Rheumatoid arthritis is associated with increased gut permeability and bacterial translocation that are reversed by inflammation control

Abstract

Objective to assess how rheumatoid arthritis (RA) and Disease Modifying Anti Rheumatic Drugs (DMARDs) affect gut permeability. Methods to explore colonic mucosa integrity, tight junction proteins ZO-1, occludin and claudin 2 were quantified by immunohistochemistry on colonic biopsies in 20 RA patients and 20 age- and sex-matched controls. Staining intensity was assessed by two blinded independent readers. To explore intestinal permeability, serum concentrations of LPS-binding protein (LBP), sCD14 and zonulin-related proteins (ZRP) were evaluated by ELISA in another cohort of 59 RA: 21 patients naive of DMARDs (17 before and after introduction of a conventional synthetic (cs) DMARDs), 38 patients with severe RA (before and after introduction of a biological (b) DMARDs), and 33 healthy controls. Results Z0-1 protein was less expressed in colon of RA patients than controls (mean score ± SEM of 1.6 ± 0.56 vs 2.0 ± 0.43; p= 0.01), while no significant difference was detected for occludin and claudin-2. RA patients had higher serum LBP and sCD14 concentrations than controls. LBP and sCD14 levels were significantly correlated with DAS28 (r = 0.61, p= 0.005 and r = 0.57, p= 0.01, respectively) while ZRP did not. bDMARD responders had significantly reduced LBP and sCD14 concentrations unlike bDMARDs non-responders and patients treated with csDMARDs. Conclusion RA patients have altered colonic tight junction proteins and increased serum biomarkers of intestinal permeability. There was a correlation between serological markers of intestinal permeability and disease activity as well as bDMARD response. These results suggest a link between impaired gut integrity and systemic inflammation in RA.

Gut-joint axis: Gut dysbiosis can contribute to the onset of rheumatoid arthritis via multiple pathways

“…Zonulin is an enterotoxin secreted by enterocytes in response to dietary and microbial stimuli that disengages proteins zonula occludens-1 (ZO-1) and occludin from the tight junction (TJ) complex, leading to intestinal barrier damage, an increased permeability, translocation of bacterial products in the blood, and initiation of inflammatory responses (Xu et al, 2022b;Tajik et al, 2020;Audo et al, 2022). Zonulin induces T-cell-mediated mucosal inflammation and may control immune cells' transmigration from the gut into the joints (Tajik et al, 2020).…”

“…The interaction of Toll-like receptors (TLR) and pathogen-associated molecular patterns (PAMP) on microbes have the potential to activate the immune system, leading to the production of pro-inflammatory cytokines such as interleukin (IL)-6 (IL-6), tumor necrosis factoralpha (TNF-a), or IL-1b to eliminate the pathogen (Chiang et al, 2019;Opoku et al, 2022;Parantainen et al, 2022). The disruption of the epithelial barrier function occurs in the preclinical phase of RA in murine models and humans (Tajik et al, 2020;Audo et al, 2022). Gut dysbiosis might trigger the breakdown of gut barrier integrity and the leakage of microbiota or their metabolites into gut tissue and even venous or lymphatic circulation, enabling exposure of the immune cells to bacterial antigens leading to local and systemic inflammation, increased pro-inflammatory cytokines such as TNF-a and IL-17A, and differentiation of autoreactive Th17 cells (Figure 2) (Berthelot et al, 2019;Chiang et al, 2019;Man et al, 2020;Tajik et al, 2020;Garabatos and Santamaria, 2022;Zhao et al, 2022).…”

“…The fiber-containing diet in mice colonized with P. copri increased inflammatory cytokine production, adaptive immunity activation, and gut barrier dysfunction (Jiang et al, 2022). In rodents, intestinal inflammation occurred earlier than the onset of arthritis, and restoration of the intestinal barrier by probiotics (Bifidobacterium adolescentis), butyrate, or using larazotide, was found to attenuate arthritis (Tajik et al, 2020;Fan et al, 2020a;Audo et al, 2022).…”

“…the colon, as well as increased serological gut permeability markers (i.e., zonulin/ZRPs, LBP and sCD14) (Tajik et al, 2020;Audo et al, 2022).…”

The Blood Microbiome and Health: Current Evidence, Controversies, and Challenges

“…Likewise, distinct bacterial communities were found in the blood of rheumatoid arthritis patients, where the genera Halomonas and Shewanella , both implicated in inflammation and several human infections, were significantly elevated compared to healthy subjects [ 55 ]. Given that the perturbed circulating bacterial populations in both rheumatic diseases are primarily oral or gut commensals, the integrity of the mucosal barrier may be jeopardized, allowing more bacterial translocation and microbial-induced host inflammation [ 56 ]. Therefore, it is crucial to understand whether blood microbiome dysbiosis is a cause or effect of rheumatoid disorders.…”