HIV-associated changes in the enteric microbial community: Potential role in loss of homeostasis and development of systemic inflammation

Current Opinion in Infectious Diseases

Volumn 30, Issue 1, 2017, Pages 31-43

  Gootenberg, David B ^a,b   Paer, Jeffrey M ^a   Luevano, Jesus Mario ^a,b   Kwon, Douglas S ^a,b  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

Author keywords

Developing world; Enteric; HIV; Microbiome; Systemic inflammation; Virome

Indexed keywords

CD14 ANTIGEN; CD163 ANTIGEN; INTERLEUKIN 6;

BACTERIAL FLORA; BACTERIAL MICROBIOME; CD4+ T LYMPHOCYTE; CLOSTRIDIUM DIFFICILE INFECTION; DISEASE COURSE; GEOGRAPHY; HOST; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; INFLAMMATION; INFLAMMATORY BOWEL DISEASE; MICROBIAL COMMUNITY; MICROBIOME; OBESITY; REVIEW; CARDIOVASCULAR DISEASE; COMPLICATION; ENTEROBACTERIACEAE; HOMEOSTASIS; IMMUNOLOGY; INTESTINE FLORA; INTESTINE MUCOSA; KIDNEY DISEASE; MICROBIOLOGY; MUCOSAL IMMUNITY; VIROLOGY;

CARDIOVASCULAR DISEASES; ENTEROBACTERIACEAE; GASTROINTESTINAL MICROBIOME; HIV INFECTIONS; HOMEOSTASIS; HUMANS; IMMUNITY, MUCOSAL; INFLAMMATION; INTESTINAL MUCOSA; KIDNEY DISEASES;

EID: 85001996750     PISSN: 09517375     EISSN: 14736527     Source Type: Journal    
DOI: 10.1097/QCO.0000000000000341     Document Type: Review

References (208)

1. Delwart E. A roadmap to the human virome. PLoS Pathog 2013; 9:e1003146.
2. Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 2006; 124:837-848.
3. Virgin HW, Todd JA. Metagenomics and personalized medicine. Cell 2011; 147:44-56.
4. Virgin HW, Wherry EJ, Ahmed R. Redefining chronic viral infection. Cell 2009; 138:30-50.
5. Wylie KM, Weinstock GM, Storch GA. Emerging view of the human virome. Transl Res 2012; 160:283-290.
6. Honda K, Littman DR. The microbiome in infectious disease and inflammation. Annu Rev Immunol 2012; 30:759-795.
7. Cho I, Blaser MJ. The human microbiome: at the interface of health and disease. Nat Rev Genet 2012; 13:260-270.
8. Friedrich MJ. Genomes of microbes inhabiting the body offer clues to human health and disease. JAMA 2013; 309:1447-1449.
9. Littman DR, Pamer EG. Role of the commensal microbiota in normal and pathogenic host immune responses. Cell Host Microbe 2011; 10: 311-323.
10. Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science 2012; 336:1268-1273.
11. Zhang H, Luo XM. Control of commensal microbiota by the adaptive immune system. Gut Microbes 2015; 6:156-160.
12. Thaiss CA, Zmora N, Levy M, Elinav E. The microbiome and innate immunity. Nature 2016; 535:65-74.
13. Okoye AA, Picker LJ. CD4(+) T-cell depletion in HIV infection: mechanisms of immunological failure. Immunol Rev 2013; 254: 54-64.
14. Andrews CA, Koup RA. The immunopathology of HIV infection. J Antimicrob Chemother 1996; 37 (Suppl B):13-25.
15. Douek DC, Roederer M, Koup RA. Emerging concepts in the immunopathogenesis of AIDS. Annu Rev Med 2009; 60:471-484.
16. Sandler NG, Douek DC. Microbial translocation in HIV infection: causes, consequences and treatment opportunities. Nat Rev Microbiol 2012; 10:655-666.
17. Lozupone CA, Li M, Campbell TB, et al. Alterations in the gut microbiota associated with HIV-1 infection. Cell Host Microbe 2013; 14:329-339.
18. Lozupone CA, Rhodes ME, Neff CP, et al. HIV-induced alteration in gut microbiota: driving factors, consequences, and effects of antiretroviral therapy. Gut Microbes 2014; 5:562-570.
19. McHardy IH, Li X, Tong M, et al. HIV Infection is associated with compositional and functional shifts in the rectal mucosal microbiota. Microbiome 2013; 1:26.
20. Mutlu EA, Keshavarzian A, Losurdo J, et al. A compositional look at the human gastrointestinal microbiome and immune activation parameters in HIV infected subjects. PLoS Pathog 2014; 10:e1003829.
