VUJKOVIC-CVIJIN LAB
SELECTED PUBLICATIONS
Impaired gut microbiota-mediated short-chain fatty acid production precedes morbidity and mortality in people with HIV
Sereti I, Verburgh ML, Gifford J, Lo A, Boyd A, Verheij E, Verhoeven A, Wit FWNM,
Schim van der Loeff MF, Giera M, Kootstra NA, Reiss P, Vujkovic-Cvijin I
Antiretroviral therapy (ART) has dramatically lengthened lifespan among people with HIV (PWH), but this population experiences heightened rates of inflammation-related comorbidities. HIV-associated inflammation is linked with an altered microbiome; whether such alterations precede inflammation-related comorbidities or occur as their consequence remains unknown. We find that ART-treated PWH exhibit depletion of gut-resident bacteria that produce short-chain fatty acids (SCFAs)—crucial microbial metabolites with anti-inflammatory properties. Prior reports establish that fecal SCFA concentrations are not depleted in PWH. We find that gut-microbiota-mediated SCFA production capacity is better reflected in serum than in feces and that PWH exhibit reduced serum SCFA, which associates with inflammatory markers. Leveraging stool and serum samples collected prior to comorbidity onset, we find that HIV-specific microbiome alterations precede morbidity and mortality in ART-treated PWH. Among these microbiome alterations, reduced microbiome-mediated conversion of lactate to propionate precedes mortality in PWH. Thus, gut microbial fiber/lactate conversion to SCFAs may modulate HIV-associated comorbidity risk.
The systemic anti-microbiota IgG repertoire can identify gut bacteria that translocate across gut barrier surfaces
Science Translational Medicine. August 17, 2022
Vujkovic-Cvijin I, Welles HC, Ha CWY, Huq L, Mistry S, Brenchley JM, Trinchieri G, Devkota S, Belkaid Y.
Unique gut microbiota compositions have been associated with inflammatory diseases, but identifying gut bacterial functions linked to immune activation in humans remains challenging. Translocation of pathogens from mucosal surfaces into peripheral tissues can elicit immune activation, although whether and which gut commensal bacteria translocate in inflammatory diseases is difficult to assess. We report that a subset of commensal gut microbiota constituents that translocate across the gut barrier in mice and humans are associated with heightened systemic immunoglobulin G (IgG) responses. We present a modified high-throughput, culture-independent approach to quantify systemic IgG against gut commensal bacteria in human serum samples without the need for paired stool samples. Using this approach, we highlight several commensal bacterial species that elicit elevated IgG responses in patients with inflammatory bowel disease (IBD) including taxa within the clades Collinsella, Bifidobacterium, Lachnospiraceae, and Ruminococcaceae. These and other taxa identified as translocating bacteria or targets of systemic immunity in IBD concomitantly exhibited heightened transcriptional activity and growth rates in IBD patient gut microbiomes. Our approach represents a complementary tool to illuminate interactions between the host and its gut microbiota and may provide an additional method to identify microbes linked to inflammatory disease.
Host variables confound gut microbiota studies of human disease
Low concordance between studies that examine the microbiota in human diseases is a pervasive challenge that limits capacity to identify causal relationships between host-associated microbes and pathology. Risks of obtaining false positives in human microbiota research are exacerbated by wide inter-individual heterogeneity in microbiota composition likely due to population-wide differences in human lifestyle and physiological variables that exert differential impacts on the microbiota. Herein, we infer the greatest, generalized sources of heterogeneity in human gut microbiota profiles and, further, identify human lifestyle and physiological characteristics that, if not evenly matched between cases and controls, confound microbiota analyses to produce spurious microbial associations with human diseases. Surprisingly, we identify alcohol consumption frequency and bowel movement quality as unexpectedly strong sources of gut microbiota variance that differ in distribution between healthy and diseased subjects and can confound study designs. We demonstrate that for numerous prevalent, high-burden human diseases, matching cases and controls for confounding variables reduces observed microbiota differences and incidence of spurious associations. Thus, we present a list of recommended host variables to capture in human microbiota studies for the purpose of matching comparison groups, which we anticipate will increase robustness and reproducibility in resolving true disease-associated gut microbiota members in human disease.
