Can intestinal bacteria trigger rheumatological diseases?

What is this research project about?

Professor Witte (right) is talking with a patient.

What is this research project about?

Spondyloarthritis (SpA) is a group of frequent chronic rheumatological diseases which start in young adults and lead to disability of the patients. Current therapies are not efficient enough in stopping the progressive impairment of the musculoskeletal system. There is evidence that the microbiome of the gut is involved in triggering the disease. Clarifying the role of infections and the microbiome composition in the pathogenesis of SpA and its subform reactive arthritis may pave the way to new treatment modalities with better efficacy and less side effects.

What’s the current status?

With respect to a potential pathomechanism linking microbial colonization with autoimmunity and induction of SpA, it has been demonstrated that antibodies against Shigella flexneri, Klebsiella pneumoniae and Yersinia enterocolitica may crossreact with HLA-B27, the dominant genetic risk factor of SpA, and that antibodies against Klebsiella were found to be cytotoxic for cells expressing HLA-B27. Whether similar autoantibodies are induced by other members of the microbiota and if yes, under which conditions remains unresolved.

The image shows: Shigella flexneri (Shigellen), group of bacteria. Transmission electron microscopy, negative contrast. Scale = 1 μm. Source: Hans R. Gelderblom, Gabi Schlier, Rolf Reissbrodt/RKI

What are the project goals?

We want to identify alteration in the gut microbiota that are involved in triggering spondyloarthritis. Specifically we want to characterize dynamic microbiome  changes during the development and treatment of different forms of arthritis. Furthermore we want to identify antibodies associated with poor prognosis of SpA and members of the microbiome as well as antigens targeted by the immune system in arthritis patients. And our aim is to determine cross-reactivity between antibodies targeting microbial antigens and autoantigens develop intervention strategies to prevent the development of SpA and reactive arthritis.

How do we get there?

In the project RHEUMA-VOR we recruit a large number of patients from Lower Saxony with acute onset of SpA and control diseases. Stool, serum and DNA samples as well as PBMC and, when a joint aspiration was clinically indicated, synovial fluid (SF) and SF cells will be obtained and stored, and various disease-related clinical data as well as dietary habits will be collected. The patients from this inception cohort will be followed for > 2 years, and response to therapy, disease activity and disease progression will be monitored.

The photo shows Professor Strowig in his laboratory. © HZI/Waldthausen & Kreibig


Project title: The microbiome – a trigger in arthritis? Linking alterations in microbiota composition to autoantibody development.

Prof. Dr. Alice McHardy

Projekt: B2, B10

Prof. Dr. Till Strowig

Projekte: B1, B2, RESIST-Kohorte

Prof. Dr. Torsten Witte

Projekte: A2, B2

Project B2 Publications

Publications of the year 2023

Spondyloarthritis, acute anterior uveitis, and Crohn’s disease have both shared and distinct gut microbiota. Essex M, Rios Rodriguez V, Rademacher J, Proft F, Löber U, Markó L, Pleyer U, Strowig T, Marchand J, Kirwan JA, Siegmund B, Forslund SK, Poddubnyy D.  Arthritis Rheumatol. 2023 Jul 20.

Brief report: Assessment of mucosal barrier integrity using serological biomarkers in preclinical stages of rheumatoid arthritis. Gilbert BTP, Lamacchia C, Amend L, Strowig T, Rodriguez E, Palmer G, Finckh A.  Front Immunol. 2023 Feb 16;14:1117742.

The link between rheumatic disorders and inborn errors of immunity. Sogkas G, Witte T. EBioMedicine. 2023 Mar 2;90:104501.

The natural product chlorotonil A preserves colonization resistance and prevents relapsing Clostridioides difficile infection. Bublitz A, Brauer M, Wagner S, Hofer W, Müsken M, Deschner F, Lesker TR, Neumann-Schaal M, Paul LS, Nübel U, Bartel J, Kany AM, Zühlke D, Bernecker S, Jansen R, Sievers S, Riedel K, Herrmann J, Müller R, Fuchs TM, Strowig T. Cell Host Microbe. 2023 Apr 18:S1931-3128(23)00147-6.

