A Compositional Look at the Human Gastrointestinal Microbiome and Immune Activation Parameters in HIV Infected Subjects

Mutlu, Ece; Keshavarzian, Ali; Losurdo, John; Swanson, Garth; Siewe, Basile; Forsyth, Christopher B.; French, Audrey L.; Demarais, Patricia; Sun, Yan; Koenig, Lars M.; Cox, Stephen B.; Engen, Phillip A.; Chakradeo, Prachi; Abbasi, Rawan; Gorenz, Annika; Burns, Charles M.; Landay, Alan

doi:10.1371/journal.ppat.1003829

Cited by 363 publications

(550 citation statements)

References 58 publications

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“…In chronic HIV infection, an altered gut microbiome is associated with mucosal dysfunction, systemic inflammation, and disease progression (9,10,12,39). FMT is emerging as an effective treatment option for antibiotic-refractory intestinal infections, such as C. difficile infections, as well as for chronic inflammatory conditions of the gut that are known to be associated with dysbiosis (24,25,40).…”

Section: Discussionmentioning

confidence: 99%

“…This is typically characterized by an overall loss of diversity, with alterations to the phyla Bacteroidetes, Firmicutes, and Proteobacteria (11). Specifically, the loss of beneficial bacterial genera, such as Bacteroides, Lactobacillus, and Bifidobacterium, has been observed and associated with pathogenesis (9,10,12,13). Furthermore, the levels of several pathogenic Proteobacteria have been observed to increase during HIV infection, including those within the genera Campylobacter, Escherichia, Acinetobacter, Desulfovibrio, and Pseudomonas, as have those of Prevotella species (9)(10)(11).…”

mentioning

confidence: 99%

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Effects of Fecal Microbial Transplantation on Microbiome and Immunity in Simian Immunodeficiency Virus-Infected Macaques

Hensley-McBain

Zevin

Manuzak

et al. 2016

J Virol

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An altered intestinal microbiome during chronic human immunodeficiency virus (HIV) infection is associated with mucosal dysfunction, inflammation, and disease progression. We performed a preclinical evaluation of the safety and efficacy of fecal microbiota transplantation (FMT) as a potential therapeutic in HIV-infected individuals. Antiretroviral-treated, chronically simian immunodeficiency virus (SIV)-infected rhesus macaques received antibiotics followed by FMT. The greatest microbiota shift was observed after antibiotic treatment. The bacterial community composition at 2 weeks post-FMT resembled the pre-FMT community structure, although differences in the abundances of minor bacterial populations remained. Immunologically, we observed significant increases in the number of peripheral Th17 and Th22 cells and reduced CD4؉ T cell activation in gastrointestinal tissues post-FMT. Importantly, the transplant was well tolerated with no negative clinical side effects. Although this pilot study did not control for the differential contributions of antibiotic treatment and FMT to the observed results, the data suggest that FMT may have beneficial effects that should be further evaluated in larger studies. IMPORTANCE Due to the immunodeficiency and chronic inflammation that occurs during HIV infection, determination of the safety of FMT is crucial to prevent deleterious consequences if it is to be used as a treatment in the future. Here we used the macaque model of HIV infection and performed FMT on six chronically SIV-infected rhesus macaques on antiretroviral treatment. In addition toproviding a preclinical demonstration of the safety of FMT in primates infected with a lentivirus, this study provided a unique opportunity to examine the relationships between alterations to the microbiome and immunological parameters. In this study, we found increased numbers of Th17 and Th22 cells as well as decreased activation of CD4 ؉ T cells post-FMT, and these changes correlated most strongly across all sampling time points with lower-abundance taxonomic groups and other taxonomic groups in the colon. Overall, these data provide evidence that changes in the microbiome, particularly in terms of diversity and changes in minor populations, can enhance immunity and do not have adverse consequences.A ntiretroviral treatment (ART) has substantially decreased the progression to AIDS in human immunodeficiency virus (HIV)-infected individuals. However, despite the ability to suppress viremia, HIV-infected individuals in whom the infection is suppressed by ART have increased rates of morbidity and mortality compared to those of uninfected individuals (1). One mechanism underlying the increased mortality is dysfunction of the gastrointestinal (GI) tract, which is associated with inflammation during HIV infection. Several lines of evidence support the role of GI dysfunction in HIV-related disease, including (i) a consistent association between mortality in HIV-infected individuals and markers of microbial translocation and gut epithe...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Effects of Fecal Microbial Transplantation on Microbiome and Immunity in Simian Immunodeficiency Virus-Infected Macaques

Hensley-McBain

Zevin

Manuzak

et al. 2016

J Virol

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“…Results from a study by Gaardbo et al showed that microberelated effects in the gut are associated with CD4 T-cell loss during HIV-1 infection (35). The dysbiosis that occurs in the gut of HIV-1-infected subjects persisting on ART describes the imbalance of bacterial diversity that is illustrated by increased proinflammatory pathogenic strains (63,64). Importantly, the enhanced tryptophan metabolism related to the composition of the gut microbiota has been linked to the disease progression contributed by enhanced Kyn production in the gut (65).…”

