Analysis of Gut Microbiota in Rheumatoid Arthritis Patients: Disease-Related Dysbiosis and Modifications Induced by Etanercept

Andrea Picchianti-Diamanti, Concetta Panebianco, Simonetta Salemi, Maria Laura Sorgi, Roberta Di Rosa, Alessandro Tropea, Mayla Sgrulletti, Gerardo Salerno, Fulvia Terracciano, Raffaele D'Amelio, Bruno Laganà, Valerio Pazienza, Andrea Picchianti-Diamanti, Concetta Panebianco, Simonetta Salemi, Maria Laura Sorgi, Roberta Di Rosa, Alessandro Tropea, Mayla Sgrulletti, Gerardo Salerno, Fulvia Terracciano, Raffaele D'Amelio, Bruno Laganà, Valerio Pazienza

Abstract

A certain number of studies were carried out to address the question of how dysbiosis could affect the onset and development of rheumatoid arthritis (RA), but little is known about the reciprocal influence between microbiota composition and immunosuppressive drugs, and how this interaction may have an impact on the clinical outcome. The aim of this study was to characterize the intestinal microbiota in a groups of RA patients treatment-naïve, under methotrexate, and/or etanercept (ETN). Correlations between the gut microbiota composition and validated immunological and clinical parameters of disease activity were also evaluated. In the current study, a 16S analysis was employed to explore the gut microbiota of 42 patients affected by RA and 10 healthy controls. Disease activity score on 28 joints (DAS-28), erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, anti-cyclic citrullinated peptides, and dietary and smoking habits were assessed. The composition of the gut microbiota in RA patients free of therapy is characterized by several abnormalities compared to healthy controls. Gut dysbiosis in RA patients is associated with different serological and clinical parameters; in particular, the phylum of Euryarchaeota was directly correlated to DAS and emerged as an independent risk factor. Patients under treatment with ETN present a partial restoration of a beneficial microbiota. The results of our study confirm that gut dysbiosis is a hallmark of the disease, and shows, for the first time, that the anti-tumor necrosis factor alpha (TNF-α) ETN is able to modify microbial communities, at least partially restoring a beneficial microbiota.

Keywords: anti-TNF-α; disease activity; etanercept; methotrexate; microbiota; rheumatoid arthritis.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Box plots of Shannon diversity index (A) and species richness (B) of microbiota of healthy controls and different treatment groups of rheumatoid arthritis (RA) patients. The triangle represents the median value.
Figure 2
Figure 2
Microbiota composition of healthy controls and different treatment groups of RA patients at the phylum (A), class (B), and order (C) levels. The mean value of the eight top taxonomic classifications at each level is represented.
Figure 3
Figure 3
Microbiota composition of healthy controls and different treatment groups of RA patients at the family (A), genus (B), and species (C) levels. The mean value of the eight top taxonomic classifications at each level is represented.
Figure 4
Figure 4
Association of gut microbiota profile with clinical pathological features in RA patients at the phylum (A), class (B), order (C), family (D), genus (E), and species (F) levels.

References

    1. Ursell L.K., Haiser H.J., Van Treuren W., Garg N., Reddivari L., Vanamala J., Dorrestein P.C., Turnbaugh P.J., Knight R. The intestinal metabolome: An intersection between microbiota and host. Gastroenterology. 2014;146:1470–1476. doi: 10.1053/j.gastro.2014.03.001.
    1. Maslowski K.M., Vieira A.T., Ng A., Kranich J., Sierro F., Yu D., Schilter H.C., Rolph M.S., Mackay F., Artis D., et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009;461:1282–1286. doi: 10.1038/nature08530.
    1. Rogier R., Koenders M.I., Abdollahi-Roodsaz S. Toll-like receptor mediated modulation of T cell response by commensal intestinal microbiota as a trigger for autoimmune arthritis. J. Immunol. Res. 2015;2015:527696. doi: 10.1155/2015/527696.
    1. Stecher B., Hardt W.D. Mechanisms controlling pathogen colonization of the gut. Curr. Opin. Microbiol. 2011;14:82–91. doi: 10.1016/j.mib.2010.10.003.