21. Vujkovic-Cvijin I, Dunham RM, Iwai S, et al. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci Transl Med 2013; 5:193ra91.
22. Yu G, Fadrosh D, Ma B, et al. Anal microbiota profiles in HIV-positive and HIVnegative MSM. AIDS 2014; 28:753-760.
23. Dillon SM, Lee EJ, Kotter CV, et al. An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia. Mucosal Immunol 2014; 7:983-994.
24. Dinh DM, Volpe GE, Duffalo C, et al. Intestinal microbiota, microbial translocation, and systemic inflammation in chronic HIV infection. J Infect Dis 2015; 211:19-27.
25. Nowak P, Troseid M, Avershina E, et al. Gut microbiota diversity predicts immune status in HIV-1 infection. AIDS (London, England) 2015; 29:2409-2418.
26. Vázquez-Castellanos JF, Serrano-Villar S, Latorre A, et al. Altered metabolism of gut microbiota contributes to chronic immune activation in HIV-infected individuals. Mucosal Immunol 2015; 8:760-772.
27. Yang L, Poles MA, Fisch GS, et al. HIV-induced immunosuppression is associated with colonization of the proximal gut by environmental bacteria. AIDS 2016; 30:19-29.
28. Dillon SM, Lee EJ, Kotter CV, et al. Gut dendritic cell activation links an altered colonic microbiome to mucosal and systemic T-cell activation in untreated HIV-1 infection. Mucosal Immunol 2016; 9:24-37.
29. Monaco CL, Gootenberg DB, Zhao G, et al. Altered virome and bacterial icrobiome in human immunodeficiency virus-associated Acquired Immunodeficiency Syndrome. Cell Host Microbe 2016; 19:311-322.
30. Sun Y, Ma Y, Lin P, et al. Fecal bacterial microbiome diversity in chronic HIVinfected patients in China. Emerg Microbes Infect 2016; 5:e31.
31. Bender JM, Li F, Martelly S, et al. Maternal HIV infection influences the microbiome of HIV-uninfected infants. Sci Transl Med 2016; 8:; 349ra100.
32. Dubourg G, Lagier JC, Hue S, et al. Gut microbiota associated with HIV infection is significantly enriched in bacteria tolerant to oxygen. BMJ Open Gastroenterol 2016; 3:e000080.
33. Ling Z, Jin C, Xie T, et al. Alterations in the fecal microbiota of patients with HIV-1 infection: an observational study in a Chinese population. Sci Rep 2016; 6:30673.
34. Centers for Disease Control and Prevention: HIV Surveillance Report; 2008.
35. Egger M, May M, Chene G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 2002; 360:119-129.
36. Guaraldi G, Orlando G, Zona S, et al. Premature age-related comorbidities among HIV-infected persons compared with the general population. Clin Infect Dis 2011; 53:1120-1126.
37. Lewden C, Chene G, Morlat P, et al. HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr 2007; 46:72-77.
38. Lohse N, Hansen A-BE, Pedersen G, et al. Survival of persons with and without HIV infection in Denmark, 1995-2005. Ann Intern Med 2007; 146:87-95.
39. Reid MJA, Mosepele M, Tsima BM, Gross R. Addressing the challenge of the emerging NCD epidemic: lessons learned from Botswana's response to the HIV epidemic. Public Health Action 2012; 2:47-49.
40. Muyanja D, Muzoora C, Muyingo A, et al. High prevalence of metabolic syndrome and cardiovascular disease risk among people with HIV on stable ART in Southwestern Uganda. AIDS Patient Care STDS 2015; 30:4-10.
41. Okello S, Kanyesigye M, Muyindike WR, et al. Incidence and predictors of hypertension in adults with HIV-initiating antiretroviral therapy in southwestern Uganda. J Hypertens 2015; 33:2039-2045.
42. Siedner MJ, Kim J-H, Nakku RS, et al. Persistent immune activation and carotid atherosclerosis in HIV-infected Ugandans receiving antiretroviral therapy. J Infect Dis 2016; 213:370-378.
43. Chow FC, Regan S, Feske S, et al. Comparison of ischemic stroke incidence in HIV-infected and non-HIV-infected patients in a US healthcare system. J Acquir Immune Defic Syndr 2012; 60:351-358.
44. Freiberg MS, Chang C-CH, Kuller LH, et al. HIV infection and the risk of acute myocardial infarction. JAMA Intern Med 2013; 173:614-622.
45. Marcus JL, Leyden WA, Chao CR, et al. HIV infection and incidence of ischemic stroke. AIDS 2014; 28:1911-1919.
46. Duprez DA, Neuhaus J, Kuller LH, et al. Inflammation, coagulation and cardiovascular disease in HIV-infected individuals. PLoS One 2012; 7:e44454.
