Abstract
The biological mechanisms underlying emotional distress in HIV infection are likely to be complex but remain understudied. We investigated whether dysbiotic signatures in the gut microbiome of persons living with HIV (PLWH) are associated with their emotional status. We retrospectively examined the gut microbiome and clinical evaluation of 129 adults (94 PLWH and 35 HIV−) enrolled at UC San Diego’s HIV Neurobehavioral Research Program. A subset of participants (32 PLWH vs. 13 HIV−) underwent an emotional assessment using the NIH Toolbox Emotion Battery summarized by three composite scores (negative affect, social satisfaction, and psychological well-being). We then sequenced the 16S rDNA V3-V4 regions from stool and performed taxonomic assignment using CLC Microbial Genomics Module. The gut microbiota profiles were evaluated in relation to participants’ emotional assessment. All analyses were done in R statistical software. We found that the relative abundance of aerotolerant bacteria was significantly higher in PLWH (p < 0.01) and was associated with a lifetime major depression diagnosis independently of HIV status (p = 0.05). Moreover, PLWH experienced significantly worse psychological well-being (p = 0.02), less social satisfaction (p = 0.03), and more negative affect (p = 0.02). Higher levels of aerotolerant bacteria were associated with worse psychological well-being (rho = -0.35, p = 0.02), less social satisfaction (r = − 0.42, p < 0.01), and more negative affect (rho = 0.46, p < 0.01). The association of aerotolerant bacteria with social satisfaction and negative affect was independent of HIV status (p < 0.05, for both). The over-representation of aerotolerant bacteria in the gut may reflect worse oxidative stress and barrier defects and may contribute to emotional distress during HIV infection.
Similar content being viewed by others
References
American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC
Babakhanyan I, McKenna BS, Casaletto KB, Nowinski CJ, Heaton RK (2018) National Institutes of Health Toolbox Emotion Battery for English- and Spanish-speaking adults: normative data and factor-based summary scores. Patient Relat Outcome Meas 9:115–127
Bixler SL, Mattapallil JJ (2013) Loss and dysregulation of Th17 cells during HIV infection. Clin Dev Immunol 2013:852418
Brandt CP, Paulus DJ, Jardin C, Heggeness L, Lemaire C, Zvolensky MJ (2017) Examining anxiety sensitivity as an explanatory construct underlying HIV-related stigma: relations to anxious arousal, social anxiety, and HIV symptoms among persons living with HIV. J Anxiety Disord 48:95–101
Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, Fierer N, Pena AG, Goodrich JK, Gordon JI, Huttley GA, Kelley ST, Knights D, Koenig JE, Ley RE, Lozupone CA, McDonald D, Muegge BD, Pirrung M, Reeder J, Sevinsky JR, Turnbaugh PJ, Walters WA, Widmann J, Yatsunenko T, Zaneveld J, Knight R (2010) QIIME allows analysis of high-throughput community sequencing data. Nat Methods 7(5):335–336
Carroll IM, Ringel-Kulka T, Siddle JP, Ringel Y (2012) Alterations in composition and diversity of the intestinal microbiota in patients with diarrhea-predominant irritable bowel syndrome. Neurogastroenterol Motil 24(6):521–530, e248
Catalfamo M, Le Saout C, Lane HC (2012) The role of cytokines in the pathogenesis and treatment of HIV infection. Cytokine Growth Factor Rev 23(4–5):207–214
Cheung SG, Goldenthal AR, Uhlemann AC, Mann JJ, Miller JM, Sublette ME (2019) Systematic review of gut microbiota and major depression. Front Psychiatry 10:34
Ciccone EJ, Read SW, Mannon PJ, Yao MD, Hodge JN, Dewar R, Chairez CL, Proschan MA, Kovacs JA, Sereti I (2010) Cycling of gut mucosal CD4+ T cells decreases after prolonged anti-retroviral therapy and is associated with plasma LPS levels. Mucosal Immunol 3(2):172–181