Pulsed antibiotic treatments of gnotobiotic mice manifest in complex bacterial community dynamics and resistance effects. Münch PC, Eberl C, Woelfel S, Ring D, Fritz A, Herp S, Lade I, Geffers R, Franzosa EA, Huttenhower C, McHardy AC, Stecher B. Pulsed antibiotic treatments of gnotobiotic mice manifest in complex bacterial community dynamics and resistance effects. Cell Host Microbe. 2023 Jun 14;31(6):1007-1020.e4.

Publications of the year 2022

Critical Assessment of Metagenome Interpretation: the second round of challenges. Meyer F, Fritz A, Deng ZL, Koslicki D, Lesker TR, Gurevich A, Robertson G, Alser M, Antipov D, Beghini F, Bertrand D, Brito JJ, Brown CT, Buchmann J, Buluç A, Chen B, Chikhi R, Clausen PTLC, Cristian A, Dabrowski PW, Darling AE, Egan R, Eskin E, Georganas E, Goltsman E, Gray MA, Hansen LH, Hofmeyr S, Huang P, Irber L, Jia H, Jørgensen TS, Kieser SD, Klemetsen T, Kola A, Kolmogorov M, Korobeynikov A, Kwan J, LaPierre N, Lemaitre C, Li C, Limasset A, Malcher-Miranda F, Mangul S, Marcelino VR, Marchet C, Marijon P, Meleshko D, Mende DR, Milanese A, Nagarajan N, Nissen J, Nurk S, Oliker L, Paoli L, Peterlongo P, Piro VC, Porter JS, Rasmussen S, Rees ER, Reinert K, Renard B, Robertsen EM, Rosen GL, Ruscheweyh HJ, Sarwal V, Segata N, Seiler E, Shi L, Sun F, Sunagawa S, Sørensen SJ, Thomas A, Tong C, Trajkovski M, Tremblay J, Uritskiy G, Vicedomini R, Wang Z, Wang Z, Wang Z, Warren A, Willassen NP, Yelick K, You R, Zeller G, Zhao Z, Zhu S, Zhu J, Garrido-Oter R, Gastmeier P, Hacquard S, Häußler S, Khaledi A, Maechler F, Mesny F, Radutoiu S, Schulze-Lefert P, Smit N, Strowig T, Bremges A, Sczyrba A, McHardy AC. Nat Methods. 2022 Apr;19(4):429-440. doi: 10.1038/s41592-022-01431-4. Epub 2022 Apr 8. PMID: 35396482.

Strain Identification and Quantitative Analysis in Microbial Communities. Ghazi AR, Münch PC, Chen D, Jensen J, Huttenhower C. J Mol Biol. 2022 Aug; Epub 2022 Apr 7.

Primary antibody deficiency-associated arthritis shares features with spondyloarthritis and enteropathic arthritis. Pott NM, Atschekzei F, Pott CC, Ernst D, Witte T, Sogkas G. RMD Open. 2022 Dec

Publications of the year 2021

Klebsiella oxytoca causes colonization resistance against multidrug-resistant K. pneumoniae in the gut via cooperative carbohydrate competition. Osbelt L, Wende M, Almási É, Derksen E, Muthukumarasamy U, Lesker TR, Galvez EJC, Pils MC, Schalk E, Chhatwal P, Färber J, Neumann-Schaal M, Fischer T, Schlüter D, Strowig T. Cell Host Microbe.

Novel aspects of regulatory T cell dysfunction as a therapeutic target in giant cell arteritis. Adriawan IR, Atschekzei F, Dittrich-Breiholz O, Garantziotis P, Hirsch S, Risser LM, Kosanke M, Schmidt RE, Witte T, Sogkas G. Ann Rheum Dis.

B cell depletion impairs vaccination-induced CD8+ T cell responses in a type I interferon-dependent manner. Graalmann T, Borst K, Manchanda H, Vaas L, Bruhn M, Graalmann L, Koster M, Verboom M, Hallensleben M, Guzmán CA, Sutter G, Schmidt RE, Witte T, Kalinke U. Ann Rheum Dis.

Haploflow: strain-resolved de novo assembly of viral genomes. Genome Biol 22:212. Fritz A, Bremges A, Deng Z-L, Lesker TR, Götting J, Ganzenmueller T, Sczyrba A, Dilthey A, Klawonn F, McHardy AC. 2021.

