The gut microbiome and HLA-B27-associated anterior uveitis: a case-control study.
Bacteroides caccae
Eubacterium ramulus
Phocaeicola vulgatus
Anterior uveitis
Gut microbiome
HLA-B27
Lipid IVA biosynthesis
Whole metagenome shotgun sequencing
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
07 May 2024
07 May 2024
Historique:
received:
20
10
2023
accepted:
22
04
2024
medline:
8
5
2024
pubmed:
8
5
2024
entrez:
7
5
2024
Statut:
epublish
Résumé
The human gut microbiome (GM) is involved in inflammation and immune response regulation. Dysbiosis, an imbalance in this ecosystem, facilitates pathogenic invasion, disrupts immune equilibrium, and potentially triggers diseases including various human leucocyte antigen (HLA)-B27-associated autoinflammatory and autoimmune diseases such as inflammatory bowel disease (IBD) and spondyloarthropathy (SpA). This study assesses compositional and functional alterations of the GM in patients with HLA-B27-associated non-infectious anterior uveitis (AU) compared to healthy controls. The gut metagenomes of 20 patients with HLA-B27-associated non-infectious AU, 21 age- and sex-matched HLA-B27-negative controls, and 6 HLA-B27-positive healthy controls without a history of AU were sequenced using the Illumina NovaSeq 6000 platform for whole metagenome shotgun sequencing. To identify taxonomic and functional features with significantly different relative abundances between groups and to identify associations with clinical metadata, the multivariate association by linear models (MaAsLin) R package was applied. Significantly higher levels of the Eubacterium ramulus species were found in HLA-B27-negative controls (p = 0.0085, Mann-Whitney U-test). No significant differences in microbial composition were observed at all other taxonomic levels. Functionally, the lipid IV In our cohort, non-infectious AU development is associated with compositional and functional alterations of the GM. Further research is needed to assess the causality of these associations, offering potentially novel therapeutic strategies.
Sections du résumé
BACKGROUND
BACKGROUND
The human gut microbiome (GM) is involved in inflammation and immune response regulation. Dysbiosis, an imbalance in this ecosystem, facilitates pathogenic invasion, disrupts immune equilibrium, and potentially triggers diseases including various human leucocyte antigen (HLA)-B27-associated autoinflammatory and autoimmune diseases such as inflammatory bowel disease (IBD) and spondyloarthropathy (SpA). This study assesses compositional and functional alterations of the GM in patients with HLA-B27-associated non-infectious anterior uveitis (AU) compared to healthy controls.
METHODS
METHODS
The gut metagenomes of 20 patients with HLA-B27-associated non-infectious AU, 21 age- and sex-matched HLA-B27-negative controls, and 6 HLA-B27-positive healthy controls without a history of AU were sequenced using the Illumina NovaSeq 6000 platform for whole metagenome shotgun sequencing. To identify taxonomic and functional features with significantly different relative abundances between groups and to identify associations with clinical metadata, the multivariate association by linear models (MaAsLin) R package was applied.
RESULTS
RESULTS
Significantly higher levels of the Eubacterium ramulus species were found in HLA-B27-negative controls (p = 0.0085, Mann-Whitney U-test). No significant differences in microbial composition were observed at all other taxonomic levels. Functionally, the lipid IV
CONCLUSION
CONCLUSIONS
In our cohort, non-infectious AU development is associated with compositional and functional alterations of the GM. Further research is needed to assess the causality of these associations, offering potentially novel therapeutic strategies.
Identifiants
pubmed: 38715051
doi: 10.1186/s12974-024-03109-4
pii: 10.1186/s12974-024-03109-4
doi:
Substances chimiques
HLA-B27 Antigen
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
120Subventions
Organisme : Gottfried und Julia Bangerter-Rhyner-Stiftung
ID : YTCR 24/22
Informations de copyright
© 2024. The Author(s).
Références
Durrani OM, Tehrani NN, Marr JE, Moradi P, Stavrou P, Murray PI. Degree, duration, and causes of visual loss in uveitis. Br J Ophthalmol. 2004;88(9):1159–62.
pubmed: 15317708
pmcid: 1772296
doi: 10.1136/bjo.2003.037226
Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005;140(3):509–16.