    1. Petersen C., Round J.L. Defining dysbiosis and its influence on host immunity and disease. Cell Microbiol. 2014;16:1024–1033. doi: 10.1111/cmi.12308.
    1. Picchianti-Diamanti A., Rosado M.M. D’Amelio, R. Infectious Agents and Inflammation: The Role of Microbiota in Autoimmune Arthritis. Front. Microbiol. 2018;8:2696. doi: 10.3389/fmicb.2017.02696.
    1. Asquith M., Elewaut D., Lin P., Rosenbaum J.T. The role of the gut and microbes in the pathogenesis of spondyloarthritis. Best Pract. Res. Clin. Rheumatol. 2014;28:687–702. doi: 10.1016/j.berh.2014.10.018.
    1. Ciccia F., Bombardieri M., Rizzo A., Principato A., Giardina A.R., Raiata F., Peralta S., Ferrante A., Drago S., Cottone M., et al. Over-expression of paneth cell-derived anti-microbial peptides in the gut of patients with ankylosing spondylitis and subclinical intestinal inflammation. Rheumatology. 2010;49:2076–2083. doi: 10.1093/rheumatology/keq239.
    1. Picchianti Diamanti A., Lagana B., Cox M.C., Pilozzi E., Amodeo R., Bove M., Markovic M., di Rosa R., Salemi S., Sorgi M.L., et al. TCD4pos lymphocytosis in rheumatoid and psoriatic arthritis patients following TNFα blocking agents. J. Transl. Med. 2017;15:38. doi: 10.1186/s12967-017-1135-6.
    1. Ciccia F., Ferrante A., Guggino G., Triolo G. The role of the gastrointestinal tract in the pathogenesis of rheumatic diseases. Best Pract. Res. Clin. Rheumatol. 2016;30:889–900. doi: 10.1016/j.berh.2016.10.003.
    1. Panebianco C., Andriulli A., Pazienza V. Pharmacomicrobiomics: Exploiting the drug-microbiota interactions in anticancer therapies. Microbiome. 2018;6:92. doi: 10.1186/s40168-018-0483-7.
    1. Zhang X., Zhang D., Jia H., Feng Q., Wang D., Liang D., Wu X., Li J., Tang L., Li Y., et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat. Med. 2015;21:895–905. doi: 10.1038/nm.3914.
    1. Enright E.F., Gahan C.G., Joyce S.A., Griffin B.T. The impact of the gut microbiota on drug metabolism and clinical outcome. Yale J. Biol. Med. 2016;89:37.
    1. Quirke A.M., Lugli E.B., Wegner N., Hamilton B.C., Charles P., Chowdhury M., Ytterberg A.J., Zubarev R.A., Potempa J., Culshaw S., et al. Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: A potential mechanism for breaching immunologic tolerance in rheumatoid arthritis. Ann. Rheum. Dis. 2014;73:263–269. doi: 10.1136/annrheumdis-2012-202726.
    1. Wegner N., Wait R., Sroka A., Eick S., Nguyen K.A., Lundberg K., Kinloch A., Culshaw S., Potempa J., Venables P.J. Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and alpha-enolase: Implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum. 2010;62:2662–2672. doi: 10.1002/art.27552.
    1. Smolen J.S., Landewe R., Bijlsma J., Burmester G., Chatzidionysiou K., Dougados M., Nam J., Ramiro S., Voshaar M., van Vollenhoven R., et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 Update. Ann. Rheum. Dis. 2017;76:960–977. doi: 10.1136/annrheumdis-2016-210715.
    1. Bhat M., Pasini E., Copeland J., Angeli M., Husain S., Kumar D., Renner E., Teterina A., Allard J., Guttman D.S., et al. Impact of immunosuppression on the metagenomic composition of the intestinal microbiome: A systems biology approach to post-transplant diabetes. Sci. Rep. 2017;7:10277. doi: 10.1038/s41598-017-10471-2.
    1. Liu X., Zou Q., Zeng B., Fang Y., Wei H. Analysis of fecal Lactobacillus community structure in patients with early rheumatoid arthritis. Curr. Microbiol. 2013;67:170–176. doi: 10.1007/s00284-013-0338-1.
