The gut microbiome and HIV-1 pathogenesis: a two-way street.

HIV-1 infection is associated with substantial damage to the gastrointestinal tract resulting in structural impairment of the epithelial barrier and a disruption of intestinal homeostasis. The accompanying translocation of microbial products and potentially microbes themselves from the lumen into systemic circulation has been linked to immune activation, inflammation, and HIV-1 disease progression. The importance of microbial translocation in the setting of HIV-1 infection has led to a recent focus on understanding how the communities of microbes that make up the intestinal microbiome are altered during HIV-1 infection and how they interact with mucosal immune cells to contribute to inflammation. This review details the dysbiotic intestinal communities associated with HIV-1 infection and their potential link to HIV-1 pathogenesis. We detail studies that begin to address the mechanisms driving microbiota-associated immune activation and inflammation and the various treatment strategies aimed at correcting dysbiosis and improving the overall health of HIV-1-infected individuals. Finally, we discuss how this relatively new field of research can advance to provide a more comprehensive understanding of the contribution of the gut microbiome to HIV-1 pathogenesis.

[1]  B. Palmer,et al.  HIV-induced alteration in gut microbiota , 2014, Gut microbes.

[2]  D. Douek,et al.  Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. , 2008, Blood.

[3]  Matthew J. Gebert,et al.  Alterations in the gut microbiota associated with HIV-1 infection. , 2013, Cell host & microbe.

[4]  F. Bushman,et al.  The Macaque Gut Microbiome in Health, Lentiviral Infection, and Chronic Enterocolitis , 2008, PLoS pathogens.

[5]  J. Gordon,et al.  Human nutrition, the gut microbiome and the immune system , 2011, Nature.

[6]  M. McCarter,et al.  HIV-1 Infection of Human Intestinal Lamina Propria CD4+ T Cells In Vitro Is Enhanced by Exposure to Commensal Escherichia coli , 2012, The Journal of Immunology.

[7]  L. Hooper,et al.  Immune responses to the microbiota at the intestinal mucosal surface. , 2009, Immunity.

[8]  S. Gianella,et al.  An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia , 2014, Mucosal Immunology.

[9]  E. Haddad,et al.  Enhancement of Microbiota in Healthy Macaques Results in Beneficial Modulation of Mucosal and Systemic Immune Function , 2016, The Journal of Immunology.

[10]  A. Kjær,et al.  Microbiota-Dependent Marker TMAO is Not Associated With Decreased Myocardial Perfusion in Well-Treated HIV-Infected Patients as Assessed by 82Rubidium PET/CT. , 2016, Journal of acquired immune deficiency syndromes.

[11]  Ajay S. Gulati,et al.  Inflammatory Bowel Diseases Phenotype, C. difficile and NOD2 Genotype Are Associated with Shifts in Human Ileum Associated Microbial Composition , 2012, PloS one.

[12]  D. Gauguier,et al.  Plaque burden in HIV-infected patients is associated with serum intestinal microbiota-generated trimethylamine , 2015, AIDS.

[13]  Z. Pei,et al.  Fecal bacterial microbiome diversity in chronic HIV-infected patients in China , 2016, Emerging Microbes & Infections.

[14]  G. Huffnagle,et al.  The microbiome and regulation of mucosal immunity , 2014, Immunology.

[15]  Jeff E. Mold,et al.  Tryptophan Catabolism by Indoleamine 2,3-Dioxygenase 1 Alters the Balance of TH17 to Regulatory T Cells in HIV Disease , 2010, Science Translational Medicine.

[16]  S. Hazen,et al.  The contributory role of gut microbiota in cardiovascular disease. , 2014, The Journal of clinical investigation.

[17]  N. Pace,et al.  Disease phenotype and genotype are associated with shifts in intestinal‐associated microbiota in inflammatory bowel diseases , 2011, Inflammatory bowel diseases.

[18]  J. Margolick,et al.  Brief Report: Intestinal Microbiota-Produced Trimethylamine-N-Oxide and Its Association With Coronary Stenosis and HIV Serostatus , 2016, Journal of acquired immune deficiency syndromes.