Dillon SM, Lee EJ, Kotter CV, Austin GL, Dong Z, Hecht DK, Gianella S, Siewe B, Smith DM, Landay AL, Robertson CE, Frank DN, Wilson CC (2014) An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia. Mucosal Immunol 7(4):983–994
Dillon SM, Lee EJ, Kotter CV, Austin GL, Gianella S, Siewe B, Smith DM, Landay AL, McManus MC, Robertson CE, Frank DN, McCarter MD, Wilson CC (2016) Gut dendritic cell activation links an altered colonic microbiome to mucosal and systemic T-cell activation in untreated HIV-1 infection. Mucosal Immunol 9(1):24–37
Dubourg G, Lagier JC, Hue S, Surenaud M, Bachar D, Robert C, Michelle C, Ravaux I, Mokhtari S, Million M, Stein A, Brouqui P, Levy Y, Raoult D (2016) Gut microbiota associated with HIV infection is significantly enriched in bacteria tolerant to oxygen. BMJ Open Gastroenterol 3(1):e000080
Dumitrescu L, Popescu-Olaru I, Cozma L, Tulba D, Hinescu ME, Ceafalan LC, Gherghiceanu M, Popescu BO (2018) Oxidative stress and the microbiota-gut-brain axis. Oxid Med Cell Longev 2018:2406594
Favre D, Mold J, Hunt PW, Kanwar B, Loke P, Seu L, Barbour JD, Lowe MM, Jayawardene A, Aweeka F, Huang Y, Douek DC, Brenchley JM, Martin JN, Hecht FM, Deeks SG, McCune JM (2010) Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci Transl Med 2(32):32ra36
First MB, Spitzer RL, Gibbon M, BW, WJ (2002) Structured clinical interview for DSM-IV-TR axis I disorders, research version, patient edition. (SCID-I/P). New York State Psychiatric New York, NY USA
Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR (2007) Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A 104(34):13780–13785
Gaynes BN, O’Donnell J, Nelson E, Heine A, Zinski A, Edwards M, McGuinness T, Riddhi MA, Montgomery C, Pence BW (2015) Psychiatric comorbidity in depressed HIV-infected individuals: common and clinically consequential. Gen Hosp Psychiatry 37(4):277–282
Gootenberg DB, Paer JM, Luevano JM, Kwon DS (2017) HIV-associated changes in the enteric microbial community: potential role in loss of homeostasis and development of systemic inflammation. Curr Opin Infect Dis 30(1):31–43
Guihot A, Bourgarit A, Carcelain G, Autran B (2011) Immune reconstitution after a decade of combined antiretroviral therapies for human immunodeficiency virus. Trends Immunol 32(3):131–137
Hasin DS, Trautman KD, Miele GM, Samet S, Smith M, Endicott J (1996) Psychiatric Research Interview for Substance and Mental Disorders (PRISM): reliability for substance abusers. Am J Psychiatry 153(9):1195–1201
Hunt PW, Sinclair E, Rodriguez B, Shive C, Clagett B, Funderburg N, Robinson J, Huang Y, Epling L, Martin JN, Deeks SG, Meinert CL, Van Natta ML, Jabs DA, Lederman MM (2014) Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection. J Infect Dis 210(8):1228–1238
Jenkins TA, Nguyen JC, Polglaze KE, Bertrand PP (2016) Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis. Nutrients 8 (1)
Jiang W, Lederman MM, Hunt P, Sieg SF, Haley K, Rodriguez B, Landay A, Martin J, Sinclair E, Asher AI, Deeks SG, Douek DC, Brenchley JM (2009) Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis 199(8):1177–1185
Kamen C, Arganbright J, Kienitz E, Weller M, Khaylis A, Shenkman T, Smith S, Koopman C, Gore-Felton C (2015) HIV-related stigma: implications for symptoms of anxiety and depression among Malawian women. Afr J AIDS Res 14(1):67–73
Kanwar B, Favre D, McCune JM (2010) Th17 and regulatory T cells: implications for AIDS pathogenesis. Curr Opin HIV AIDS 5(2):151–157
Kaur US, Shet A, Rajnala N, Gopalan BP, Moar PDH, Singh BP, Chaturvedi R, Tandon R (2018) High Abundance of genus Prevotella in the gut of perinatally HIV-infected children is associated with IP-10 levels despite therapy. Sci Rep 8(1):17679
Kelley CF, Kitchen CM, Hunt PW, Rodriguez B, Hecht FM, Kitahata M, Crane HM, Willig J, Mugavero M, Saag M, Martin JN, Deeks SG (2009) Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis 48(6):787–794
