Nadira Vadaq1,2, Yue Zhang3, Elise Meeder4,5,6, Lisa Van de Wijer1, Muhammad Hussein Gasem2,7, Leo Ab Joosten1, Mihai G Netea1,8, Quirijn de Mast1, Vasiliki Matzaraki1, Arnt Schellekens4,5,6, Jingyuan Fu3,9, André Jam van der Ven1. 1. Department of Internal Medicine, Radboudumc Center for Infectious Diseases, Radboud Institute of Health Science (RIHS), Radboud University Medical Center, Nijmegen, The Netherlands. 2. Center for Tropical and Infectious Diseases (CENTRID), Faculty of Medicine, Diponegoro University, Dr. Kariadi Hospital, Semarang, Indonesia. 3. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 4. Department of Psychiatry, Radboud University Medical Centre, Nijmegen, The Netherlands. 5. Nijmegen Institute for Scientist-Practitioners in Addiction (NISPA), Nijmegen, The Netherlands. 6. Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, The Netherlands. 7. Department of Internal Medicine, Faculty of Medicine Diponegoro University-Dr. Kariadi Hospital, Semarang, Indonesia. 8. Department for Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany. 9. Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Abstract
Background: People living with HIV (PLHIV) exhibit dysregulation of tryptophan metabolism. Altered gut microbiome composition in PLHIV might be involved. Mechanistic consequences within the 3 major tryptophan metabolism pathways (serotonin, kynurenine, and indoles), and functional consequences for platelet, immune and behavioral functions are unknown. We investigated plasma tryptophan metabolites, gut microbiome composition, and their association with platelet function, inflammation, and psychiatric symptoms. Methods: This study included 211 PLHIV on long-term antiretroviral treatment (ART). Plasma tryptophan pathway metabolites were measured using time-of-flight mass spectrometry. Bacterial composition was profiled using metagenomic sequencing. Platelet reactivity and serotonin levels were quantified by flowcytometry and ELISA, respectively. Circulating inflammatory markers were determined using ELISA. Symptoms of depression and impulsivity were measured by DASS-42 and BIS-11 self-report questionnaires, respectively. Results: Plasma serotonin and indole metabolites were associated with gut bacterial composition. Notably, species enriched in PLHIV were associated with 3-methyldioxyindole. Platelet serotonin concentrations were elevated in PLHIV, without effects on platelet reactivity. Plasma serotonin and indole metabolites were positively associated with plasma IL-10 and TNF-α concentrations. Finally, higher tryptophan, serotonin, and indole metabolites were associated with lower depression and anxiety, whereas higher kynurenine metabolites were associated with increased impulsivity. Conclusion: Our results suggest that gut bacterial composition and dysbiosis in PLHIV on ART contribute to tryptophan metabolism, which may have clinical consequences for immune function and behavior.
Background: People living with HIV (PLHIV) exhibit dysregulation of tryptophan metabolism. Altered gut microbiome composition in PLHIV might be involved. Mechanistic consequences within the 3 major tryptophan metabolism pathways (serotonin, kynurenine, and indoles), and functional consequences for platelet, immune and behavioral functions are unknown. We investigated plasma tryptophan metabolites, gut microbiome composition, and their association with platelet function, inflammation, and psychiatric symptoms. Methods: This study included 211 PLHIV on long-term antiretroviral treatment (ART). Plasma tryptophan pathway metabolites were measured using time-of-flight mass spectrometry. Bacterial composition was profiled using metagenomic sequencing. Platelet reactivity and serotonin levels were quantified by flowcytometry and ELISA, respectively. Circulating inflammatory markers were determined using ELISA. Symptoms of depression and impulsivity were measured by DASS-42 and BIS-11 self-report questionnaires, respectively. Results: Plasma serotonin and indole metabolites were associated with gut bacterial composition. Notably, species enriched in PLHIV were associated with 3-methyldioxyindole. Platelet serotonin concentrations were elevated in PLHIV, without effects on platelet reactivity. Plasma serotonin and indole metabolites were positively associated with plasma IL-10 and TNF-α concentrations. Finally, higher tryptophan, serotonin, and indole metabolites were associated with lower depression and anxiety, whereas higher kynurenine metabolites were associated with increased impulsivity. Conclusion: Our results suggest that gut bacterial composition and dysbiosis in PLHIV on ART contribute to tryptophan metabolism, which may have clinical consequences for immune function and behavior.
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