[19]  M. Ferrer,et al.  HIV infection results in metabolic alterations in the gut microbiota different from those induced by other diseases , 2016, Scientific Reports.

[20]  E. Zoetendal,et al.  Mucosa-Associated Bacteria in the Human Gastrointestinal Tract Are Uniformly Distributed along the Colon and Differ from the Community Recovered from Feces , 2002, Applied and Environmental Microbiology.

[21]  M. McCarter,et al.  Microbial exposure alters HIV-1-induced mucosal CD4+ T cell death pathways Ex vivo , 2014, Retrovirology.

[22]  M. Vijay-Kumar,et al.  Gut microbiome as a novel cardiovascular therapeutic target. , 2016, Current opinion in pharmacology.

[23]  O. Yang,et al.  Immunomodulation of antiretroviral drug-suppressed chronic HIV-1 infection in an oral probiotic double-blind placebo-controlled trial. , 2014, AIDS research and human retroviruses.

[24]  G. Silvestri,et al.  Microbial Translocation in the Pathogenesis of HIV Infection and AIDS , 2013, Clinical Microbiology Reviews.

[25]  E. Purdom,et al.  Diversity of the Human Intestinal Microbial Flora , 2005, Science.

[26]  Piotr Nowak,et al.  Gut microbiota diversity predicts immune status in HIV-1 infection , 2015, AIDS.

[27]  R. Kaul,et al.  Sigmoid Th17 populations, the HIV latent reservoir, and microbial translocation in men on long-term antiretroviral therapy , 2011, AIDS.

[28]  J. Lampe,et al.  The gut microbiome and obesity. , 2012, Nestle Nutrition Institute workshop series.

[29]  D. Nixon,et al.  Bacteroides are associated with GALT iNKT cell function and reduction of microbial translocation in HIV-1 infection , 2016, Mucosal Immunology.

[30]  Z. Klase,et al.  Dysbiotic Bacteria Translocate in Progressive SIV Infection , 2014, Mucosal Immunology.

[31]  J. Brenchley,et al.  Probiotics Reduce Inflammation in Antiretroviral Treated, HIV-Infected Individuals: Results of the “Probio-HIV” Clinical Trial , 2015, PloS one.

[32]  G. Olsen,et al.  Critical Evaluation of Two Primers Commonly Used for Amplification of Bacterial 16S rRNA Genes , 2008, Applied and Environmental Microbiology.

[33]  D. Price,et al.  CD4+ T Cell Depletion during all Stages of HIV Disease Occurs Predominantly in the Gastrointestinal Tract , 2004, The Journal of experimental medicine.

[34]  G. Gloor,et al.  High throughput sequencing methods and analysis for microbiome research. , 2013, Journal of microbiological methods.

[35]  G. Silvestri,et al.  Nonpathogenic simian immunodeficiency virus infections. , 2012, Cold Spring Harbor perspectives in medicine.

[36]  S. Miehlke,et al.  Prevalence of Bacteroides and Prevotella spp. in ulcerative colitis. , 2006, Journal of medical microbiology.

[37]  J. J. Abellán,et al.  Assessing Gut Microbial Diversity from Feces and Rectal Mucosa , 2010, Microbial Ecology.

[38]  M. Markowitz,et al.  Mechanisms of Gastrointestinal CD4+ T-Cell Depletion during Acuteand Early Human Immunodeficiency Virus Type 1 Infection , 2006, Journal of Virology.

[39]  R. Kaul,et al.  A role for mucosal IL-22 production and Th22 cells in HIV-associated mucosal immunopathogenesis , 2012, Mucosal Immunology.

[40]  A. Keshavarzian,et al.  A Compositional Look at the Human Gastrointestinal Microbiome and Immune Activation Parameters in HIV Infected Subjects , 2014, PLoS pathogens.

[41]  A. Kjær,et al.  Microbiota-Dependent Marker TMAO Is Elevated in Silent Ischemia but Is Not Associated With First-Time Myocardial Infarction in HIV Infection , 2016, Journal of acquired immune deficiency syndromes.

[42]  K. Brown,et al.  Diet-Induced Dysbiosis of the Intestinal Microbiota and the Effects on Immunity and Disease , 2012, Nutrients.