    1. Liu X., Zeng B., Zhang J., Li W., Mou F., Wang H., Zou Q., Zhong B., Wu L., Wei H., et al. Role of the gut microbiome in modulating arthritis progression in mice. Sci Rep. 2016;6:30594. doi: 10.1038/srep30594.
    1. Alipour B., Homayouni-Rad A., Vaghef-Mehrabany E., Sharif S.K., Vaghef-Mehrabany L., Asghari-Jafarabadi M., Nakhjavani M.R., Mohtadi-Nia J. Effects of Lactobacillus casei supplementation on disease activity and inflammatory cytokines in rheumatoid arthritis patients: A randomized double-blind clinical trial. Int. J. Rheum. Dis. 2014;17:519–527.
    1. Amdekar S., Singh V., Singh R., Sharma P., Keshav P., Kumar A. Lactobacillus casei reduces the inflammatory joint damage associated with collagen-induced arthritis (CIA) by reducing the pro-inflammatory cytokines: Lactobacillus casei: COX-2 inhibitor. J. Clin. Immunol. 2011;31:147–154. doi: 10.1007/s10875-010-9457-7.
    1. Kano H., Kaneko T., Kaminogawa S. Oral intake of Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1 prevents collagen-induced arthritis in mice. J. Food Prot. 2002;65:153–160. doi: 10.4315/0362-028X-65.1.153.
    1. So J.S., Kwon H.K., Lee C.G., Yi H.J., Park J.A., Lim S.Y., Hwang K.C., Jeon Y.H., Im S.H. Lactobacillus casei suppresses experimental arthritis by down-regulating T helper 1 effector functions. Mol. Immunol. 2008;45:2690–2699. doi: 10.1016/j.molimm.2007.12.010.
    1. Hatakka K., Martio J., Korpela M., Herranen M., Poussa T., Laasanen T., Saxelin M., Vapaatalo H., Moilanen E., Korpela R. Effects of probiotic therapy on the activity and activation of mild rheumatoid arthritis—A pilot study. Scand. J. Rheumatol. 2003;32:211–215. doi: 10.1080/03009740310003695.
    1. Pineda Mde L., Thompson S.F., Summers K., de Leon F., Pope J., Reid G. A randomized, double-blinded, placebo-controlled pilot study of probiotics in active rheumatoid arthritis. Med. Sci. Monit. 2011;17:CR347–CR354.
    1. Chen J., Wright K., Davis J.M., Jeraldo P., Marietta E.V., Murray J., Nelson H., Matteson E.L., Taneja V. An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome Med. 2015;8:43. doi: 10.1186/s13073-016-0299-7.
    1. Wu X., Liu J., Xiao L., Lu A., Zhang G. Alterations of gut microbiome in rheumatoid arthritis. Osteoarthr. Cartil. 2017;25:S287–S288. doi: 10.1016/j.joca.2017.02.484.
    1. Arvonen M., Berntson L., Pokka T., Karttunen T.J., Vahasalo P., Stoll M.L. Gut microbiota-host interactions and juvenile idiopathic arthritis. Pediatr. Rheumatol. Online J. 2016;14:44. doi: 10.1186/s12969-016-0104-6.
    1. Cao Y., Shen J., Ran Z.H. Association between Faecalibacterium prausnitzii reduction and inflammatory bowel disease: A meta-analysis and systematic review of the literature. Gastroenterol. Res. Pract. 2014;2014:872725. doi: 10.1155/2014/872725.
    1. Sokol H., Pigneur B., Watterlot L., Lakhdari O., Bermudez-Humaran L.G., Gratadoux J.J., Blugeon S., Bridonneau C., Furet J.P., Corthier G., et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl. Acad. Sci. USA. 2008;105:16731–16736. doi: 10.1073/pnas.0804812105.
    1. Lopez P., de Paz B., Rodriguez-Carrio J., Hevia A., Sanchez B., Margolles A., Suarez A. Th17 responses and natural IgM antibodies are related to gut microbiota composition in systemic lupus erythematosus patients. Sci. Rep. 2016;6:24072. doi: 10.1038/srep24072.