47. McKibben RA, Margolick JB, Grinspoon S, et al. Elevated levels of monocyte activation markers are associated with subclinical atherosclerosis in men with and those without HIV infection. J Infect Dis 2015; 211:1219-1228.
48. Ross AC, Rizk N, O'Riordan MA, et al. McComsey Ga: Relationship between inflammatory markers, endothelial activation markers, and carotid intimamedia thickness in HIV-infected patients receiving antiretroviral therapy. Clin Infect Dis 2009; 49:1119-1127.
49. Subramanian S, Tawakol A, Burdo TH, et al. Arterial inflammation in patients with HIV. JAMA 2012; 308:379-386.
50. Triant VA, Grinspoon SK. Immune dysregulation and vascular risk in HIVinfected patients: implications for clinical care. J Infect Dis 2011; 203:439-441.
51. Triant VA, Meigs JB, Grinspoon SK. Association of C-reactive protein and HIV infection with acute myocardial infarction. J Acquir Immune Defic Syndr 2009; 51:268-273.
52. Fisher EA, Feig JE, Hewing B, et al. High-density lipoprotein function, dysfunction, and reverse cholesterol transport. Arterioscler Thromb Vasc Biol 2012; 32:2813-2820.
53. Khovidhunkit W, Kim M-S, Memon RA, et al. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. J Lipid Res 2004; 45:1169-1196.
54. Neves AL, Coelho J, Couto L, et al. Metabolic endotoxemia: a molecular link between obesity and cardiovascular risk. J Mol Endocrinol 2013; 51:R51-R64.
55. Yuan H, Zelkha S, Zelka S, et al. Pivotal role of NOD2 in inflammatory processes affecting atherosclerosis and periodontal bone loss. Proc Natl Acad Sci U S A 2013; 110:E5059-E5068.
56. Hunt PW. HIV and inflammation: mechanisms and consequences. Curr HIV/AIDS Rep 2012; 9:139-147.
57. Tien PC, Choi AI, Zolopa AR, et al. Inflammation and mortality in HIV-infected adults: analysis of the FRAM study cohort. J Acquir Immune Defic Syndr 2010; 55:316-322.
58. Gandhi RT, Spritzler J, Chan E, et al. Effect of baseline- and treatment-related factors on immunologic recovery after initiation of antiretroviral therapy in HIV- 1-positive subjects: results from ACTG 384. J Acquir Immune Defic Syndr 2006; 42:426-434.
59. Goicoechea M, Smith DM, Liu L, et al. Determinants of CD4- T cell recovery during suppressive antiretroviral therapy: association of immune activation, T cell maturation markers, and cellular HIV-1 DNA. J Infect Dis 2006; 194:29-37.
60. Hunt PW, Martin JN, Sinclair E, et al. T cell activation is associated with lower CD4- T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis 2003;187:1534-1543.
61. Hunt Peter W, Brenchley J, Sinclair E, et al. Relationship between T cell activation and CD4 - T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis 2008; 197:126-133.
62. Hunt PW, Cao HL, Muzoora C, et al. Impact of CD8- T-cell activation on CD4- T-cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy. AIDS 2011; 25:2123-2131.
63. Brenchley JM, Douek DC. Microbial translocation across the GI tract. Annu Rev Immunol 2012; 30:149-173.
64. Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006; 12:1365-1371.
65. Jenabian MA, El-Far M, Vyboh K, et al. Immunosuppressive tryptophan catabolism and gut mucosal dysfunction following early HIV infection. J Infect Dis 2015; 212:355-366.
66. Hunt PW, Sinclair E, Rodriguez B, et al. Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection. J Infect Dis 2014; 210:1228-1238.
67. Brown JM, Hazen SL. The gut microbial endocrine organ: bacterially derived signals driving cardiometabolic diseases. Annu Rev Med 2015; 66:343-359.
68. Koeth RA, Levison BS, Culley MK, et al. g-butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO. Cell Metab 2014; 20:799-812.
69. Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013; 19:576-585.
70. Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011; 472:57-63.
71. Zhu W, Gregory JC, Org E, et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 2016; 165:111-124.
72. Brenchley JM, Schacker TW, Ruff LE, et al. CD4- T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 2004; 200:749-759.
73. Clayton F, Snow G, Reka S, Kotler DP. Selective depletion of rectal lamina propria rather than lymphoid aggregate CD4 lymphocytes in HIV infection. Clin Exp Immunol 1997; 107:288-292.