[43]  Leah M. Feazel,et al.  Sex Differences in the Gut Microbiome Drive Hormone-Dependent Regulation of Autoimmunity , 2013, Science.

[44]  A. d’Arminio Monforte,et al.  Microbial translocation predicts disease progression of HIV-infected antiretroviral-naive patients with high CD4+ cell count , 2011, AIDS.

[45]  K. McCoy,et al.  The interplay between the gut microbiota and the immune system , 2014, Gut microbes.

[46]  Wei Zhu,et al.  Investigating the biological and clinical significance of human dysbioses. , 2011, Trends in microbiology.

[47]  C. Deming,et al.  Probiotic/prebiotic supplementation of antiretrovirals improves gastrointestinal immunity in SIV-infected macaques. , 2013, The Journal of clinical investigation.

[48]  Daniel N. Frank,et al.  Enhancement of HIV-1 infection and intestinal CD4+ T cell depletion ex vivo by gut microbes altered during chronic HIV-1 infection , 2016, Retrovirology.

[49]  D. Douek,et al.  Microbial translocation across the GI tract. , 2012, Annual review of immunology.

[50]  J. Flamm,et al.  Severe CD4+ T-Cell Depletion in Gut Lymphoid Tissue during Primary Human Immunodeficiency Virus Type 1 Infection and Substantial Delay in Restoration following Highly Active Antiretroviral Therapy , 2003, Journal of Virology.

[51]  Zeneng Wang,et al.  Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk , 2013 .

[52]  J. Brenchley,et al.  Paucity of IL-21-producing CD4(+) T cells is associated with Th17 cell depletion in SIV infection of rhesus macaques. , 2012, Blood.

[53]  H. Miller,et al.  The effect of probiotics on CD4 counts among people living with HIV: a systematic review. , 2016, Beneficial microbes.

[54]  A. Kane,et al.  Associations of cocaine use and HIV infection with the intestinal microbiota, microbial translocation, and inflammation. , 2014, Journal of studies on alcohol and drugs.

[55]  J. Brenchley,et al.  Microbial translocation is a cause of systemic immune activation in chronic HIV infection , 2006, Retrovirology.

[56]  C. Huttenhower,et al.  Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis , 2013, eLife.

[57]  Young-Seok Cho,et al.  Fecal Microbiota Transplantation: Current Applications, Effectiveness, and Future Perspectives , 2016, Clinical endoscopy.

[58]  J. Horcajada,et al.  Effect of Probiotics (Saccharomyces boulardii) on Microbial Translocation and Inflammation in HIV-Treated Patients: A Double-Blind, Randomized, Placebo-Controlled Trial , 2015, Journal of acquired immune deficiency syndromes.

[59]  Z. Pei,et al.  HIV-induced immunosuppression is associated with colonization of the proximal gut by environmental bacteria , 2015, AIDS.

[60]  Ali A. Faruqi,et al.  Gut-Resident Lactobacillus Abundance Associates with IDO1 Inhibition and Th17 Dynamics in SIV-Infected Macaques. , 2015, Cell reports.

[61]  P. Bork,et al.  Gut Microbiota Linked to Sexual Preference and HIV Infection , 2016, EBioMedicine.

[62]  M. Moeschberger,et al.  New Bacterial Species Associated with Chronic Periodontitis , 2003, Journal of dental research.

[63]  A. Kane,et al.  Intestinal microbiota, microbial translocation, and systemic inflammation in chronic HIV infection. , 2015, The Journal of infectious diseases.

[64]  H. Virgin,et al.  SIV Infection-Mediated Changes in Gastrointestinal Bacterial Microbiome and Virome Are Associated with Immunodeficiency and Prevented by Vaccination. , 2016, Cell host & microbe.

[65]  M. Clerici,et al.  Early Impairment of Gut Function and Gut Flora Supporting a Role for Alteration of Gastrointestinal Mucosa in Human Immunodeficiency Virus Pathogenesis , 2007, Journal of Clinical Microbiology.

[66]  P. Ueland,et al.  Reduced Levels of D-dimer and Changes in Gut Microbiota Composition After Probiotic Intervention in HIV-Infected Individuals on Stable ART , 2015, Journal of acquired immune deficiency syndromes.