Joltikov KA, Lobo-Chan AM. Epidemiology and risk factors in non-infectious Uveitis: a systematic review. Front Med (Lausanne). 2021;8:695904.
pubmed: 34568364
doi: 10.3389/fmed.2021.695904
Forrester JV, Kuffova L, Dick AD. Autoimmunity, autoinflammation, and infection in Uveitis. Am J Ophthalmol. 2018;189:77–85.
pubmed: 29505775
doi: 10.1016/j.ajo.2018.02.019
Willermain F, Rosenbaum JT, Bodaghi B, Rosenzweig HL, Childers S, Behrend T, et al. Interplay between innate and adaptive immunity in the development of non-infectious uveitis. Prog Retin Eye Res. 2012;31(2):182–94.
pubmed: 22120610
doi: 10.1016/j.preteyeres.2011.11.004
Thorne JE, Suhler E, Skup M, Tari S, Macaulay D, Chao J, Ganguli A. Prevalence of noninfectious Uveitis in the United States: a claims-based analysis. JAMA Ophthalmol. 2016;134(11):1237–45.
pubmed: 27608193
doi: 10.1001/jamaophthalmol.2016.3229
Barisani-Asenbauer T, Maca SM, Mejdoubi L, Emminger W, Machold K, Auer H. Uveitis- a rare disease often associated with systemic diseases and infections- a systematic review of 2619 patients. Orphanet J Rare Dis. 2012;7:57.
pubmed: 22932001
pmcid: 3503654
doi: 10.1186/1750-1172-7-57
Fragoulis GE, Liava C, Daoussis D, Akriviadis E, Garyfallos A, Dimitroulas T. Inflammatory bowel diseases and spondyloarthropathies: from pathogenesis to treatment. World J Gastroenterol. 2019;25(18):2162–76.
pubmed: 31143068
pmcid: 6526158
doi: 10.3748/wjg.v25.i18.2162
Zinkernagel RM, Doherty PC. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature. 1974;248(5450):701–2.
pubmed: 4133807
doi: 10.1038/248701a0
Rosenbaum JT, Asquith M. The microbiome and HLA-B27-associated acute anterior uveitis. Nat Rev Rheumatol. 2018;14(12):704–13.
pubmed: 30301938
pmcid: 6597169
doi: 10.1038/s41584-018-0097-2
Wakefield D, Clarke D, McCluskey P. Recent developments in HLA B27 Anterior Uveitis. Front Immunol. 2020;11:608134.
pubmed: 33469457
doi: 10.3389/fimmu.2020.608134
Horai R, Zárate-Bladés CR, Dillenburg-Pilla P, Chen J, Kielczewski JL, Silver PB, et al. Microbiota-dependent activation of an autoreactive T cell receptor provokes autoimmunity in an immunologically privileged site. Immunity. 2015;43(2):343–53.
pubmed: 26287682
pmcid: 4544742
doi: 10.1016/j.immuni.2015.07.014
Rodriguez VR, Essex M, Rademacher J, Proft F, Löber U, Marko L, OP0031 SHARED AND DISTINCT GUT MICROBIOME SIGNATURES IN PATIENTS WITH AXIAL SPONDYLOARTHRITIS AND ITS RELATED IMMUNE-MEDIATED DISEASES, et al. Ann Rheum Dis. 2021;80(Suppl 1):17.
doi: 10.1136/annrheumdis-2021-eular.3434
Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. Hum Microbiome Project Nat. 2007;449(7164):804–10.
Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping Microbial Diversity in the human intestine. Cell. 2006;124(4):837–48.
pubmed: 16497592
doi: 10.1016/j.cell.2006.02.017
Afzaal M, Saeed F, Shah YA, Hussain M, Rabail R, Socol CT et al. Human gut microbiota in health and disease: unveiling the relationship. Front Microbiol. 2022;13.
Lin P, Bach M, Asquith M, Lee AY, Akileswaran L, Stauffer P, et al. HLA-B27 and human β2-microglobulin affect the gut microbiota of transgenic rats. PLoS ONE. 2014;9(8):e105684.
pubmed: 25140823
pmcid: 4139385
doi: 10.1371/journal.pone.0105684
Kubinak JL, Stephens WZ, Soto R, Petersen C, Chiaro T, Gogokhia L, et al. MHC variation sculpts individualized microbial communities that control susceptibility to enteric infection. Nat Commun. 2015;6(1):8642.
pubmed: 26494419
doi: 10.1038/ncomms9642
Clemente JC, Manasson J, Scher JU. The role of the gut microbiome in systemic inflammatory disease. BMJ. 2018;360:j5145.
pubmed: 29311119
pmcid: 6889978
doi: 10.1136/bmj.j5145
Floyd JL, Grant MB. The Gut-Eye Axis: lessons learned from murine models. Ophthalmol Ther. 2020;9(3):499–513.
pubmed: 32617914
pmcid: 7406577
doi: 10.1007/s40123-020-00278-2
Zysset-Burri DC, Morandi S, Herzog EL, Berger LE, Zinkernagel MS. The role of the gut microbiome in eye diseases. Prog Retin Eye Res. 2022:101117.