Publications of the year 2020

Strategic Anti-SARS-CoV-2 Serology Testing in a Low Prevalence Setting: The COVID-19 Contact (CoCo) Study in Healthcare Professionals. Behrens GMN, Cossmann A, Stankov MV, Schulte B, Streeck H, Förster R, Bosnjak B, Willenzon S, Boeck AL, Thu Tran A, Thiele T, Graalmann T, Kayser MZ, Zychlinsky Scharff A, Dopfer C, Horke A, Pink I, Witte T, Wetzke M, Ernst D, Jablonka A, Happle C. Infect Dis Ther. 2020 Dec;9(4):837-849. doi: 10.1007/s40121-020-00334-1. Epub 2020 Sep 4. PMID: 32886335; PMCID: PMC7472691.

An Integrated Metagenome Catalog Reveals New Insights into the Murine Gut Microbiome. Lesker TR, Durairaj AC, Gálvez EJC, Lagkouvardos I, Baines JF, Clavel T, Sczyrba A, McHardy AC, Strowig T.  Cell Rep. 2020 Mar 3;30(9):2909-2922.e6. doi: 10.1016/j.celrep.2020.02.036. PMID: 32130896; PMCID: PMC7059117.

Peripheral Blood Lymphocyte Phenotype Differentiates Secondary Antibody Deficiency in Rheumatic Disease from Primary Antibody Deficiency. Jablonka A, Etemadi H, Adriawan IR, Ernst D, Jacobs R, Buyny S, Witte T, Schmidt RE, Atschekzei F, Sogkas G. J Clin Med. 2020 Apr 7;9(4):1049. doi: 10.3390/jcm9041049. PMID: 32272789; PMCID: PMC7230453.

Distinct Polysaccharide Utilization Determines Interspecies Competition between Intestinal Prevotella spp. Gálvez EJC, Iljazovic A, Amend L, Lesker TR, Renault T, Thiemann S, Hao L, Roy U, Gronow A, Charpentier E, Strowig T.  Cell Host Microbe. 2020 Dec 9;28(6):838-852.e6. doi: 10.1016/j.chom.2020.09.012. Epub 2020 Oct 27. PMID: 33113351.

Identification of Natural CRISPR Systems and Targets in the Human Microbiome. Cell Host Microbe. Münch PC, Franzosa EA, Stecher B, McHardy AC, Huttenhower C. 2021 Jan 13;29(1):94-106.e4. doi: 10.1016/j.chom.2020.10.010. Epub 2020 Nov 19. PMID: 33217332; PMCID: PMC7813156.

Dietary Short-Term Fiber Interventions in Arthritis Patients Increase Systemic SCFA Levels and Regulate Inflammation. Dürholz K, Hofmann J, Iljazovic A, Häger J, Lucas S, Sarter K, Strowig T, Bang H, Rech J, Schett G, Zaiss MM. Nutrients. 2020 Oct 20;12(10):3207. doi: 10.3390/nu12103207. PMID: 33092271; PMCID: PMC7589100.

The Role of Ames Dwarfism and Calorie Restriction on Gut Microbiota. Wiesenborn DS, Gálvez EJC, Spinel L, Victoria B, Allen B, Schneider A, Gesing A, Al-Regaiey KA, Strowig T, Schäfer KH, Masternak MM. J Gerontol A Biol Sci Med Sci. 2020 Jun 18;75(7):e1-e8. doi: 10.1093/gerona/glz236. PMID: 31665244; PMCID: PMC7302176.

Perturbation of the gut microbiome by Prevotella spp. enhances host susceptibility to mucosal inflammation. Iljazovic A, Roy U, Gálvez EJC, Lesker TR, Zhao B, Gronow A, Amend L, Will SE, Hofmann JD, Pils MC, Schmidt-Hohagen K, Neumann-Schaal M, Strowig T. Mucosal Immunol. 2021 Jan;14(1):113-124. doi: 10.1038/s41385-020-0296-4. Epub 2020 May 20. PMID: 32433514; PMCID: PMC7790746.

Clinical, Radiological, and Laboratory Features of Spinal Cord Involvement in Primary Sjögren’s Syndrome. Butryn M, Neumann J, Rolfes L, Bartels C, Wattjes MP, Mahmoudi N, Seeliger T, Konen FF, Thiele T, Witte T, Meuth SG, Skripuletz T, Pawlitzki M. J Clin Med. 2020 May 14;9(5):1482. doi: 10.3390/jcm9051482. PMID: 32423153; PMCID: PMC7290729.