HIV-associated gut dysbiosis is independent of sexual practice and correlates with noncommunicable diseases
Nature Communications. May 15, 2020
Vujkovic-Cvijin I, Sortino O, Verheij E, Sklar J, Wit FW, Kootstra NA, Sellers B, Brenchley JM, Ananworanich J, Schim van der Loeff M, Belkaid Y, Reiss P, Sereti I.
Loss of gut mucosal integrity and an aberrant gut microbiota are proposed mechanisms contributing to chronic inflammation and increased morbidity and mortality during antiretroviral-treated HIV disease. Sexual practice has recently been uncovered as a major source of microbiota variation, potentially confounding prior observations of gut microbiota alterations among persons with HIV (PWH). To overcome this and other confounding factors, we examine a well-powered subset of AGEhIV Cohort participants comprising antiretroviral-treated PWH and seronegative controls matched for age, body-mass index, sex, and sexual practice. We report significant gut microbiota differences in PWH regardless of sex and sexual practice including Gammaproteobacteria enrichment, Lachnospiraceae and Ruminococcaceae depletion, and decreased alpha diversity. Men who have sex with men (MSM) exhibit a distinct microbiota signature characterized by Prevotella enrichment and increased alpha diversity, which is linked with receptive anal intercourse in both males and females. Finally, the HIV-associated microbiota signature correlates with inflammatory markers including suPAR, nadir CD4 count, and prevalence of age-associated noncommunicable comorbidities.
The complement pathway is activated in people with Human Immunodeficiency Virus and is associated with non-AIDS comorbidities
Journal of Infectious Diseases. February 19, 2021
Vujkovic-Cvijin I, Sortino O, Verheij E, Wit F, Kootstra N A, Sellers B, Schim van der Loeff M, Belkaid Y, Reiss P, Sereti I
Unbiased plasma proteomics in a matched case-control study of treated people with HIV (PWH) revealed the complement cascade as being among the top pathways enriched in PWH. Specific complement components, namely C5, associated significantly with non-AIDS comorbidity prevalence, and did so more strongly than previously established predictive biomarkers.
HIV and the gut microbiota: composition, consequences, and avenues for amelioration
We discuss recent advances in understanding of gut bacterial microbiota composition in HIV-infected subjects and comment on controversies. We discuss the putative effects of microbiota shifts on systemic inflammation and HIV disease progression and potential mechanisms, as well as ongoing strategies being developed to modulate the gut microbiota in humans for amelioration of infectious and inflammatory diseases. Lifestyle and behavioral factors relevant to HIV infection studies have independent effects on the microbiota. Microbial metabolism of immunomodulatory compounds and direct immune stimulation by translocation of microbes are putative mechanisms contributing to HIV disease. Fecal microbiota transplantation, microbial enzyme inhibition, phage therapy, and rationally selected probiotic cocktails have emerged as promising strategies for microbiota modulation. Numerous surveys of the HIV gut microbiota matched for lifestyle factors suggest consistent shifts in gut microbiota composition among HIV-infected subjects. Evidence exists for a complex pathogenic role of the gut microbiota in HIV disease progression, warranting further study.
Limited engraftment of donor microbiome via one-time fecal microbial transplantation in treated HIV-infected individuals
Vujkovic-Cvijin I, Rutishauser RL, Pao M, Hunt PW, Lynch SV, McCune JM, Somsouk M.
