, venlafaxine, and mirtazapine [36].…”

Section: Strobe Itemsmentioning

confidence: 99%

“…Of the studies evaluated in our review, 21 evaluated therapeutic approaches [ 10 , 13 , 14 , 18 - 21 , 26 , 29 , 33 , 36 - 38 , 40 , 43 , 48 - 50 , 55 , 56 , 58 ]. One study assessed arms with bupropion, venlafaxine, and mirtazapine [ 36 ].…”

Section: Reviewmentioning

confidence: 99%

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Metabolomics of Major Depressive Disorder: A Systematic Review of Clinical Studies

Costa¹,

Carneiro²,

Alves³

et al. 2022

Cureus

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Although the understanding of the pathophysiology of major depressive disorder (MDD) has advanced greatly, this has not been translated into improved outcomes. To date, no biomarkers have been identified for the diagnosis, prognosis, and therapeutic management of MDD. Thus, we aim to review the biomarkers that are differentially expressed in MDD. A systematic review was conducted in January 2022 in the PubMed/MEDLINE, Scopus, Embase, PsycINFO, and Gale Academic OneFile databases for clinical studies published from January 2001 onward using the following terms: "Depression" OR "Depressive disorder" AND "Metabolomic." Multiple metabolites were found at altered levels in MDD, demonstrating the involvement of cellular signaling metabolites, components of the cell membrane, neurotransmitters, inflammatory and immunological mediators, hormone activators and precursors, and sleep controllers. Kynurenine and acylcarnitine were identified as consistent with depression and response to treatment. The most consistent evidence found was regarding kynurenine and acylcarnitine. Although the data obtained allow us to identify how metabolic pathways are affected in MDD, there is still not enough evidence to propose changes to current diagnostic and therapeutic actions. Some limitations are the heterogeneity of studies on metabolites, methods for detection, analyzed body fluids, and treatments used. The experiments contemplated in the review identified increased or reduced levels of metabolites, but not necessarily increased or reduced the activity of the associated pathways. The information acquired through metabolomic analyses does not specify whether the changes identified in the metabolites are a cause or a consequence of the pathology.

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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

Cited by 57 publications

References 84 publications

Gut microbiome-linked metabolites in the pathobiology of depression and anxiety - a role for bile acids

Gut microbiome-linked metabolites in the pathobiology of depression and anxiety - a role for bile acids

The Human Meconium Metabolome and Its Evolution during the First Days of Life

Metabolomics of Major Depressive Disorder: A Systematic Review of Clinical Studies

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