Zysset-Burri DC, Keller I, Berger LE, Neyer PJ, Steuer C, Wolf S, Zinkernagel MS. Retinal artery occlusion is associated with compositional and functional shifts in the gut microbiome and altered trimethylamine-N-oxide levels. Sci Rep. 2019;9(1):1–11.
doi: 10.1038/s41598-019-51698-5
Zysset-Burri DC, Keller I, Berger LE, Largiadèr CR, Wittwer M, Wolf S, Zinkernagel MS. Associations of the intestinal microbiome with the complement system in neovascular age-related macular degeneration. NPJ Genomic Med. 2020;5(1):1–11.
doi: 10.1038/s41525-020-00141-0
Parthasarathy R, Santiago F, McCluskey P, Kaakoush NO, Tedla N, Wakefield D. The microbiome in HLA-B27-associated disease: implications for acute anterior uveitis and recommendations for future studies. Trends Microbiol. 2022.
Segata N, Waldron L, Ballarini A, Narasimhan V, Jousson O, Huttenhower C. Metagenomic microbial community profiling using unique clade-specific marker genes. Nat Methods. 2012;9(8):811–4.
pubmed: 22688413
pmcid: 3443552
doi: 10.1038/nmeth.2066
Abubucker S, Segata N, Goll J, Schubert AM, Izard J, Cantarel BL, et al. Metabolic Reconstruction for Metagenomic Data and its application to the human microbiome. PLoS Comput Biol. 2012;8(6):e1002358.
pubmed: 22719234
pmcid: 3374609
doi: 10.1371/journal.pcbi.1002358
Dray S, Dufour A-B. The ade4 Package: implementing the duality Diagram for ecologists. J Stat Softw. 2007;22(4):1–20.
doi: 10.18637/jss.v022.i04
Anderson M. A new method for non-parametric multivariate analysis of variance. Austral Ecol. 2001;26:32–46.
Mallick H, Rahnavard A, McIver LJ, Ma S, Zhang Y, Nguyen LH, et al. Multivariable association discovery in population-scale meta-omics studies. PLoS Comput Biol. 2021;17(11):e1009442.
pubmed: 34784344
pmcid: 8714082
doi: 10.1371/journal.pcbi.1009442
Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, et al. Enterotypes of the human gut microbiome. Nature. 2011;473(7346):174–80.
pubmed: 21508958
pmcid: 3728647
doi: 10.1038/nature09944
Scior T, Alexander C, Zaehringer U. Reviewing and identifying amino acids of human, murine, canine and equine TLR4 / MD-2 receptor complexes conferring endotoxic innate immunity activation by LPS/lipid A, or antagonistic effects by Eritoran, in contrast to species-dependent modulation by lipid IVa. Comput Struct Biotechnol J. 2013;5:e201302012.
pubmed: 24688705
pmcid: 3962135
doi: 10.5936/csbj.201302012
Braune A, Gütschow M, Blaut M. An NADH-Dependent reductase from Eubacterium ramulus catalyzes the Stereospecific Heteroring cleavage of Flavanones and Flavanonols. Appl Environ Microbiol. 2019;85:19.
doi: 10.1128/AEM.01233-19
Ullah A, Munir S, Badshah SL, Khan N, Ghani L, Poulson BG et al. Important flavonoids and their role as a therapeutic Agent. Molecules. 2020;25(22).
Chen P, Xu H, Tang H, Zhao F, Yang C, Kwok LY, et al. Modulation of gut mucosal microbiota as a mechanism of probiotics-based adjunctive therapy for ulcerative colitis. Microb Biotechnol. 2020;13(6):2032–43.
pubmed: 32969200
pmcid: 7533322
doi: 10.1111/1751-7915.13661
Garrett WS, Onderdonk AB. 249 - Bacteroides, Prevotella, Porphyromonas, and Fusobacterium species (and other medically important anaerobic gram-negative Bacilli). In: Bennett JE, Dolin R, Blaser MJ, editors. Mandell, Douglas, and Bennett’s principles and practice of Infectious diseases (Eighth Edition). Philadelphia: W.B. Saunders; 2015. pp. 2773–80.
