The immunology of the gut-joint axis

Smith, Annabelle Nicola (2025) The immunology of the gut-joint axis. PhD thesis, University of Glasgow.

Abstract

Axial spondyloarthritis (axSpA) is a form of arthritis that results in inflammation in the spine and sacroiliac joints. A large portion of people with axSpA have microscopic intestinal inflammation and the prevalence of inflammatory bowel disease (IBD) is markedly higher in this group of people compared to the general population. IBD is an umbrella term for Crohn’s disease (CD) and ulcerative colitis which causes intestinal inflammation as a result of aberrant inflammation towards bacteria within the intestine. Likewise, a substantial proportion of people with IBD have articular inflammation.

Although intestinal inflammation in people with axSpA and articular inflammation in people with IBD may be caused by non-specific systemic inflammation, there is evidence to suggest that these diseases have shared immune mechanisms that may drive this inflammation. However, there is a limited number of studies in humans directly comparing the immunology of axSpA and IBD. Understanding whether intestinal inflammation is an integral feature of axSpA or a consequence of systemic inflammation may help inform treatment strategies within the disease. For example, non-steroidal anti-inflammatory drugs (NSAIDs) are a first line intervention for axSpA, however, NSAIDs cause gastrointestinal side effects. In the case that articular inflammation is driven by intestinal changes in this disease, prevention of disease progression and long-term remission may be hindered by the current therapies used to treat axSpA.

We therefore aimed to compare changes in the frequencies of various immune cells – including monocytes, DCs, NK cells, NKT-like cells, B cells, CD4+ T cells, and CD8+ T cells – in both people with axSpA and people with CD to identify common changes to circulating immune cells within these two diseases. In addition, we aimed to investigate the expression of activation markers on each of these cell subsets to understand which cells may contribute to inflammation within each disease. To achieve this, we deployed an unbiased, R-based
workflow to analyze flow cytometry data. We also quantified the systemic concentrations of various cytokines, including proinflammatory cytokines associated with innate immunity and cytokines associated with type 1, type 2, and type 3 immune responses. Finally, we aimed to determine whether monocytes from people with axSpA exhibit an activated and hyperinflammatory phenotype compared to monocytes from controls by determining phenotypic and functional responses of these cells to LPS stimulation.

We found shared changes in the frequencies of nonclassical monocyte, natural killer cell, CD4+ T cell, and CD8+ T cell clusters, alongside shared phenotypic changes on natural killer cells, CD4+ T cells, and CD8+ T cells in both axSpA and CD. In addition, we found shared systemic increases of IL-6, IL-10, IL-17A, IL-17F, IL-22, IL-27, and TNFα, with a shared systemic decrease of IL-4 in both axSpA and CD. While we found decreased CD86+ monocytes in people with axSpA and decreased basal production of IL-10, we did not find any evidence of
increased activation or a hyperinflammatory phenotype within monocytes in people with axSpA. This work provides the basis for future research to determine how functional changes in monocytes, natural killer cells, CD4+ T cells, and CD8+T cells may contribute to inflammation in the gut-joint axis.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QR Microbiology > QR180 Immunology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Supervisor's Name: Milling, Professor Simon and Siebert, Professor Stefan
• Date of Award: 2025
• Depositing User: Theses Team
• Unique ID: glathesis:2025-85370
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 08 Aug 2025 12:14
• Last Modified: 08 Aug 2025 12:17
• Thesis DOI: 10.5525/gla.thesis.85370
• URI: https://theses.gla.ac.uk/id/eprint/85370