Four Weeks of Treatment With Rifaximin Fails to Significantly Alter Microbial Diversity in Rectal Samples of HIV-Infected Immune Non-Responders (ACTG A5286) Which May be Attributed to Rectal Swab Use

Main Article Content

Brett B. Williams
Stefan J. Green
Ronald J. Bosch
Ellen S. Chan
Jeffrey M. Jacobson
David M. Margolis
Phillip Engen
Alan L. Landay
Cara C. Wilson

Abstract

Introduction: HIV-infected individuals have evidence of intestinal microbial translocation which is associated with immune activation and unfavorable clinical outcomes. Rifaximin, a non-absorbable antibiotic which reduces microbial translocation in other disease states, was shown to have a marginal beneficial effect on microbial translocation, T-cell activation, and inflammation in a multisite randomized trial (ACTG A5286; NCT01466595) of HIV-infected persons with poor immunologic recovery receiving ART. Here, we report analysis of the rectal microbiome changes associated with that trial.

Methods: HIV-1-infected individuals receiving ART with CD4-T cell count <350cells/mm3 and viral suppression were randomized 2:1 to rifaximin or no therapy for 4 weeks. Rectal swabs were collected at baseline (pre-treatment) and at week 4 of rifaximin therapy. Genomic DNA extracted from rectal swab samples was analyzed using high throughput sequencing and quantitative PCR of bacterial 16S ribosomal RNA (rRNA) genes.

Results: Forty-eight HIV-infected participants (31 received rifaximin, 17 no treatment) were included. There was broad variability in the recovery of bacterial rRNA from the specimens at baseline. No major significant (FDR P<0.05) effects of rifaximin treatment on alpha- or beta- diversity or individual taxa were observed between or within the treatment arms, with analyses conducted at taxonomic levels from phylum to genus.

Conclusions: Rifaximin did not meaningfully alter the diversity or composition of the rectal microbiome of HIV-infected individuals after 4 weeks of therapy, although rectal swab specimens varied widely in their microbial load.

Downloads

Download data is not yet available.

Article Details

Section
Articles
Author Biography

Brett B. Williams, Division of Infectious Disease; Rush University Medical Center; Chicago, Illinois

Assistant Professor

Rush University 

Infectious Disease

References

1. Papa E, Docktor M, Smillie C, Weber S, Preheim SP, Gevers D, Giannoukos G, Ciulla D, Tabbaa D, Ingram J, Schauer DB, Ward DV, Korzenik JR, Xavier RJ, Bousvaros A, Alm EJ. Non-invasive mapping of the gastrointestinal microbiota identifies children with inflammatory bowel disease. PLoS One. 2012;7(6):e39242. PubMed PMID: 22768065. Pubmed Central PMCID: 3387146. doi: 10.1371/journal.pone.0039242

2. Saad MJ, Santos A, Prada PO. Linking Gut Microbiota and Inflammation to Obesity and Insulin Resistance. Physiology (Bethesda). 2016;31(4):283-93. PubMed PMID: 27252163. doi: 10.1152/physiol.00041.2015

3. 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. An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia. Mucosal Immunol. 2014;7(4):983-94. PubMed PMID: 24399150. Pubmed Central PMCID: 4062575. doi: 10.1038/mi.2013.116

4. 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. A compositional look at the human gastrointestinal microbiome and immune activation parameters in HIV infected subjects. PLoS Pathog. 2014;10(2):e1003829. PubMed PMID: 24586144. Pubmed Central PMCID: 3930561. doi: 10.1371/journal.ppat.1003829

5. Dinh DM, Volpe GE, Duffalo C, Bhalchandra S, Tai AK, Kane AV, Wanke CA, Ward HD. Intestinal microbiota, microbial translocation, and systemic inflammation in chronic HIV infection. J Infect Dis. 2015;211(1):19-27. PubMed PMID: 25057045. Pubmed Central PMCID: 4326316. doi: 10.1093/infdis/jiu409

6. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, Blazar BR, Rodriguez B, Teixeira-Johnson L, Landay A, Martin JN, Hecht FM, Picker LJ, Lederman MM, Deeks SG, Douek DC. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12(12):1365-71. PubMed PMID: 17115046. doi: 10.1038/nm1511