doi: 10.1016/B978-1-4557-4801-3.00249-6
Taurog JD, Richardson JA, Croft JT, Simmons WA, Zhou M, Fernández-Sueiro JL, et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med. 1994;180(6):2359–64.
pubmed: 7964509
doi: 10.1084/jem.180.6.2359
Hoentjen F, Tonkonogy SL, Qian BF, Liu B, Dieleman LA, Sartor RB. CD4(+) T lymphocytes mediate colitis in HLA-B27 transgenic rats monoassociated with nonpathogenic Bacteroides vulgatus. Inflamm Bowel Dis. 2007;13(3):317–24.
pubmed: 17206701
doi: 10.1002/ibd.20040
Mills RH, Dulai PS, Vázquez-Baeza Y, Sauceda C, Daniel N, Gerner RR, et al. Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity. Nat Microbiol. 2022;7(2):262–76.
pubmed: 35087228
pmcid: 8852248
doi: 10.1038/s41564-021-01050-3
Rosenbaum JT, McDevitt HO, Guss RB, Egbert PR. Endotoxin-induced uveitis in rats as a model for human disease. Nature. 1980;286(5773):611–3.
pubmed: 7402339
doi: 10.1038/286611a0
Wakefield D, Gray P, Chang J, Di Girolamo N, McCluskey P. The role of PAMPs and DAMPs in the pathogenesis of acute and recurrent anterior uveitis. Br J Ophthalmol. 2010;94(3):271–4.
pubmed: 19264730
doi: 10.1136/bjo.2008.146753
Bryant CE, Spring DR, Gangloff M, Gay NJ. The molecular basis of the host response to lipopolysaccharide. Nat Rev Microbiol. 2010;8(1):8–14.
pubmed: 19946286
doi: 10.1038/nrmicro2266
Muhammad FY, Peters K, Wang D, Lee DJ. Exacerbation of autoimmune uveitis by obesity occurs through the melanocortin 5 receptor. J Leukoc Biol. 2019;106(4):879–87.
pubmed: 31287586
doi: 10.1002/JLB.MA0119-030RR
You HJ, Si J, Kim J, Yoon S, Cha KH, Yoon HS, et al. Bacteroides vulgatus SNUG 40005 restores Akkermansia Depletion by Metabolite Modulation. Gastroenterology. 2023;164(1):103–16.
pubmed: 36240952
doi: 10.1053/j.gastro.2022.09.040
Nicolucci AC, Hume MP, Martínez I, Mayengbam S, Walter J, Reimer RA. Prebiotics Reduce Body Fat and Alter Intestinal Microbiota in Children who are overweight or with obesity. Gastroenterology. 2017;153(3):711–22.
pubmed: 28596023
doi: 10.1053/j.gastro.2017.05.055
Fu L, Li Y, Bian Y, Wang Q, Li J, Wang Y, et al. The nutritional intervention improves the Metabolic Profile of overweight and obese PCOS along with the differences in gut microbiota. Reprod Sci. 2023;30(7):2210–8.
pubmed: 36656424
doi: 10.1007/s43032-022-01131-6
Li Y, Yang Y, Wang J, Cai P, Li M, Tang X, et al. Bacteroides ovatus-mediated CD27 – MAIT cell activation is associated with obesity-related T2D progression. Cell Mol Immunol. 2022;19(7):791–804.
pubmed: 35545662
pmcid: 9243016
doi: 10.1038/s41423-022-00871-4
Nilsen M, Rehbinder EM, Lødrup Carlsen KC, Haugen G, Hedlin G, Jonassen CM, et al. A globally distributed Bacteroides caccae strain is the most prevalent Mother-Child Shared Bacteroidaceae strain in a large scandinavian cohort. Appl Environ Microbiol. 2023;89(7):e0078923.
pubmed: 37338379
doi: 10.1128/aem.00789-23
Ashorn S, Honkanen T, Kolho KL, Ashorn M, Välineva T, Wei B, et al. Fecal calprotectin levels and serological responses to microbial antigens among children and adolescents with inflammatory bowel disease. Inflamm Bowel Dis. 2009;15(2):199–205.
pubmed: 18618670
doi: 10.1002/ibd.20535
Wei B, Dalwadi H, Gordon LK, Landers C, Bruckner D, Targan SR, 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(10):6044–54.
pubmed: 11553542
pmcid: 98733
doi: 10.1128/IAI.69.10.6044-6054.2001
Nakamura RM, Matsutani M, Barry M. Advances in clinical laboratory tests for inflammatory bowel disease. Clin Chim Acta. 2003;335(1):9–20.
pubmed: 12927679
doi: 10.1016/S0009-8981(03)00286-9
Iltanen S, Tervo L, Halttunen T, Wei B, Braun J, Rantala I, et al. Elevated serum anti-I2 and anti-OmpW antibody levels in children with IBD. Inflamm Bowel Dis. 2006;12(5):389–94.
pubmed: 16670528
doi: 10.1097/01.MIB.0000218765.84087.42
Malik TF, Aurelio DM. Extraintestinal manifestations of Inflammatory Bowel Disease. StatPearls. Treasure Island (FL): StatPearls Publishing Copyright © 2024. StatPearls Publishing LLC.; 2024.
Clinical Connections. Arthritis Rheumatol. 2023;75(1).
Stoll ML, DeQuattro K, Li Z, Sawhney H, Weiss PF, Nigrovic PA et al. Impact of HLA-B27 and Disease Status on the gut microbiome of the offspring of Ankylosing Spondylitis patients. Child (Basel). 2022;9(4).
Liu G, Hao Y, Yang Q, Deng S. The Association of Fecal Microbiota in Ankylosing Spondylitis cases with C-Reactive protein and erythrocyte sedimentation rate. Mediat Inflamm. 2020;2020:8884324.
doi: 10.1155/2020/8884324
Di Jiang C, Raine T. IBD considerations in spondyloarthritis. Ther Adv Musculoskelet Dis. 2020;12:1759720x20939410.
pubmed: 32695235
pmcid: 7350041
doi: 10.1177/1759720X20939410
Vich Vila A, Collij V, Sanna S, Sinha T, Imhann F, Bourgonje AR, et al. Impact of commonly used drugs on the composition and metabolic function of the gut microbiota. Nat Commun. 2020;11(1):362.
pubmed: 31953381
pmcid: 6969170
doi: 10.1038/s41467-019-14177-z
Yin J, Sternes PR, Wang M, Song J, Morrison M, Li T, et al. Shotgun metagenomics reveals an enrichment of potentially cross-reactive bacterial epitopes in ankylosing spondylitis patients, as well as the effects of TNFi therapy upon microbiome composition. Ann Rheum Dis. 2020;79(1):132–40.
pubmed: 31662318
doi: 10.1136/annrheumdis-2019-215763
Weersma RK, Zhernakova A, Fu J. Interaction between drugs and the gut microbiome. Gut. 2020;69(8):1510–9.
pubmed: 32409589
doi: 10.1136/gutjnl-2019-320204
Chalabi M, Cardona A, Nagarkar DR, Dhawahir Scala A, Gandara DR, Rittmeyer A, et al. Efficacy of chemotherapy and atezolizumab in patients with non-small-cell lung cancer receiving antibiotics and proton pump inhibitors: pooled post hoc analyses of the OAK and POPLAR trials. Ann Oncol. 2020;31(4):525–31.
pubmed: 32115349
doi: 10.1016/j.annonc.2020.01.006
Asquith M, Sternes PR, Costello M-E, Karstens L, Diamond S, Martin TM, et al. HLA alleles Associated with Risk of Ankylosing spondylitis and Rheumatoid Arthritis Influence the gut Microbiome. Arthritis Rheumatol. 2019;71(10):1642–50.
pubmed: 31038287
doi: 10.1002/art.40917
Berland M, Meslier V, Berreira Ibraim S, Le Chatelier E, Pons N, Maziers N, et al. Both Disease activity and HLA–B27 status are Associated with gut Microbiome Dysbiosis in Spondyloarthritis patients. Arthritis Rheumatol. 2023;75(1):41–52.
pubmed: 35818337
doi: 10.1002/art.42289
Essex M, Rios Rodriguez V, Rademacher J, Proft F, Löber U, Markó L, et al. Shared and distinct gut microbiota in Spondyloarthritis, Acute Anterior Uveitis, and Crohn’s Disease. Arthritis Rheumatol. 2024;76(1):48–58.
pubmed: 37471465
doi: 10.1002/art.42658
Breban M, Tap J, Leboime A, Said-Nahal R, Langella P, Chiocchia G, et al. Faecal microbiota study reveals specific dysbiosis in spondyloarthritis. Ann Rheum Dis. 2017;76(9):1614–22.
pubmed: 28606969
doi: 10.1136/annrheumdis-2016-211064