Unbiased Metabolomics Links Fatty Acid Pathways to Psychiatric Symptoms in People Living with HIV

Abstract

Psychiatric symptoms are prevalent in people living with HIV (PLWH), especially depression, anxiety, impulsivity, and substance use. Various biological mechanisms might play a role in the occurrence of psychiatric symptoms in this population. A hypothesis free, data-driven metabolomics approach can further our understanding of these mechanisms. In this study, we identified metabolic pathways associated with impulsivity, depression and substance use in 157 PLWH. First, Spearman’s rank correlations between metabolite feature intensities and psychiatric symptom levels were calculated, while controlling for age, gender and body mass index. Subsequently, a mummichog pathway analysis was performed. Finally, we analyzed which individual metabolites drove the observed effects. In our cohort of PLWH, fatty acid-related pathways were associated with both depressive as well as impulsive symptomatology. Substance use showed most extensive metabolic associations, and was positively associated with short chain fatty acids (SCFA’s), and negatively associated with glutamate levels. These findings suggest that PUFA metabolism might be associated with both internalising and externalising symptomatology in PLWH. Furthermore, glutamate and SCFA’s—microbiome derivatives with known neuroactive properties—might be involved in substance use in these patients. Future studies should explore potential causal mechanisms involved and whether these findings are HIV-specific.

Genome-scale metabolic models for natural and long-term drug-induced viral control in HIV infection

“…Disrupted AA and central carbon metabolism have been proposed as a prominent characteristic of PLWH on long-term successful cART as reported by us and others ( Mukerji et al, 2016 ; Babu et al, 2019 ; Rosado-Sánchez et al, 2019 ; Valle-Casuso et al, 2019 ; Gelpi et al, 2021 ; Meeder et al, 2021 ; Shytaj et al, 2021 ; Villumsen et al, 2022 ). Altered glutaminolysis (i.e., glutamine lysed to glutamate) and increased plasma glutamate have been observed in several cohorts from both high income ( Gelpi et al, 2021 ) and low- and middle-income countries ( Gelpi et al, 2021 ) and are required for optimal HIV-1 infection of CD4 + T cells ( Clerc et al, 2019 ).…”

“…In our recent extensive multi-omics system biology studies on cohorts from India ( Babu et al, 2019 ; Gelpi et al, 2021 ), Cameroon ( Gelpi et al, 2021 ), and Denmark ( Gelpi et al, 2021 ; Villumsen et al, 2022 ), we mapped the in-depth metabolomic dysregulation associated with long-term treatment in PLWH. Our group ( Babu et al, 2019 ; Gelpi et al, 2021 ; Villumsen et al, 2022 ), and others ( Mukerji et al, 2016 ; Rosado-Sánchez et al, 2019 ; Valle-Casuso et al, 2019 ; Meeder et al, 2021 ; Shytaj et al, 2021 ), have highlighted how the coordinated modulation of central carbon metabolism, AA metabolism, glutaminolysis, and fatty acid biosynthesis can potentiate accentuated immune aging and cognitive decline in a subset of PLWH on therapy who have dysregulated metabolic profile.…”

Role of myeloid cells in system-level immunometabolic dysregulation during prolonged successful HIV-1 treatment

“…Successful long-term antiretroviral therapy (ART) inhibits human immunodeficiency virus type-1 (HIV-1) replication for a prolonged period in people with HIV-1 (PWH). We and others have earlier reported metabolic modifications involving dysregulation of the amino acid (AA) and central carbon metabolism in PWH on successful long-term ART (PWH ART ) [1][2][3][4][5][6][7][8][9]. Our recent study also reported a system-level upregulation of oxidative phosphorylation (OXPHOS) and glycolysis in PWH ART compared to HIV-1 positive elite controllers who naturally control viral replication [10].…”

Microbiome-Related Indole and Serotonin Metabolites are Linked to Inflammation and Psychiatric Symptoms in People Living with HIV

“…Plasma metabolomics measurements were performed using flow injection electrospray–time-of-flight mass spectrometry by General Metabolics (Massachusetts, United States), according to the previously described methodology. 44 , 45 There were no dietary restrictions prior to blood collection. Venous blood sample was collected for each participant in EDTA BD Vacutainer® tubes between 8 and 11 am and stored at −80°C prior to measurements.…”

“…50,51 An elaborate description of these questionnaires has been published elsewhere. 45 Psychiatric symptom levels were expressed as a total score of DASS-42 and its subscores (depression, anxiety, and stress), and a total score of BIS-11 and its subscores (attentional, motor impulsivity, and non-planning impulsivity). DASS-42 and BIS-11 have high validity and internal consistency and both have been used in PLHIV populations in previous literature.…”