    1. Vijayakumar S., Menakha M. Pharmaceutical applications of cyanobacteria—A review. J. Acute Med. 2015;5:15–23. doi: 10.1016/j.jacme.2015.02.004.
    1. Roediger W.E., Moore J., Babidge W. Colonic sulfide in pathogenesis and treatment of ulcerative colitis. Dig. Dis. Sci. 1997;42:1571–1579. doi: 10.1023/A:1018851723920.
    1. Rizzatti G., Lopetuso L.R., Gibiino G., Binda C., Gasbarrini A. Proteobacteria: A common factor in human diseases. BioMed Res. Int. 2017;2017:9351507. doi: 10.1155/2017/9351507.
    1. Muniz-Pedrogo D.A., Chen J., Hillmann B.M., Jeraldo P., Saffouri G., Al-Ghalith G.A., Friton J., Taneja V., Davis J.M., Knights D., et al. Gut microbial markers of arthritis including inflammatory bowel disease associated arthropathy. Gastroenterology. 2018;154:S–586. doi: 10.1016/S0016-5085(18)32898-1.
    1. Ramos-Romero S., Hereu M., Atienza L., Casas J., Jauregui O., Amezqueta S., Dasilva G., Medina I., Nogues M.R., Romeu M., et al. Mechanistically different effects of fat and sugar on insulin resistance, hypertension, and gut microbiota in rats. Am. J. Physiol. Endocrinol. Metab. 2018;314:E552–E563. doi: 10.1152/ajpendo.00323.2017.
    1. Pedersen C., Ijaz U.Z., Gallagher E., Horton F., Ellis R.J., Jaiyeola E., Duparc T., Russell-Jones D., Hinton P., Cani P.D., et al. Fecal Enterobacteriales enrichment is associated with increased in vivo intestinal permeability in humans. Physiol. Rep. 2018;6:e13649. doi: 10.14814/phy2.13649.
    1. Bjarnason I., Williams P., So A., Zanelli G.D., Levi A.J., Gumpel J.M., Peters T.J., Ansell B. Intestinal permeability and inflammation in rheumatoid arthritis: Effects of non-steroidal anti-inflammatory drugs. Lancet. 1984;2:1171–1174. doi: 10.1016/S0140-6736(84)92739-9.
    1. Jangi S., Gandhi R., Cox L.M., Li N., von Glehn F., Yan R., Patel B., Mazzola M.A., Liu S., Glanz B.L., et al. Alterations of the human gut microbiome in multiple sclerosis. Nat. Commun. 2016;7:12015. doi: 10.1038/ncomms12015.
    1. Wei B., Dalwadi H., Gordon L.K., Landers C., Bruckner D., Targan S.R., Braun J. Molecular cloning of a Bacteroides caccae TonB-linked outer membrane protein identified by an inflammatory bowel disease marker antibody. Infect. Immun. 2001;69:6044–6054. doi: 10.1128/IAI.69.10.6044-6054.2001.
    1. Johansson L., Sherina N., Kharlamova N., Potempa B., Larsson B., Israelsson L., Potempa J., Rantapaa-Dahlqvist S., Lundberg K. Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis. Arthritis Res. Ther. 2016;18:201. doi: 10.1186/s13075-016-1100-4.
    1. Aletaha D., Neogi T., Silman A.J., Funovits J., Felson D.T., Bingham C.O., III, Birnbaum N.S., Burmester G.R., Bykerk V.P., Cohen M.D., et al. 2010 rheumatoid arthritis classification criteria: An american college of rheumatology/European league against rheumatism collaborative initiative. Ann. Rheum. Dis. 2010;69:1580–1588. doi: 10.1136/ard.2010.138461.
    1. Klindworth A., Pruesse E., Schweer T., Peplies J., Quast C., Horn M., Glockner F.O. Evaluation of general 16S ribosomal RNA gene PCR primers for classical and next-generation sequencing-based diversity studies. Nucleic Acids Res. 2013;41:e1. doi: 10.1093/nar/gks808.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner