Gut microbiota and ankylosing spondylitis: current insights and future challenges

Abstract

Ankylosing spondylitis (AS) is a chronic inflammatory disease with complex pathogenesis influenced by genetic, immunological and environmental factors. Recent evidence suggests that gut microbiota significantly contributes to AS etiopathogenesis. Dysbiosis and altered immune responses in the gut potentially trigger or exacerbate the disease through intestinal barrier disruption, alteration of the IL-23/17 axis and metabolite production. This review explores the growing role of gut microbiota in AS and its potential to reshape targeted treatment strategies and facilitate development of adjunct therapies to address disease onset and progression. AS is a multifactorial disease in which gut dysbiosis plays a significant role influencing immune regulation notably through the IL-23/17 pathway. Alterations in gut microbiota composition and its metabolites contribute to systemic inflammation, reinforcing a self-perpetuating feedback loop between gut and spinal inflammation that drives disease progression. Emerging evidence has linked microbial mechanisms to HLA-B27 misfolding promoting endoplasmic reticulum stress and triggering molecular mimicry through gut microbial-associated molecular patterns further contributing to AS pathogenesis. Given the crucial role of gut microbiota in AS, targeting microbiota imbalances presents a promising avenue for novel therapeutic strategies. Although it remains unclear whether gut inflammation and microbial changes precedes AS onset, current evidence suggests an ongoing cycle of autoimmune inflammation involving both the gut and joints. Further research, particularly longitudinal studies, are needed to better understand the gut-joint axis and its potential therapeutic implications in AS management.

Keywords: HLA-B27; IL-23/17 axis; autoimmune disease; dysbiosis; gut-joint axis; microorganisms; spondyloarthritis.

Figure 1. FIGURE 1: The IL-23/IL-17 pathogenetical axis in AS.

From left to right: Specific triggers can initiate inflammation in the gut, skin, and entheses of individuals with a genetic predisposition for AS. These triggers activate myeloid cells, such as DCs, macrophages, and intestinal epithelial cells, to secrete IL-23, a heterodimer composed of two subunits, p19 and p40. CD4+ T cells undergo differentiation and activation, influenced by cytokines like IL-1, IL-6, and TGF-β (transforming growth factor-β), to become Th17 cells. IL-23 amplifies and stabilizes Th17 cells, which then produce pro-inflammatory cytokines. Activated Th17 cells secrete IL-17 (variants A through F) and other cytokines, including GM-CSF (granulocyte-macrophage colony-stimulating factor), IL-6, IL-22, IL-26, IFN-γ, and TNF-α, which act synergistically with IL-17 to enhance inflammatory responses. Other cells, such as MAIT (mucosal-associated invariant T) cells, CD8+ T cells, NK cells, mast cells, tissue-TRM (resident memory) cells, and Paneth cells, can also produce IL-17. IL-17 promotes the release of chemokines (e.g., CCL2, CCL7, CXCL1, CXCL2), recruiting inflammatory cells such as neutrophils and T cells to the inflammation site. IL-17 acts on various cell types- fibroblasts, synoviocytes, DCs, T cells, neutrophils, endothelial cells, and B cells- primarily via IL-17R. This binding induces these cells to secrete additional cytokines, perpetuating the inflammatory cycle. Despite AS being classified as a seronegative disease, antibodies (K. pneumoniae) secreted by B cells could be involved. Combined with ongoing inflammation, these immune responses contribute to joint inflammation and the characteristic new bone formation in AS (adapted from 3237162163164165166).

Figure 2. FIGURE 2: Compositional alterations of gut microbiota in AS.

Taxonomic distribution (top to bottom). Red border: increased in AS. Blue border: decreased in AS. Red dotted border: generally increased, though some studies report a decrease. Blue dotted border: generally decreased, though some studies report an increase. Brighter red border: most significantly increased in AS.

Figure 3. FIGURE 3: Gut dysbiosis and immune activation in AS.

Gut microbiota dysbiosis in AS is marked by an increase in pro-inflammatory bacteria (shown in orange, yellow, pink) and a decrease in commensal bacteria (blue). Microbial antigens (LPS, peptidoglycans) compromise gut barrier integrity through the dysregulation of zonulin, ZO-1, occludin, and claudin, triggering immune activation via TLRs and the NLRP3 inflammasome. This leads to IL-17/IL-23 axis activation, promoting Th17 differentiation and the recruitment of macrophages, neutrophils, and NK cells that recognize microbial antigens. These processes drive an increase in pro-inflammatory cytokines (TNF-α, IL-1β, IL-17, IL-18, IFN-γ) and a decrease in regulatory cytokines (e.g. IL-10), ultimately contributing to synovial inflammation, osteoclast differentiation (pathologic bone remodeling, syndesmophyte formation), and synovial fibroblast activation (joint erosion).

Figure 4. FIGURE 4: Schematic view of SCFA influence on intestinal and immune cells.

↑ enhance/stimulate; ↓inhibit/reduce. All three SCFAs do promote lectin and defensins expression, stimulate CD4+T cells and ILCs to express IL-22, have effects on neutrophils functions. Butyrate (green) upregulates TJ proteins, induces TJ assembly; regulates CD8+T cell’s function; regulates Th1 and Th17 cells differentiation. Butyrate + propionate (blue) block DCs development, enhance MUCs (mucins) expression, promote cathelicidin expression. Propionate reduces proinflammatory cytokines, e.g., IL-1B, IL-17A, and IFN-γ-promoting colonic inflammation. Acetate (red) promotes IgA response to microbiota. Acetate + Butyrate restore macrophage’s response to inflammation; repress ERK1/2 phosphorylation, decrease iNOS (inducible nitric oxide synthase), TNF-α, and IL-6 and enhance IL-10. Acetate + Propionate inhibit HDAC (histone deacetylase) activity and NF-kB activation. Adapted from .