7. Tenorio AR, Zheng Y, Bosch RJ, Krishnan S, Rodriguez B, Hunt PW, Plants J, Seth A, Wilson CC, Deeks SG, Lederman MM, Landay AL. Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment. J Infect Dis. 2014;210(8):1248-59. PubMed PMID: 24795473. Pubmed Central PMCID: 4192039. doi: 10.1093/infdis/jiu254

8. 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. Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection. J Infect Dis. 2014;210(8):1228-38. PubMed PMID: 24755434. Pubmed Central PMCID: 4192038. doi: 10.1093/infdis/jiu238

9. Lederman MM, Calabrese L, Funderburg NT, Clagett B, Medvik K, Bonilla H, Gripshover B, Salata RA, Taege A, Lisgaris M, McComsey GA, Kirchner E, Baum J, Shive C, Asaad R, Kalayjian RC, Sieg SF, Rodriguez B. Immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory CD4 cells. J Infect Dis. 2011;204(8):1217-26. PubMed PMID: 21917895. Pubmed Central PMCID: 3218674. doi: 10.1093/infdis/jir507

10. Marchetti G, Bellistri GM, Borghi E, Tincati C, Ferramosca S, La Francesca M, Morace G, Gori A, Monforte AD. Microbial translocation is associated with sustained failure in CD4+ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy. AIDS. 2008;22(15):2035-8. PubMed PMID: 18784466. doi: 10.1097/QAD.0b013e3283112d29

11. Guadalupe M, Reay E, Sankaran S, Prindiville T, Flamm J, McNeil A, Dandekar S. 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. J Virol. 2003;77(21):11708-17. PubMed PMID: 14557656. Pubmed Central PMCID: 229357. doi: 10.1128/jvi.77.21.11708-11717.2003

12. Vlachogiannakos J, Saveriadis AS, Viazis N, Theodoropoulos I, Foudoulis K, Manolakopoulos S, Raptis S, Karamanolis DG. Intestinal decontamination improves liver haemodynamics in patients with alcohol-related decompensated cirrhosis. Aliment Pharmacol Ther. 2009;29(9):992-9. PubMed PMID: 19210289. doi: 10.1111/j.1365-2036.2009.03958.x

13. Tenorio AR, Chan ES, Bosch RJ, Macatangay BJ, Read SW, Yesmin S, Taiwo B, Margolis DM, Jacobson JM, Landay AL, Wilson CC, Team A. Rifaximin has a marginal impact on microbial translocation, T-cell activation and inflammation in HIV-positive immune non-responders to antiretroviral therapy - ACTG A5286. J Infect Dis. 2015;211(5):780-90. PubMed PMID: 25214516. Pubmed Central PMCID: 4334803. doi: 10.1093/infdis/jiu515

14. Nadkarni MA, Martin FE, Jacques NA, Hunter N. Determination of bacterial load by real-time PCR using a broad-range (universal) probe and primers set. Microbiology. 2002;148(Pt 1):257-66. PubMed PMID: 11782518. doi: 10.1099/00221287-148-1-257

15. Caporaso JG, Lauber CL, Walters WA, Berg-Lyons D, Huntley J, Fierer N, Owens SM, Betley J, Fraser L, Bauer M, Gormley N, Gilbert JA, Smith G, Knight R. Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms. ISME J. 2012;6(8):1621-4. PubMed PMID: 22402401. Pubmed Central PMCID: 3400413. doi: 10.1038/ismej.2012.8

16. Edgar RC. Search and clustering orders of magnitude faster than BLAST. Bioinformatics. 2010;26(19):2460-1. PubMed PMID: 20709691. doi: 10.1093/bioinformatics/btq461

17. 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. QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010;7(5):335-6. PubMed PMID: 20383131. Pubmed Central PMCID: 3156573. doi: 10.1038/nmeth.f.303

18. Gihring TM, Green SJ, Schadt CW. Massively parallel rRNA gene sequencing exacerbates the potential for biased community diversity comparisons due to variable library sizes. Environ Microbiol. 2012;14(2):285-90. PubMed PMID: 21923700. doi: 10.1111/j.1462-2920.2011.02550.x