Many HIV-infected individuals on antiretroviral therapy (ART) exhibit persistent systemic inflammation, which predicts morbidity and mortality. ART-treated subjects concurrently exhibit marked compositional alterations in the gut bacterial microbiota and the degree of dysbiosis correlates with systemic inflammation. Whether interventions to modulate the microbiome can affect systemic inflammation is unknown. An open-label fecal microbial transplantation (FMT) was delivered by colonoscopy to asymptomatic HIV-infected ART-suppressed individuals without antibiotic pre-treatment. Stool was assessed before and after FMT for engraftment of donor microbes, and peripheral blood was assayed for immune activation biomarkers. Six participants received FMT and 2 participants served as controls. No serious adverse effects occurred during 24 weeks of follow-up. At baseline, HIV-infected individuals exhibited microbiota profiles distinct from uninfected donors. During the 8 weeks post-FMT, recipients demonstrated partial engraftment of the donor microbiome (P < 0.05). Recipient microbiota remained significantly distant from donors, unlike that observed following FMT for treatment of C. difficile infection. Systemic inflammatory markers showed no significant change post-FMT. FMT was well-tolerated in ART-treated, HIV-infected individuals. Engraftment was detectable but modest, and appeared to be limited to specific bacterial taxa. Whether antibiotic conditioning can enhance engraftment and the capacity of microbiota to modulate inflammation remains to be investigated.
Gut-resident Lactobacillus abundance associates with IDO1 inhibition and Th17 dynamics in SIV-infected macaques
Vujkovic-Cvijin I, Swainson L, Chu S, Ortiz A, Santee C, Petriello A, Dunham RM, Faruqi A, Huang Y, Apetrei C, Pandrea I, Klatt N, Brenchley J, Lynch SV, McCune JM.
Gut microbes can profoundly modulate mucosal barrier-promoting Th17 cells in mammals. A salient feature of HIV/simian immunodeficiency virus (SIV) immunopathogenesis is the loss of Th17 cells, which has been linked to increased activity of the immuno- modulatory enzyme, indoleamine 2,3-dioxygenase 1 (IDO 1). The role of gut microbes in this system remains unknown, and the SIV-infected rhesus macaque provides a well-described model for HIV-associated Th17 loss and mucosal immune disruption. We observed a specific depletion of gut-resident Lactobacillus during acute and chronic SIV infection of rhesus macaques, which was also seen in early HIV- infected humans. This depletion in rhesus macaques correlated with increased IDO1 activity and Th17 loss. Macaques supplemented with a Lactobacillus- containing probiotic exhibited decreased IDO1 activity during chronic SIV infection. We propose that Lactobacillus species inhibit mammalian IDO1 and thus may help to preserve Th17 cells during pathogenic SIV infection, providing support for Lactobacillus species as modulators of mucosal immune homeostasis.
Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism
Science Translational Medicine. July 10, 2013
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.
Progressive HIV infection is characterized by dysregulation of the intestinal immune barrier, translocation of immunostimulatory microbial products, and chronic systemic inflammation that is thought to drive progression of disease to AIDS. Elements of this pathologic process persist despite viral suppression during highly active antiretroviral therapy (HAART), and drivers of these phenomena remain poorly understood. Disrupted intestinal immunity can precipitate dysbiosis that induces chronic inflammation in the mucosa and periphery of mice. However, putative microbial drivers of HIV-associated immunopathology versus recovery have not been identified in humans. Using high-resolution bacterial community profiling, we identified a dysbiotic mucosal-adherent community enriched in Proteobacteria and depleted of Bacteroidia members that was associated with markers of mucosal immune disruption, T cell activation, and chronic inflammation in HIV-infected subjects. Furthermore, this dysbiosis was evident among HIV-infected subjects undergoing HAART, and the extent of dysbiosis correlated with activity of the kynurenine pathway of tryptophan catabolism and plasma concentrations of the inflammatory cytokine interleukin-6 (IL-6), two established markers of disease progression. Gut-resident bacteria with capacity to catabolize tryptophan through the kynurenine pathway were found to be enriched in HIV-infected subjects, strongly correlated with kynurenine levels in HIV-infected subjects, and capable of kynurenine production in vitro. These observations demonstrate a link between mucosal-adherent colonic bacteria and immunopathogenesis during progressive HIV infection that is apparent even in the setting of viral suppression during HAART. This link suggests that gut-resident microbial populations may influence intestinal homeostasis during HIV disease.