Kelly JR, Borre Y, C OB, Patterson E, El Aidy S, Deane J, Kennedy PJ, Beers S, Scott K, Moloney G, Hoban AE, Scott L, Fitzgerald P, Ross P, Stanton C, Clarke G, Cryan JF, Dinan TG (2016) Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res 82:109–118
Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, Ledergerber B, Lundgren J, Neuhaus J, Nixon D, Paton NI, Neaton JD, Group, I.S.S (2008) Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 5(10):e203
Lozupone C, Knight R (2005) UniFrac: a new phylogenetic method for comparing microbial communities. Appl Environ Microbiol 71(12):8228–8235
Lozupone CA, Li M, Campbell TB, Flores SC, Linderman D, Gebert MJ, Knight R, Fontenot AP, Palmer BE (2013) Alterations in the gut microbiota associated with HIV-1 infection. Cell Host Microbe 14(3):329–339
Maes M, Kubera M, Leunis JC (2008) The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinol Lett 29(1):117–124
Maes M, Kubera M, Leunis JC, Berk M (2012) Increased IgA and IgM responses against gut commensals in chronic depression: further evidence for increased bacterial translocation or leaky gut. J Affect Disord 141(1):55–62
Maes M, Kubera M, Leunis JC, Berk M, Geffard M, Bosmans E (2013) In depression, bacterial translocation may drive inflammatory responses, oxidative and nitrosative stress (O&NS), and autoimmune responses directed against O&NS-damaged neoepitopes. Acta Psychiatr Scand 127(5):344–354
Mai V, Young CM, Ukhanova M, Wang X, Sun Y, Casella G, Theriaque D, Li N, Sharma R, Hudak M, Neu J (2011) Fecal microbiota in premature infants prior to necrotizing enterocolitis. PLoS ONE 6(6):e20647
Marchetti G, Tincati C, Silvestri G (2013) Microbial translocation in the pathogenesis of HIV infection and AIDS. Clin Microbiol Rev 26(1):2–18
Marin B, Thiebaut R, Bucher HC, Rondeau V, Costagliola D, Dorrucci M, Hamouda O, Prins M, Walker S, Porter K, Sabin C, Chene G (2009) Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy. AIDS 23(13):1743–1753
Miller E, Bhardwaj N (2013) Dendritic cell dysregulation during HIV-1 infection. Immunol Rev 254(1):170–189
Moore CL, Grulich AE, Prestage G, Gidding HF, Jin F, Petoumenos K, Zablotska IB, Poynten IM, Mao L, Law MG, Amin J (2016) Hospitalization for anxiety and mood disorders in HIV-infected and -uninfected gay and bisexual men. J Acquir Immune Defic Syndr 73(5):589–597
Mutlu EA, Keshavarzian A, Losurdo J, Swanson G, Siewe B, Forsyth C, French A, Demarais P, Sun Y, Koenig L, Cox S, Engen P, Chakradeo P, Abbasi R, Gorenz A, Burns C, Landay A (2014) A compositional look at the human gastrointestinal microbiome and immune activation parameters in HIV infected subjects. PLoS Pathog 10(2):e1003829
Nilsson J, Boasso A, Velilla PA, Zhang R, Vaccari M, Franchini G, Shearer GM, Andersson J, Chougnet C (2006) HIV-1-driven regulatory T-cell accumulation in lymphoid tissues is associated with disease progression in HIV/AIDS. Blood 108(12):3808–3817
Paquin-Proulx D, Ching C, Vujkovic-Cvijin I, Fadrosh D, Loh L, Huang Y, Somsouk M, Lynch SV, Hunt PW, Nixon DF, SenGupta D (2017) Bacteroides are associated with GALT iNKT cell function and reduction of microbial translocation in HIV-1 infection. Mucosal Immunol 10(1):69–78
Pence BW, Miller WC, Whetten K, Eron JJ, Gaynes BN (2006) Prevalence of DSM-IV-defined mood, anxiety, and substance use disorders in an HIV clinic in the Southeastern United States. J Acquir Immune Defic Syndr 42(3):298–306
Pereira M, Canavarro MC (2012) Quality of life and emotional distress among HIV-positive women during transition to motherhood. Span J Psychol 15(3):1303–1314
Petra AI, Panagiotidou S, Hatziagelaki E, Stewart JM, Conti P, Theoharides TC (2015) Gut-microbiota-brain axis and its effect on neuropsychiatric disorders with suspected immune dysregulation. Clin Ther 37(5):984–995
Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55(5):453–462