19. McDonald D, Clemente JC, Kuczynski J, Rideout JR, Stombaugh J, Wendel D, Wilke A, Huse S, Hufnagle J, Meyer F, Knight R, Caporaso JG. The Biological Observation Matrix (BIOM) format or: how I learned to stop worrying and love the ome-ome. Gigascience. 2012;1(1):7. PubMed PMID: 23587224. Pubmed Central PMCID: 3626512. doi: 10.1186/2047-217X-1-7

20. Voigt RM, Forsyth CB, Green SJ, Mutlu E, Engen P, Vitaterna MH, Turek FW, Keshavarzian A. Circadian disorganization alters intestinal microbiota. PLoS One. 2014;9(5):e97500. PubMed PMID: 24848969. Pubmed Central PMCID: 4029760. doi: 10.1371/journal.pone.0097500

21. Clarke KR. Non-parametric multivariate analyses of changes in community structure. Aust J Ecol 1993;18:117-143. doi: 10.1111/j.1442-9993.1993.tb00438.x

22. Benjamini, Y. and Hochberg, Y., 1995. Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal statistical society: series B (Methodological), 57(1), pp.289-300.

23. Bajaj JS, Heuman DM, Sanyal AJ, Hylemon PB, Sterling RK, Stravitz RT, Fuchs M, Ridlon JM, Daita K, Monteith P, Noble NA, White MB, Fisher A, Sikaroodi M, Rangwala H, Gillevet PM. Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy. PLoS One. 2013;8(4):e60042. PubMed PMID: 23565181. Pubmed Central PMCID: 3615021. doi: 10.1371/journal.pone.0060042

24. Pandrea I, Xu C, Stock JL, Frank DN, Ma D, Policicchio BB, He T, Kristoff J, Cornell E, Haret-Richter GS, Trichel A, Ribeiro RM, Tracy R, Wilson C, Landay AL, Apetrei C. Antibiotic and Antiinflammatory Therapy Transiently Reduces Inflammation and Hypercoagulation in Acutely SIV-Infected Pigtailed Macaques. PLoS Pathog. 2016;12(1):e1005384. PubMed PMID: 26764484. Pubmed Central PMCID: 4713071. doi: 10.1371/journal.ppat.1005384

25. Lozupone CA, Li M, Campbell TB, Flores SC, Linderman D, Gebert MJ, Knight R, Fontenot AP, Palmer BE. Alterations in the gut microbiota associated with HIV-1 infection. Cell Host Microbe. 2013;14(3):329-39. PubMed PMID: 24034618. Pubmed Central PMCID: 3864811. doi: 10.1016/j.chom.2013.08.006

26. 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. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci Transl Med. 2013;5(193):193ra91. PubMed PMID: 23843452. Pubmed Central PMCID: 4094294. doi: 10.1126/scitranslmed.3006438

27. Noguera-Julian M, Rocafort M, Guillen Y, Rivera J, Casadella M, Nowak P, Hildebrand F, Zeller G, Parera M, Bellido R, Rodriguez C, Carrillo J, Mothe B, Coll J, Bravo I, Estany C, Herrero C, Saz J, Sirera G, Torrela A, Navarro J, Crespo M, Brander C, Negredo E, Blanco J, Guarner F, Calle ML, Bork P, Sonnerborg A, Clotet B, Paredes R. Gut Microbiota Linked to Sexual Preference and HIV Infection. EBioMedicine. 2016;5:135-46. PubMed PMID: 27077120. Pubmed Central PMCID: 4816837. doi: 10.1016/j.ebiom.2016.01.032

28. Yang L, Poles MA, Fisch GS, Ma Y, Nossa C, Phelan JA, Pei Z. HIV-induced immunosuppression is associated with colonization of the proximal gut by environmental bacteria. AIDS. 2016;30(1):19-29. PubMed PMID: 26731752. Pubmed Central PMCID: 4813506. doi: 10.1097/QAD.0000000000000935

29. McHardy IH, Li X, Tong M, Ruegger P, Jacobs J, Borneman J, Anton P, Braun J. HIV Infection is associated with compositional and functional shifts in the rectal mucosal microbiota. Microbiome. 2013;1(1):26. PubMed PMID: 24451087. Pubmed Central PMCID: 3971626. doi: 10.1186/2049-2618-1-26

30. Perez-Santiago J, Gianella S, Massanella M, Spina CA, Karris MY, Var SR, Patel D, Jordan PS, Young JA, Little SJ, Richman DD, Smith DM. Gut Lactobacillales are associated with higher CD4 and less microbial translocation during HIV infection. AIDS. 2013;27(12):1921-31. PubMed PMID: 24180001. Pubmed Central PMCID: 3816380. doi: 10.1097/qad.0b013e3283611816

31. Budding AE, Grasman ME, Eck A, Bogaards JA, Vandenbroucke-Grauls CM, van Bodegraven AA, Savelkoul PH. Rectal swabs for analysis of the intestinal microbiota. PLoS One. 2014;9(7):e101344. PubMed PMID: 25020051. Pubmed Central PMCID: 4096398. doi: 10.1371/journal.pone.0101344

32. Bassis CM, Moore NM, Lolans K, Seekatz AM, Weinstein RA, Young VB, Hayden MK, Program CDCPE. Comparison of stool versus rectal swab samples and storage conditions on bacterial community profiles. BMC Microbiol. 2017;17(1):78. PubMed PMID: 28359329. Pubmed Central PMCID: 5374586. doi: 10.1186/s12866-017-0983-9

33. Maccaferri S, Vitali B, Klinder A, Kolida S, Ndagijimana M, Laghi L, Calanni F, Brigidi P, Gibson GR, Costabile A. Rifaximin modulates the colonic microbiota of patients with Crohn's disease: an in vitro approach using a continuous culture colonic model system. J Antimicrob Chemother. 2010;65(12):2556-65. PubMed PMID: 20852272. doi: 10.1093/jac/dkq345

34. Soldi S, Vasileiadis S, Uggeri F, Campanale M, Morelli L, Fogli MV, Calanni F, Grimaldi M, Gasbarrini A. Modulation of the gut microbiota composition by rifaximin in non-constipated irritable bowel syndrome patients: a molecular approach. Clin Exp Gastroenterol. 2015;8:309-25. PubMed PMID: 26673000. Pubmed Central PMCID: 4675645. doi: 10.2147/CEG.S89999

35. Kothary V, Scherl EJ, Bosworth B, Jiang ZD, Dupont HL, Harel J, Simpson KW, Dogan B. Rifaximin resistance in Escherichia coli associated with inflammatory bowel disease correlates with prior rifaximin use, mutations in rpoB, and activity of Phe-Arg-beta-naphthylamide-inhibitable efflux pumps. Antimicrob Agents Chemother. 2013;57(2):811-7. PubMed PMID: 23183443. Pubmed Central PMCID: 3553721. doi: 10.1128/AAC.02163-12

36. Jiang ZD, Ke S, Dupont HL. Rifaximin-induced alteration of virulence of diarrhoea-producing Escherichia coli and Shigella sonnei. Int J Antimicrob Agents. 2010;35(3):278-81. PubMed PMID: 20045287. doi: 10.1016/j.ijantimicag.2009.11.013

37. Taylor DN, Bourgeois AL, Ericsson CD, Steffen R, Jiang ZD, Halpern J, Haake R, Dupont HL. A randomized, double-blind, multicenter study of rifaximin compared with placebo and with ciprofloxacin in the treatment of travelers' diarrhea. Am J Trop Med Hyg. 2006;74(6):1060-6. PubMed PMID: 16760520.

38. DuPont HL, Jiang ZD, Ericsson CD, Adachi JA, Mathewson JJ, DuPont MW, Palazzini E, Riopel LM, Ashley D, Martinez-Sandoval F. Rifaximin versus ciprofloxacin for the treatment of traveler's diarrhea: a randomized, double-blind clinical trial. Clin Infect Dis. 2001;33(11):1807-15. PubMed PMID: 11692292. doi: 10.1086/323814

Most read articles by the same author(s)