74. Heise C, Miller CJ, Lackner A, Dandekar S. Primary acute simian immunodeficiency virus infection of intestinal lymphoid tissue is associated with gastrointestinal dysfunction. J Infect Dis 1994; 169:1116-1120.
75. Li Q, Duan L, Estes JD, et al. Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature 2005; 434:1148-1152.
76. Mattapallil JJ, Douek DC, Hill B, et al. Massive infection and loss of memory CD4- T cells in multiple tissues during acute SIV infection. Nature 2005; 434:1093-1097.
77. Mehandru S, Poles MA, Tenner-Racz K, et al. Primary HIV-1 infection is associated with preferential depletion of CD4- T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med 2004; 200:761-770.
78. Schneider T, Ullrich R, Zeitz M. The immunologic aspects of human immunodeficiency virus infection in the gastrointestinal tract. Semin Gastrointest Dis 1996; 7:19-29.
79. Veazey RS, DeMaria M, Chalifoux LV, et al. Gastrointestinal tract as a major site of CD4- T cell depletion and viral replication in SIV infection. Science 1998; 280:427-431.
80. Schuetz A, Deleage C, Sereti I, et al. Initiation of ART during early acute HIV infection preserves mucosal Th17 function and reverses HIV-related immune activation. PLoS Pathog 2014; 10:e1004543.
81. Maloy KJ, Kullberg MC. IL-23 and Th17 cytokines in intestinal homeostasis. Mucosal Immunol 2008; 1:339-349.
82. Torres B, Guardo AC, Leal L, et al. Protease inhibitor monotherapy is associated with a higher level of monocyte activation, bacterial translocation and inflammation. J Int AIDS Soc 2014; 17:19246.
83. Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007; 56:1761-1772.
84. Marchetti G, Tincati C, Silvestri G. Microbial translocation in the pathogenesis of HIV infection and AIDS. Clin Microbiol Rev 2013; 26:2-18.
85. Cassol E, Malfeld S, Mahasha P, et al. Persistent microbial translocation and immune activation in HIV-1-infected South Africans receiving combination antiretroviral therapy. J Infect Dis 2010; 202:723-733.
86. Sandler NG, Wand H, Roque A, et al. Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis 2011; 203:780-790.
87. Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology 2014; 146:1489-1499.
88. Willing BP, Dicksved J, Halfvarson J, et al. A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology 2010; 139:1844-1854; e1841.
89. Scher JU, Ubeda C, Artacho A, et al. Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheumatol 2015; 67:128-139.
90. Kostic AD, Gevers D, Siljander H, et al. The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe 2015; 17:260-273.
91. Sze MA, Schloss PD. Looking for a signal in the noise: revisiting obesity and the microbiome. MBio 2016; 7:e01018-16.
92. Weingarden A,Gonzalez A, Vazquez-Baeza Y, et al. Dynamic changes in shortand long-term bacterial composition following fecal microbiota transplantation for recurrent Clostridium difficile infection. Microbiome 2015; 3:10.
93. Chang JY, Antonopoulos DA, Kalra A, et al. Decreased diversity of the fecal Microbiome in recurrent Clostridium difficile-associated diarrhea. J Infect Dis 2008; 197:435-438.
94. Ellis CL, Ma ZM, Mann SK, 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. J Acquir Immune Defic Syndr 2011; 57:363-370.
95. Gori A, Tincati C, Rizzardini G, et al. Early impairment of gut function and gut flora supporting a role for alteration of gastrointestinal mucosa in human immunodeficiency virus pathogenesis. J Clin Microbiol 2008; 46:757-758.
96. Zevin AS, McKinnon L, Burgener A, Klatt NR. Microbial translocation and microbiome dysbiosis in HIV-associated immune activation. Curr Opin HIV AIDS 2016; 11:182-190.
97. de Bentzmann S, Plesiat P. The Pseudomonas aeruginosa opportunistic pathogen and human infections. Environ Microbiol 2011; 13:1655-1665.
98. McGuckin MA, Linden SK, Sutton P, Florin TH. Mucin dynamics and enteric pathogens. Nat Rev Microbiol 2011; 9:265-278.
99. Rey FE, Gonzalez MD, Cheng J, et al. Metabolic niche of a prominent sulfatereducing human gut bacterium. Proc Natl Acad Sci U S A 2013; 110:13582-13587.
100. Peleg AY, de Breij A, Adams MD, et al. The success of acinetobacter species; genetic, metabolic and virulence attributes. PLoS One 2012; 7:e46984.
101. March C, Regueiro V, Llobet E, et al. Dissection of host cell signal transduction during Acinetobacter baumannii-triggered inflammatory response. PLoS One 2010; 5:e10033.