Anti-CD74 IgA autoantibodies in radiographic axial spondyloarthritis; a longitudinal Swedish study. Do L, Granasen G, Hellman U, Lejon K, Geijer M, Baraliakos X, Witte T, Forsblad-d’Elia H. Rheumatology (Oxford) 2020

High frequency of variants in genes associated with primary immunodeficiencies in patients with rheumatic diseases with secondary hypogammaglobulinaemia Sogkas G, Dubrowinskaja N, Adriawan IR, Anim M, Witte T, Schmidt RE, Atschekzei F.  Ann Rheum Dis 2020

Repertoire characterization and validation of gB-specific human IgGs directly cloned from humanized mice vaccinated with dendritic cells and protected against HCMV. Theobald SJ, Kreer C, Khailaie S, Bonifacius A, Eiz-Vesper B, Figueiredo C, Mach M, Backovic M, Ballmaier M, Koenig J, Olbrich H, Schneider A, Volk V, Danisch S, Gieselmann L, Ercanoglu MS, Messerle M, Kaisenberg CV, Witte T, Klawonn F, Meyer-Hermann M, Klein F, Stripecke R. PLoS Pathog. 2020 Jul 15;16(7):e1008560. doi: 10.1371/journal.ppat.1008560. PMID: 32667948; PMCID: PMC7363084.

Publications of the year 2019

The CAFA challenge reports improved protein function prediction and new functional annotations for hundreds of genes through experimental screens. Zhou N, Jiang Y, Bergquist TR, Lee AJ, Kacsoh BZ, Crocker AW, Lewis KA, Georghiou G, Nguyen HN, Hamid MN, Davis L, Dogan T, Atalay V, Rifaioglu AS, Dalkıran A, Cetin Atalay R, Zhang C, Hurto RL, Freddolino PL, Zhang Y, Bhat P, Supek F, Fernández JM, Gemovic B, Perovic VR, Davidović RS, Sumonja N, Veljkovic N, Asgari E, Mofrad MRK, Profiti G, Savojardo C, Martelli PL, Casadio R, Boecker F, Schoof H, Kahanda I, Thurlby N, McHardy AC, Renaux A, Saidi R, Gough J, Freitas AA, Antczak M, Fabris F, Wass MN, Hou J, Cheng J, Wang Z, Romero AE, Paccanaro A, Yang H, Goldberg T, Zhao C, Holm L, Törönen P, Medlar AJ, Zosa E, Borukhov I, Novikov I, Wilkins A, Lichtarge O, Chi PH, Tseng WC, Linial M, Rose PW, Dessimoz C, Vidulin V, Dzeroski S, Sillitoe I, Das S, Lees JG, Jones DT, Wan C, Cozzetto D, Fa R, Torres M, Warwick Vesztrocy A, Rodriguez JM, Tress ML, Frasca M, Notaro M, Grossi G, Petrini A, Re M, Valentini G, Mesiti M, Roche DB, Reeb J, Ritchie DW, Aridhi S, Alborzi SZ, Devignes MD, Koo DCE, Bonneau R, Gligorijević V, Barot M, Fang H, Toppo S, Lavezzo E, Falda M, Berselli M, Tosatto SCE, Carraro M, Piovesan D, Ur Rehman H, Mao Q, Zhang S, Vucetic S, Black GS, Jo D, Suh E, Dayton JB, Larsen DJ, Omdahl AR, McGuffin LJ, Brackenridge DA, Babbitt PC, Yunes JM, Fontana P, Zhang F, Zhu S, You R, Zhang Z, Dai S, Yao S, Tian W, Cao R, Chandler C, Amezola M, Johnson D, Chang JM, Liao WH, Liu YW, Pascarelli S, Frank Y, Hoehndorf R, Kulmanov M, Boudellioua I, Politano G, Di Carlo S, Benso A, Hakala K, Ginter F, Mehryary F, Kaewphan S, Björne J, Moen H, Tolvanen MEE, Salakoski T, Kihara D, Jain A, Šmuc T, Altenhoff A, Ben-Hur A, Rost B, Brenner SE, Orengo CA, Jeffery CJ, Bosco G, Hogan DA, Martin MJ, O’Donovan C, Mooney SD, Greene CS, Radivojac P, Friedberg I. Genome Biol. 2019 Nov 19;20(1):244.

Publications of the Project B2