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The Role of the Human Gut Microbiome in Ankylosing Spondylitis

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The Role of the Human Gut Microbiome in Ankylosing Spondylitis The role of the human gut microbiome in ankylosing spondylitis Mary-Ellen Clare Costello Bachelor of Applied Science (Microbiology), Masters of Science (Research) A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2015 University of Queensland Diamantina Institute Abstract Intestinal microbiome dysbiosis and microbial infections have been implicated in a number of immune mediated diseases, including multiple sclerosis, inflammatory bowel disease (IBD), and type 1 diabetes. Bacterial infections in the gut and urogenital tract are known to trigger episodes of reactive arthritis, a form of spondyloarthropathy (SpA), a group of related inflammatory arthropathies of which ankylosing spondylitis (AS) is the prototypic disease. There is a close relationship between the gut and SpA, exemplified in reactive arthritis patients, where a typically self-limiting arthropathy follows either gastrointestinal infection with Campylobacter, Salmonella, Shigella or Yersinia, or urogenital infection with Chlamydia. Microbial involvement has been suggested in AS, however, no definitive link has been established. Multiple genes associated with AS also play a role in gut immunity, such as genes involved in the IL-23 pathway, which are important regulators of intestinal ‘health’. There is a marked over-representation of genes associated with Crohn’s disease (CD) that are also associated with AS suggesting the two diseases my have similar aetiopathogenic mechanisms, possibly involving gut dysbiosis. Up to 70% of AS patients have subclinical gut inflammation with 5-10% of these patients developing clinically defined IBD resembling CD. Therefore unravelling the relationship between underlying host genetics, the intestinal microbiome and the immune system is imperative for furthering out understanding of AS pathogenesis. This thesis sought to examine the role of the gut microbiome in AS by characterising the AS microbiome, examining how changes in host genetics influences intestinal microbial composition and then exploring at the association between AS susceptibility loci and microbiome composition in healthy twins. To date, no comprehensive characterisation, using culture-independent methods, of intestinal microbiota from terminal ileal (TI) biopsies from AS patients has been performed. I firstly optimised the methods required for 16S rRNA characterisation of human intestinal tissue. This included the intestinal biopsies extraction method, 16S PCR development, next generation library construction and sequencing as well as the analysis methods employed for characterisation and comparison of the intestinal microbiome. 2 Secondly I profiled the microbiome of TI biopsies from patients with recent-onset, TNF- antagonist naïve AS and healthy controls (HC), using the methods detailed in Chapter 2 of this thesis, to investigate if the AS gut carries a distinct microbial signature. Results showed that AS patients carried a clear and distinct microbial signature when compared to HC (P<0.001) higher abundance of five families of bacteria Lachnospiraceae (P=0.001), Ruminococcaceae (P=0.012), Rikenellaceae (P=0.004), Porphyromonadaceae (P=0.001), and Bacteroidaceae (P=0.001), and a decreases in abundance of two families Veillonellaceae (P=0.01) and Prevotellaceae (P=0.004). The microbial composition was found to correlate with disease status and greater differences were observed between than within disease groups. Further investigation of the AS intestinal microbiome demonstrated that an assemblage or ‘core’ of five families of bacteria were driving the intestinal profile. These results are consistent with the hypothesis that genes associated with AS act at least in part through effects on the gut microbiome. I then further examined the role of host genetics in microbiome composition by examining the effect of Endoplasmic reticulum aminopeptidase-1 (ERAP1) in a murine model. Genome wide association studies have currently identified over 40 loci associated with ankylosing spondylitis, with ERAP1 is one of the strongest associations, along with HLA- B27. ERAP1 plays a critical role in overall immune system modulation with systemic effects. In this chapter, I asked how a lack or down regulation of ERAP1 influences the inherent gut microbiome composition, and how this impacts on the antigen repertoire and ensuing affects the immune system. In the final component of this thesis I further investigated the influence of host genetics, specifically AS risk loci, on microbiome composition by examining the association between AS SNPs and intestinal microbiome composition in a non-AS, otherwise healthy individuals. To investigate the relationship between genes known to be associated with AS and the gut microbiome, results of matched genetic and 16S rRNA profiling of 982 twins from the United Kingdom Adult Twin Registry (TwinsUK) were examined to determine if SNPs, either individually or in combination, were associated with specific microbes. We have shown, in an otherwise healthy Twin cohort, that genes associated with developing AS were linked to families of bacteria known to be inflammatory and key indicator species in the AS microbiome. The allelic risk score linked an AS genetic profile with the families of Ruminococcaceae, Lachnospiraceae and the order Clostridiales, which are keystone species of the AS microbiome and members of the core microbiome. Further investigation 3 of individual genes involved in microbial response, peptide processing, trimming and presentation were also correlated with these same families of bacteria. This intimates that host genetics play a role in not only overall microbiome composition, but also structure of core microbiome. Collectively the work presented in this thesis highlights of the role the human gut microbiome in AS. It demonstrates evidence for a discrete microbial signature in the TI of patients with AS compared to HC. The microbial composition was found to correlate with disease status and driven by a core group of five bacterial families. Genes associated with developing AS were linked to families of bacteria known to be inflammatory and key indicator species in the AS microbiome, and investigation of individual genes involved in microbial response, peptide processing, trimming and presentation were also correlated with these same families of bacteria. This indicates that underlying host genetics plays a role in core microbiome as well as overall microbiome structure. Final discussion chapter of this thesis discusses implications of these associations, limitations of the research as well as future directions to be explored. 4 Declaration by author This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my research higher degree candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis. 5 Publications during candidature Publications in peer-reviewed journals Costello M-E, Ciccia F, Willner D, Warrington N, Robinson PC, Gardiner B, Marshall M, Kenna TJ, Triolo G, Brown MA (2014). Intestinal dysbiosis in ankylosing spondylitis. Arthritis & Rheumatology 10.1002/art.38967 Available online Rosenbaum J, Lin P, Asquith M, Costello M-E, Kenna T, Brown M (2014). Does the microbiome play a causal role in spondyloarthritis? Clinical Rheumatology 33: 763-767. Kenna TJ, Lau MC, Keith P, Ciccia F, Costello M-E, Bradbury L et al (2014). Disease- associated polymorphisms in ERAP1 do not alter endoplasmic reticulum stress in patients with ankylosing spondylitis. Genes Immun. 10.1038/gene.2014.62 Costello M-E, Elewaut D, Kenna T, Brown M (2013). Microbes, the gut and ankylosing spondylitis. Arthritis Research & Therapy 15: 214. Publications included in this thesis Costello M-E, Ciccia F, Willner D, Warrington N, Robinson PC, Gardiner B, et al. Brief Report: Intestinal Dysbiosis in Ankylosing Spondylitis. Arthritis & Rheumatology. 2015;67(3):686-91.– incorporated as Chapter 3 (complete article in Appendices) Contributor Statement of contribution Author - Costello M-E (Candidate) Conceptualised the study (20%) Designed experiments (60%) Designed microbial analysis strategy (40%) Performed the experiments (95%) Performed
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