102. Knapp S, Wieland CW, Florquin S, et al. Differential roles of CD14 and tolllike receptors 4 and 2 in murine Acinetobacter pneumonia. Am J Respir Crit Care Med 2006; 173:122-129.
103. Walker RI, Caldwell MB, Lee EC, et al. Pathophysiology of Campylobacter enteritis. Microbiol Rev 1986; 50:81-94.
104. Bereswill S, Fischer A, Plickert R, et al. Novel murine infection models provide deep insights into the 'menage a trois' of Campylobacter jejuni, microbiota and host innate immunity. PLoS One 2011; 6:e20953.
105. Guentzel MN: Escherichia, Klebsiella, Enterobacter, Serratia, Citrobacter, and Proteus. In Medical Microbiology. 4th ed Edited by Baron S; 1996.
106. Lupp C, Robertson ML, Wickham ME, et al. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2007; 2:119-129.
107. Nicholson JK, Holmes E, Kinross J, et al. Host-gut microbiota metabolic interactions. Science 2012; 336:1262-1267.
108. Kostic AD, Chun E, Robertson L, et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 2013; 14:207-215.
109. Shaw KA, Bertha M, Hofmekler T, et al. Dysbiosis, inflammation, and response to treatment: a longitudinal study of pediatric subjects with newly diagnosed inflammatory bowel disease. Genome Med 2016; 8:75.
110. Sinha R, Ahn J, Sampson JN, et al. Fecal microbiota, fecal metabolome, and colorectal cancer interrelations. PLoS One 2016; 11:e0152126.
111. Lukens JR, Gurung P, Vogel P, et al. Dietary modulation of the microbiome affects autoinflammatory disease. Nature 2014; 516:246-249.
112. Scher JU, Sczesnak A, Longman RS, et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife 2013; 2:e01202.
113. De Filippo C, Cavalieri D, Di Paola M, et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci U S A 2010; 107:14691-14696.
114. Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 2011; 334:105-108.
115. Yatsunenko T, Rey FE, Manary MJ, et al. Human gut microbiome viewed across age and geography. Nature 2012; 486:222-227.
116. Martinez I, Stegen JC, Maldonado-Gomez MX, et al. The gut microbiota of rural papua new guineans: composition, diversity patterns, and ecological processes. Cell Rep 2015; 11:527-538.
117. Gorvitovskaia A, Holmes SP, Huse SM. Interpreting Prevotella and Bacteroides as biomarkers of diet and lifestyle. Microbiome 2016; 4:15.
118. Vogtmann E, Hua X, Zeller G, et al. Colorectal cancer and the human gut microbiome: reproducibility with whole-genome shotgun sequencing. PLoS One 2016; 11:e0155362.
119. Zackular JP, Baxter NT, Iverson KD, et al. The gut microbiome modulates colon tumorigenesis. MBio 2013; 4:e00692-00613.
120. Schubert AM, Sinani H, Schloss PD. Antibiotic-induced alterations of the murine gut microbiota and subsequent effects on colonization resistance against Clostridium difficile. MBio 2015; 6:e00974.
121. Milani C, Ticinesi A, Gerritsen J, et al. Gut microbiota composition and Clostridium difficile infection in hospitalized elderly individuals: a metagenomic study. Sci Rep 2016; 6:25945.
122. Schubert AM, Rogers MA, Ring C, et al. Microbiome data distinguish patients with Clostridium difficile infection and non-C. difficile-associated diarrhea from healthy controls. MBio 2014; 5:e01021-e01014.
123. Ferreira RB, Gill N, Willing BP, et al. The intestinal microbiota plays a role in Salmonella-induced colitis independent of pathogen colonization. PLoS One 2011; 6:e20338.
124. Ubeda C, Bucci V, Caballero S, et al. Intestinal microbiota containing Barnesiella species cures vancomycin-resistant Enterococcus faecium colonization. Infect Immun 2013; 81:965-973.
125. Bailey MT, Dowd SE, Parry NM, et al. Stressor exposure disrupts commensal microbial populations in the intestines and leads to increased colonization by Citrobacter rodentium. Infect Immun 2010; 78:1509-1519.
126. Wlodarska M, Willing B, Keeney KM, et al. Antibiotic treatment alters the colonic mucus layer and predisposes the host to exacerbated Citrobacter rodentium-induced colitis. Infect Immun 2011; 79:1536-1545.
127. Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 2008; 453:620-625.
128. Troy EB, Kasper DL. Beneficial effects of Bacteroides fragilis polysaccharides on the immune system. Front Biosci (Landmark Ed) 2010; 15:25-34.
129. Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci U S A 2010; 107:12204-12209.