[67]  B. Gazzard,et al.  Intestinal absorptive capacity, intestinal permeability and jejunal histology in HIV and their relation to diarrhoea. , 1995, Gut.

[68]  N. Pace,et al.  Gastrointestinal microbiology enters the metagenomics era , 2008, Current opinion in gastroenterology.

[69]  D. Kasper,et al.  Beneficial effects of Bacteroides fragilis polysaccharides on the immune system. , 2010, Frontiers in bioscience.

[70]  M. Zeitz,et al.  Enteric immunologic abnormalities in human immunodeficiency virus infection. , 1992, Seminars in liver disease.

[71]  A. Latorre,et al.  Altered metabolism of gut microbiota contributes to chronic immune activation in HIV-infected individuals , 2014, Mucosal Immunology.

[72]  S. Mazmanian,et al.  Pathobionts of the gastrointestinal microbiota and inflammatory disease. , 2011, Current opinion in immunology.

[73]  G. Reid,et al.  The Role of the Microbiome in Rheumatic Diseases , 2013, Current Rheumatology Reports.

[74]  D. Godfrey,et al.  Raising the NKT cell family , 2010, Nature Immunology.

[75]  N. Pace,et al.  Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases , 2007, Proceedings of the National Academy of Sciences.

[76]  Richard A. Flavell,et al.  NLRP6 Inflammasome Regulates Colonic Microbial Ecology and Risk for Colitis , 2011, Cell.

[77]  C. Loddenkemper,et al.  Impairment of the intestinal barrier is evident in untreated but absent in suppressively treated HIV-infected patients , 2008, Gut.

[78]  Jennifer M. Fettweis,et al.  Species-level classification of the vaginal microbiome , 2012, BMC Genomics.

[79]  Larissa B. Thackray,et al.  Pathogenic Simian Immunodeficiency Virus Infection Is Associated with Expansion of the Enteric Virome , 2012, Cell.

[80]  D. Richman,et al.  Gut Lactobacillales are associated with higher CD4 and less microbial translocation during HIV infection , 2013, AIDS.

[81]  J. Habbema,et al.  Probiotic Yogurt Consumption is Associated With an Increase of CD4 Count Among People Living With HIV/AIDS , 2010, Journal of clinical gastroenterology.

[82]  Douglas S Kwon,et al.  Altered Virome and Bacterial Microbiome in Human Immunodeficiency Virus-Associated Acquired Immunodeficiency Syndrome. , 2016, Cell host & microbe.

[83]  F. Bushman,et al.  Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis , 2013, Nature Medicine.

[84]  D. Frank,et al.  Alterations in Intestinal Microbiota Correlate With Susceptibility to Type 1 Diabetes , 2015, Diabetes.

[85]  L. McKinnon,et al.  Microbial translocation and microbiome dysbiosis in HIV-associated immune activation , 2016, Current opinion in HIV and AIDS.

[86]  M. Katze,et al.  Effects of Fecal Microbial Transplantation on Microbiome and Immunity in Simian Immunodeficiency Virus-Infected Macaques , 2016, Journal of Virology.

[87]  Christopher A. Gaulke,et al.  SIV‐infection‐driven changes of pattern recognition receptor expression in mesenteric lymph nodes and gut microbiota dysbiosis , 2015, Journal of medical primatology.

[88]  Ryan D. Hernandez,et al.  Dysbiosis of the Gut Microbiota Is Associated with HIV Disease Progression and Tryptophan Catabolism , 2013, Science Translational Medicine.

[89]  W. Garrett,et al.  Gut microbiota, metabolites and host immunity , 2016, Nature Reviews Immunology.

[90]  Harry J. Flint,et al.  Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine. , 2009, FEMS microbiology letters.

[91]  Natalie J Torok,et al.  Molecular Characterization of Stool Microbiota in HIV-Infected Subjects by Panbacterial and Order-Level 16S Ribosomal DNA (rDNA) Quantification and Correlations With Immune Activation , 2011, Journal of acquired immune deficiency syndromes.

