Gut bacteria are involved in modulating immune responses in patients with ankylosing spondylitis

Previous research has shown that gut microbiota dysbiosis may be involved in the pathogenesis of ankylosing spondylitis (AS), which is a chronic inflammatory disease that mainly affects the sacroiliac joints and spine. However, the implications it could have for both local and systemic immune responses in AS has not yet been explored.

A recent study, led by Dr. Giovanni Triolo from the Department of Internal Medicine at the Division of Rheumatology at the University of Palermo (Italy), has found that gut dysbiosis in AS patients is associated with intestinal mucosal barrier dysfunction and modulation of both local and systemic immune responses.

Ileal biopsies were obtained from 50 patients with AS and 20 normal subjects. Ileal expression of tight and adherens junction proteins were also investigated as markers of gut barrier integrity. Serum levels of lipopolysaccharide (LPS) and LPS-binding protein (LPS-BP) were measured as a markers of microbial translocation; intestinal fatty acid-BP (iFABP) was measured as a marker for gastrointestinal tract damage; and zonulin was also assayed, together with monocyte immunological functions in in vitro experiments.

Adherent and invasive bacteria, essentially Escherichia coli and Prevotella spp., were present in the ilea of patients with AS and were associated with alterations of tight junction proteins. The presence of invasive and adherent bacteria was directly correlated with the number of infiltrating mononuclear cells, which is a marker of gut inflammation. Significant downregulation of claudins 1 and 4, occludin, and zonula occludens were observed in the guts of patients with AS compared with controls.

Impairment of the gut vascular barrier was also present in patients with AS, together with a significant upregulation of zonulin and high serum levels of LPS, LPS-BP, iFABP and zonulin compared with controls.

When evaluating the role of intestinal bacteria isolated from patients with AS in modulating epithelial zonulin levels, in in vitro studies with Caco-2 epithelial cells, zonulin altered endothelial tight junctions and its release was modulated by intestinal bacteria. Furthermore, intestinal bacterial products translocated into the bloodstream in patients with AS and modulated monocyte behaviour through upregulating the production of IL-23. These data show how dysbiosis may influence both local and systemic immune responses in AS.

Besides this, the effects of antibiotics on tight junctions in human leukocyte antigen (HLA)-B27 transgenic rats were assessed, as HLA-B27 is a major risk factor for AS. Interestingly, dysbiosis and alterations of epithelial tight junctions in HLA-B27 transgenic rats were restored by antibiotic treatment. These results suggest that intestinal dysbiosis might be involved in the impairment of the epithelial barrier and was consistent with previous data.

In conclusion, adherent and invading bacteria are present in the ileum of patients with AS and are involved in the alteration of the epithelial barrier and the modulation of the innate immune system. Both bacterial products and zonulin may influence monocyte behaviour involved in innate immune responses, which opens a new possibility of targeting gut dysbiosis along with the impaired immune responses in patients with AS.

Reference:

Ciccia F, Guggino G, Rizzo A, et al. Dysbiosis and zonulin upregulation alter gut epitelial and vascular barriers in patients with ankylosing spondylitis. Ann Rheum Dis. 2017; doi: 10.1136/annrheumdis-2016-210000.