130. Gauffin Cano P, Santacruz A, Moya A, Sanz Y. Bacteroides uniformis CECT 7771 ameliorates metabolic and immunological dysfunction in mice with high-fat-diet induced obesity. PLoS One 2012; 7:e41079.
131. Vatanen T, Kostic AD, d'Hennezel E, et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell 2016; 165:842-853.
132. David LA,Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014; 505:559-563.
133. Khanna S, Montassier E, Schmidt B, et al. Gut microbiome predictors of treatment response and recurrence in primary Clostridium difficile infection. Aliment Pharmacol Ther 2016; 44:715-727.
134. Harris K, Kassis A, Major G, Chou CJ. Is the gut microbiota a new factor contributing to obesity and its metabolic disorders? J Obes 2012; 2012:879151.
135. Candon S, Perez-Arroyo A, Marquet C, et al. Antibiotics in early life alter the gut microbiome and increase disease incidence in a spontaneous mouse model of autoimmune insulin-dependent diabetes. PLoS One 2015; 10:e0125448.
136. Qin J, Li Y, Cai Z, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 2012; 490:55-60.
137. Ley R, Turnbaugh P, Klein S, Gordon J. Microbial ecology: human gut microbes associated with obesity. Nature 2006; 444:1022-1023.
138. Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006; 444:1027-1031.
139. Louis P, Flint HJ. Diversity, metabolism and microbial ecology of butyrateproducing bacteria from the human large intestine. FEMS Microbiol Lett 2009; 294:1-8.
140. Furusawa Y, Obata Y, Fukuda S, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013; 504:446-450.
141. Atarashi K, Tanoue T, Oshima K, et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 2013; 500:232-236.
142. Atarashi K, Tanoue T, Shima T, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011; 331:337-341.
143. Kunisawa J, Kiyono H. Peaceful mutualism in the gut: revealing key commensal bacteria for the creation and maintenance of immunological homeostasis. Cell Host Microbe 2011; 9:83-84.
144. Flint HJ, Bayer EA, Rincon MT, et al. Polysaccharide utilization by gut bacteria: potential for new insights from genomic analysis. Nat Rev Microbiol 2008; 6:121-131.
145. Biddle A, Stewart L, Blanchard J, Leschine S. Untangling the genetic basis of fibrolytic specialization by Lachnospiraceae and Ruminococcaceae in diverse gut communities. Diversity 2013; 5:627.
146. Meehan CJ, Beiko RG. A phylogenomic view of ecological specialization in the Lachnospiraceae, a family of digestive tract-associated bacteria. Genome Biol Evol 2014; 6:703-713.
147. Rey FE, Faith JJ, Bain J, et al. Dissecting the in vivo metabolic potential of two human gut acetogens. J Biol Chem 2010; 285:22082-22090.
148. Sangster W, Hegarty JP, Schieffer KM, et al. Bacterial and fungal microbiota changes distinguish C. difficile infection from other forms of diarrhea: results of a prospective inpatient study. Front Microbiol 2016; 7:789.
149. Ma C, Wu X, Nawaz M, et al. Molecular characterization of fecal microbiota in patients with viral diarrhea. Curr Microbiol 2011; 63:259-266.
150. Tannock GW, Lawley B, Munro K, et al. Comprehensive analysis of the bacterial content of stool from patients with chronic pouchitis, normal pouches, or familial adenomatous polyposis pouches. Inflamm Bowel Dis 2012; 18:925-934.
151. Chen W, Liu F, Ling Z, et al. Human intestinal lumen and mucosaassociated microbiota in patients with colorectal cancer. PloS one 2012; 7:e39743.
152. Wang T, Cai G, Qiu Y, et al. Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers. ISME J 2012; 6:320-329.
153. Png CW, Lindén SK, Gilshenan KS, et al. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol 2010; 105:2420-2428.
154. Ze X, Duncan SH, Louis P, Flint HJ. Ruminococcus bromii is a keystone species for the degradation of resistant starch in the human colon. ISME J 2012; 6:1535-1543.
155. Crost EH, Tailford LE, Le Gall G, et al. Utilisation of mucin glycans by the human gut symbiont Ruminococcus gnavus is strain-dependent. PLoS One 2013; 8:e76341.
156. Hsiao A, Ahmed AM, Subramanian S, et al. Members of the human gut microbiota involved in recovery from Vibrio cholerae infection. Nature 2014; 515:423-426.
157. Turroni S, Rampelli S, Centanni M, et al. Enterocyte-associated microbiome of the Hadza Hunter-Gatherers. Front Microbiol 2016; 7:865.
158. Zietak M, Kovatcheva-Datchary P, Markiewicz LH, et al. Altered microbiota contributes to reduced diet-induced obesity upon cold exposure. Cell Metab 2016; 23:1216-1223.