Rodger AJ, Fox Z, Lundgren JD, Kuller LH, Boesecke C, Gey D, Skoutelis A, Goetz MB, Phillips AN, Group, I.S.f.M.o.A.T.S (2009) Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection. J Infect Dis 200(6):973–983
Sandler NG, Wand H, Roque A, Law M, Nason MC, Nixon DE, Pedersen C, Ruxrungtham K, Lewin SR, Emery S, Neaton JD, Brenchley JM, Deeks SG, Sereti I, Douek DC, Group I.S.S (2011) Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis 203(6):780–790
Sauce D, Larsen M, Fastenackels S, Pauchard M, Ait-Mohand H, Schneider L, Guihot A, Boufassa F, Zaunders J, Iguertsira M, Bailey M, Gorochov G, Duvivier C, Carcelain G, Kelleher AD, Simon A, Meyer L, Costagliola D, Deeks SG, Lambotte O, Autran B, Hunt PW, Katlama C, Appay V (2011) HIV disease progression despite suppression of viral replication is associated with exhaustion of lymphopoiesis. Blood 117(19):5142–5151
Shaw JM, Hunt PW, Critchfield JW, McConnell DH, Garcia JC, Pollard RB, Somsouk M, Deeks SG, Shacklett BL (2011) Increased frequency of regulatory T cells accompanies increased immune activation in rectal mucosae of HIV-positive noncontrollers. J Virol 85(21):11422–11434
Sylvia KE, Demas GE (2018) A gut feeling: microbiome-brain-immune interactions modulate social and affective behaviors. Horm Behav 99:41–49
Tesfaw G, Ayano G, Awoke T, Assefa D, Birhanu Z, Miheretie G, Abebe G (2016) Prevalence and correlates of depression and anxiety among patients with HIV on-follow up at Alert Hospital, Addis Ababa. Ethiopia BMC Psychiatry 16(1):368
Ustun B, Compton W, Mager D, Babor T, Baiyewu O, Chatterji S, Cottler L, Gogus A, Mavreas V, Peters L, Pull C, Saunders J, Smeets R, Stipec MR, Vrasti R, Hasin D, Room R, Van den Brink W, Regier D, Blaine J, Grant BF, Sartorius N (1997) WHO Study on the reliability and validity of the alcohol and drug use disorder instruments: overview of methods and results. Drug Alcohol Depend 47(3):161–169
Vincent W, Fang X, Calabrese SK, Heckman TG, Sikkema KJ, Hansen NB (2017) HIV-related shame and health-related quality of life among older. HIV-positive adults J Behav Med 40(3):434–444
Vujkovic-Cvijin I, Dunham RM, Iwai S, Maher MC, Albright RG, Broadhurst MJ, Hernandez RD, Lederman MM, Huang Y, Somsouk M, Deeks SG, Hunt PW, Lynch SV, McCune JM (2013) Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci Transl Med 5(193):193ra191
Wommack KE, Ravel J (2013) Microbiome, demystifying the role of microbial communities in the biosphere. Microbiome 1(1):1
Zhao J, Bi W, Xiao S, Lan X, Cheng X, Zhang J, Lu D, Wei W, Wang Y, Li H, Fu Y, Zhu L (2019) Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Sci Rep 9(1):5790
Zheng P, Zeng B, Zhou C, Liu M, Fang Z, Xu X, Zeng L, Chen J, Fan S, Du X, Zhang X, Yang D, Yang Y, Meng H, Li W, Melgiri ND, Licinio J, Wei H, Xie P (2016) Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol Psychiatry 21(6):786–796
Acknowledgments
Special thanks to Carlos Solá-Morlá, Jamie L. Ortíz-Santiago, Jeannette L. Salgado, and André Beauchamp-Saalman.
Funding
The project described was supported by the NIH, National Institute of Mental Health R25 MH108389; K23 MH105297; R01 MH107345; U01 MH83506; P30 MH62512; K24 MH097673, and National Institute of Drug Abuse P50 DA26306. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This publication was also supported by the Comprehensive Cancer Center of the UPR (a public corporation of the Government of Puerto Rico created in virtue of Law 230 of August 26, 2004 as amended). The content is entirely the responsibility of the authors and does not necessarily represent the official views of the Comprehensive Cancer Center UPR.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Pérez-Santiago, J., Marquine, M.J., Cookson, D. et al. Gut microbiota dysbiosis is associated with worse emotional states in HIV infection. J. Neurovirol. 27, 228–238 (2021). https://doi.org/10.1007/s13365-020-00933-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13365-020-00933-1