[92]  M. Clerici,et al.  Specific prebiotics modulate gut microbiota and immune activation in HAART-naive HIV-infected adults: results of the “COPA” pilot randomized trial , 2011, Mucosal Immunology.

[93]  G. Reid,et al.  Yogurt Containing Probiotic Lactobacillus rhamnosus GR-1 and L. reuteri RC-14 Helps Resolve Moderate Diarrhea and Increases CD4 Count in HIV/AIDS Patients , 2008, Journal of clinical gastroenterology.

[94]  G. Macfarlane,et al.  Regulation of short-chain fatty acid production , 2003, Proceedings of the Nutrition Society.

[95]  N. Kaakoush Insights into the Role of Erysipelotrichaceae in the Human Host , 2015, Front. Cell. Infect. Microbiol..

[96]  F. Rey,et al.  Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide , 2015, mBio.

[97]  G. Jiang,et al.  Gut immune dysfunction through impaired innate pattern recognition receptor expression and gut microbiota dysbiosis in chronic SIV infection , 2015, Mucosal Immunology.

[98]  I. Sereti,et al.  Serious Non-AIDS Events: Therapeutic Targets of Immune Activation and Chronic Inflammation in HIV Infection , 2016, Drugs.

[99]  B. Gazzard,et al.  The immunomodulatory nutritional intervention NR100157 reduced CD4+ T-cell decline and immune activation: a 1-year multicenter randomized controlled double-blind trial in HIV-infected persons not receiving antiretroviral therapy (The BITE Study). , 2013, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[100]  P. Luciw,et al.  Randomized pilot trial of a synbiotic dietary supplement in chronic HIV-1 infection , 2012, BMC Complementary and Alternative Medicine.

[101]  J. Slavin Fiber and Prebiotics: Mechanisms and Health Benefits , 2013, Nutrients.

[102]  M. Reale,et al.  Effect of Probiotic Supplement on Cytokine Levels in HIV-Infected Individuals: A Preliminary Study , 2015, Nutrients.

[103]  D. Jonkers,et al.  Review article: the role of butyrate on colonic function , 2007, Alimentary pharmacology & therapeutics.

[104]  S. Hazen,et al.  The gut microbial endocrine organ: bacterially derived signals driving cardiometabolic diseases. , 2015, Annual review of medicine.

[105]  C. Benoist,et al.  The influence of the microbiota on type‐1 diabetes: on the threshold of a leap forward in our understanding , 2012, Immunological reviews.

[106]  A. Iwasaki,et al.  Innate control of adaptive immunity: dendritic cells and beyond. , 2007, Seminars in immunology.

[107]  Paul M. Ruegger,et al.  HIV Infection is associated with compositional and functional shifts in the rectal mucosal microbiota , 2013, Microbiome.

[108]  P. Gaulard,et al.  Early initiation of combined antiretroviral therapy preserves immune function in the gut of HIV-infected patients , 2014, Mucosal Immunology.

[109]  R. Kaul,et al.  Can Probiotics Reduce Inflammation and Enhance Gut Immune Health in People Living with HIV: Study Designs for the Probiotic Visbiome for Inflammation and Translocation (PROOV IT) Pilot Trials , 2016, HIV clinical trials.

[110]  J. Qi,et al.  Metagenomic sequencing reveals microbiota and its functional potential associated with periodontal disease , 2013, Scientific Reports.

[111]  M. McCarter,et al.  Gut Dendritic Cell Activation Links an Altered Colonic Microbiome to Mucosal and Systemic T Cell Activation in Untreated HIV-1 infection , 2015, Mucosal Immunology.

[112]  G. Silvestri,et al.  Nonhuman primate models in AIDS research , 2013, Current opinion in HIV and AIDS.

[113]  M. McCarter,et al.  Evidence for dendritic cell-dependent CD4(+) T helper-1 type responses to commensal bacteria in normal human intestinal lamina propria. , 2009, Clinical immunology.

[114]  Michael D. George,et al.  Rapid Onset of Intestinal Epithelial Barrier Dysfunction in Primary Human Immunodeficiency Virus Infection Is Driven by an Imbalance between Immune Response and Mucosal Repair and Regeneration , 2007, Journal of Virology.