159. Greiner T, Backhed F. Effects of the gut microbiota on obesity and glucose homeostasis. Trends Endocrinol Metab 2011; 22:117-123.
160. Kaakoush NO. Insights into the role of Erysipelotrichaceae in the human host. Front Cell Infect Microbiol 2015; 5:84.
161. Noguera-Julian M, Rocafort M, GuillénY, et al.Gut microbiota linked to sexual preference and HIV infection. EBioMedicine 2016; 1-12.
162. Stiksrud B, Nowak P, Nwosu FC, et al. Reduced levels of D-dimer and changes in gut microbiota composition after probiotic intervention in HIVinfected individuals on stable ART. J Acquir Immune Defic Syndr 2015; 70:329-337.
163. Serrano-Villar S, Rojo D, Martinez-Martinez M, et al. Gut bacteria metabolism impacts immune recovery in HIV-infected individuals. EBioMedicine 2016; 8:203-216.
164. Serrano-Villar S, Rojo D, Martinez-Martinez M, et al. HIV infection results in metabolic alterations in the gut microbiota different from those induced by other diseases. Sci Rep 2016; 6:26192.
165. Pé rez-Santiago J, Gianella S, Massanella M, et al. Gut Lactobacillales are associated with higher CD4 and less microbial translocation during HIV infection. AIDS 2013; 27:1921-1931.
166. Bajaj JS, Hylemon PB, Ridlon JM, et al. Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation. Am J Physiol Gastrointest Liver Physiol 2012; 303:G675-G685.
167. Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science 2005; 308:1635-1638.
168. Morgan XC, Tickle TL, Sokol H, et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol 2012; 13:R79.
169. Stearns JC, Lynch MD, Senadheera DB, et al. Bacterial biogeography of the human digestive tract. Sci Rep 2011; 1:170.
170. Yasuda K, Oh K, Ren B, et al. Biogeography of the intestinal mucosal and lumenal microbiome in the rhesus macaque. Cell Host Microbe 2015; 17:385-391.
171. Zoetendal EG, von Wright A, Vilpponen-Salmela T, et al. Mucosa-associated bacteria in the human gastrointestinal tract are uniformly distributed along the colon and differ from the community recovered from feces. Appl Environ Microbiol 2002; 68:3401-3407.
172. UNAIDS. GLOBAL REPORT: UNAIDS report on the global AIDS epidemic 2013. UNAIDS; 2013.
173. Hirschhorn LR, Kaaya SF, Garrity PS, et al. Cancer and the 'other' noncommunicable chronic diseases in older people living with HIV/AIDS in resource-limited settings: a challenge to success. AIDS 2012; 26 (Suppl 1): S65-S75.
174. Hontelez JAC, de Vlas SJ, Baltussen R, et al. The impact of antiretroviral treatment on the age composition of the HIV epidemic in sub-Saharan Africa. AIDS 2012; 26 (Suppl 1):S19-S30.
175. Justice AC, Braithwaite RS. Lessons learned from the first wave of aging with HIV. AIDS 2012; 26 (Suppl 1):S11-S18.
176. Mills EJ, Bärnighausen T, Negin J. HIV and aging: preparing for the challenges ahead. N Engl J Med 2012; 366:1270-1273.
177. Kovatcheva-Datchary P, Nilsson A, Akrami R, et al. Dietary fiber-induced improvement in glucose metabolism is associated with increased abundance of Prevotella. Cell Metab 2015; 22:971-982.
178. Virgin HW. The virome in mammalian physiology and disease. Cell 2014; 157:142-150.
179. Cadwell K. Expanding the role of the virome: commensalism in the gut. J Virol 2015; 89:1951-1953.
180. Norman JM, Handley SA, Virgin HW. Kingdom-agnostic metagenomics and the importance of complete characterization of enteric microbial communities. Gastroenterology 2014; 146:1459-1469.
181. Ogilvie LA, Jones BV. The human gut virome: a multifaceted majority. Front Microbiol 2015; 6:918.
182. Mokili JL, Rohwer F, Dutilh BE. Metagenomics and future perspectives in virus discovery. Curr Opin Virol 2012; 2:63-77.
183. Handley SA, Desai C, Zhao G, et al. SIV infection-mediated changes in gastrointestinal bacterial microbiome and virome are associated with immunodeficiency and prevented by vaccination. Cell Host Microbe 2016; 19:323-335.
184. Handley SA, Thackray LB, Zhao G, et al. Pathogenic simian immunodeficiency virus infection is associated with expansion of the enteric virome. Cell 2012; 151:253-266.