Section: Ccr7mentioning

confidence: 99%

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Dagenais-Lussier

Aounallah

Mehraj

et al. 2016

J Virol

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Early HIV-1 infection is characterized by enhanced tryptophan catabolism, which contributes to immune suppression and disease progression. However, the mechanism by which kynurenine, a tryptophan-related metabolite, induces immune suppression remains poorly understood. Herein, we show that the increased production of kynurenine correlates with defective interleukin-2 (IL-2) signaling in memory CD4 T cells from HIV-infected subjects. Defective IL-2 signaling in these subjects, which drives reduced protection from Fas-mediated apoptosis, was also associated with memory CD4 T-cell loss. Treatment of memory CD4 T cells with the concentration of kynurenine found in plasma inhibited IL-2 signaling through the production of reactive oxygen species. We further show that IL-2 signaling in memory CD4 T cells is improved by the antioxidant N-acetylcysteine. Early initiation of antiretroviral therapy restored the IL-2 response in memory CD4 T cells by reducing reactive oxygen species and kynurenine production. The study findings provide a kynurenine-dependent mechanism through IL-2 signaling for reduced CD4 T-cell survival, which can be reversed by early treatment initiation in HIV-1 infection. IMPORTANCE The persistence of functional memory CD4 T cells represents the basis for long-lasting immune protection in individuals after exposure to HIV-1. Unfortunately, primary HIV-1 infection results in the massive loss of these cells within weeks of infection, which is mainly driven by inflammation and massive infection by the virus. These new findings show that the enhanced production of kynurenine, a metabolite related to tryptophan catabolism, also impairs memory CD4 T-cell survival and interferes with IL-2 signaling early during HIV-1 infection.P rogressive depletion of CD4 T cells by pyroptosis and activation-related apoptosis is the hallmark of HIV-1 infection (1-4). The loss of memory CD4 T cells and, in particular, central memory CD4 T cells (T CM cells), which are critical to ensure longlasting immune protection, occurs from the onset of infection and independently predicts disease progression (5-8). Memory T-cell survival depends on signals provided by the gamma-chain-receptor cytokines, such as interleukin-2 (IL-2) and IL-7 (9-12). Previous data showed an impaired response to these cytokines in T cells during HIV-1 infection (13-16). However, our knowledge of the molecular mechanisms responsible for these immune defects is still incomplete.CD4 T-cell depletion is also linked with persistent inflammation, which takes place in the gut and lymphoid tissues early after infection and in the bloodstream later after infection (17-19). This inflammation is clinically relevant, since it has not been fully abrogated by long-term antiretroviral therapy (ART) (20)(21)(22)(23). Persistent inflammation during HIV-1 infection is associated with enhanced metabolic activity, which drives a Warburg-like effect on lipid, glucose, and amino acid pathways (22,(24)(25)(26)(27). The catabolism of an essential amino acid like tryptoph...

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“…An altered gastrointestinal microbiome appears to occur early in the course of HIV-infection and may contribute to, or is at least correlated with, mucosal inflammatory activity, mucosal CD4 + T-cell depletion, and peripheral CD8 + T-cell activation [39][40][41]. The microbiome alterations and accompanying local and systemic immune effects persist following the early stages of infection and do not revert with ART, possibly because of a persistent presence of HIV at the mucosal surface or the lasting depletion of gastrointestinal CD4 + T cells and other immune effectors despite effective suppression of plasma viremia [42,43]. In a study of rectosigmoid biopsy specimens from HIVinfected subjects not yet receiving ART, ART recipients, and HIV-negative controls, those with untreated HIV infection were found to have a marked dysbiosis of mucosal-adherent bacteria characterized by increased Proteobacteria levels and reduced Bacteroidetes levels, which was accompanied by increased mucosal CD4 + and CD8 + T-cell activation, increased circulating CD8 + T-cell activation, and, among ART recipients, increased circulating interleukin 6 (IL-6) levels [44].…”

Section: Malnutrition Hiv and The Microbiomementioning

confidence: 99%

From Wasting to Obesity: The Contribution of Nutritional Status to Immune Activation in HIV Infection

et al. 2016

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The impact of human immunodeficiency virus (HIV) infection on innate and adaptive immune activation occurs in the context of host factors, which serve to augment or dampen the physiologic response to the virus. Independent of HIV infection, nutritional status, particularly body composition, affects innate immune activation through a variety of conditions, including reduced mucosal barrier defenses and microbiome dysbiosis in malnutrition and the proinflammatory contribution of adipocytes and stromal vascular cells in obesity. Similarly, T-cell activation, proliferation, and cytokine expression are reduced in the setting of malnutrition and increased in obesity, potentially due to adipokine regulatory mechanisms restraining energy-avid adaptive immunity in times of starvation and exerting a paradoxical effect in overnutrition. The response to HIV infection is situated within these complex interactions between host nutritional health and immunologic function, which contribute to the varied phenotypes of immune activation among HIV-infected patients across a spectrum from malnutrition to obesity.

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A Compositional Look at the Human Gastrointestinal Microbiome and Immune Activation Parameters in HIV Infected Subjects

Cited by 363 publications

References 58 publications

Effects of Fecal Microbial Transplantation on Microbiome and Immunity in Simian Immunodeficiency Virus-Infected Macaques

Effects of Fecal Microbial Transplantation on Microbiome and Immunity in Simian Immunodeficiency Virus-Infected Macaques

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

From Wasting to Obesity: The Contribution of Nutritional Status to Immune Activation in HIV Infection

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