185. Li L, Deng X, Linsuwanon P, et al. AIDS alters the commensal plasma virome. J Virol 2013; 87:10912-10915.
186. Li S-K, Leung RK-K, Guo H-X, et al. Detection and identification of plasma bacterial and viral elements in HIV/AIDS patients in comparison to healthy adults. Clin Microbiol Infect 2012; 18:1126-1133.
187. Zhao G, Krishnamurthy S, Cai Z, et al. Identification of novel viruses using VirusHunter: an automated data analysis pipeline. PloS One 2013; 8:e78470.
188. Duerkop BA, Hooper LV. Resident viruses and their interactions with the immune system. Nat Immunol 2013; 14:654-659.
189. Focà A, Liberto MC, Quirino A, et al. Gut inflammation and immunity: what is the role of the human gut virome? Mediators Inflamm 2015; 2015:326032.
190. Reyes A, Wu M, McNulty NP, et al. Gnotobiotic mouse model of phagebacterial host dynamics in the human gut. Proc Natl Acad Sci U S A 2013; 110:20236-20241.
191. Norman JM, Handley SA, Baldridge MT. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 2015; 160:447-460.
192. Bendinelli M, Maggi F. Anellovirus. In: Tidona C, Darai G, editors. The Springer Index of Viruses. New York: Springer; 2011. pp. 1963-1973.
193. De Vlaminck I, Khush KK, Strehl C, et al. Temporal response of the human virome to immunosuppression and antiviral therapy. Cell 2013; 155:1178-1187.
194. Christensen JK, Eugen-Olsen J, Lrensen M, et al. Prevalence and prognostic significance of infection with TT virus in patients infected with human immunodeficiency virus. J Infect Dis 2000; 181:1796-1799.
195. Debiaggi M, Zara F, Sacchi P, et al. Transfusion-transmitted virus infection in HIV-1-seropositive patients. Clin Microbiol Infect 2000; 6:246-250.
196. Ley RE. Gut microbiota in 2015: Prevotella in the gut: choose carefully. Nat Rev Gastroenterol Hepatol 2016; 13:69-70.
197. Ahern PP, Faith JJ, Gordon JI. Mining the human gut microbiota for effector strains that shape the immune system. Immunity 2014; 40:815-823.
198. Faith JJ, Colombel JF, Gordon JI. Identifying strains that contribute to complex diseases through the study of microbial inheritance. Proc Natl Acad Sci U S A 2015; 112:633-640.
199. Cunningham-Rundles S, Ahrne S, Johann-Liang R, et al. Effect of probiotic bacteria on microbial host defense, growth, and immune function in human immunodeficiency virus type-1 infection. Nutrients 2011; 3: 1042-1070.
200. d'Ettorre G, Ceccarelli G, Giustini N, et al. Probiotics reduce inflammation in antiretroviral treated, HIV-infected individuals: results of the 'Probio-HIV' Clinical Trial. PLoS One 2015; 10:e0137200.
201. Gonzá lez-Hernández LA, Jave-Suarez LF, Fafutis-Morris M, et al. Synbiotic therapy decreases microbial translocation and inflammation and improves immunological status in HIV-infected patients: a double-blind randomized controlled pilot trial. Nutr J 2012; 11:90.
202. Hummelen R, Hemsworth J, Changalucha J, et al. Effect of micronutrient and probiotic fortified yogurt on immune-function of antiretroviral therapy naive HIV patients. Nutrients 2011; 3:897-909.
203. Irvine SL, Hummelen R, Hekmat S, et al. Probiotic yogurt consumption is associated with an increase of CD4 count among people living with HIV/AIDS. J Clin Gastroenterol 2010; 44:e201-e205.
204. Miller H, Ferris R, Phelps BR. The effect of probiotics on CD4 counts among people living with HIV: a systematic review. Benef Microbes 2016; 7:345-351.
205. Monachese M, Cunningham-Rundles S, Diaz MA, et al. Probiotics and prebiotics to combat enteric infections and HIV in the developing world: a consensus report. Gut Microbes 2011; 2:198-207.
206. Reid G. The potential role for probiotic yogurt for people living with HIV/AIDS. Gut Microbes 2010; 1:411-414.
207. Schunter M, Chu H, Hayes TL, et al. Randomized pilot trial of a synbiotic dietary supplement in chronic HIV-1 infection. BMC Complement Altern Med 2012; 12:84.
208. Villar-Garcia J, Hernandez JJ, Guerri-Fernandez R, et al. Effect of probiotics (Saccharomyces boulardii) on microbial translocation and inflammation in HIV-treated patients: a double-blind, randomized, placebo-controlled trial. J Acquir Immune Defic Syndr 2015; 68:256-263.