Intestinal dysbiosis in spondyloarthritis - chicken or egg?

PURPOSE OF REVIEW: The well-established link between intestinal inflammation and spondyloarthritis (SpA) remains largely unexplained. Recent sequencing technologies have given access to a thorough characterization of the gut microbiota in healthy and disease conditions. This showed that inflammatory bowel disease (IBD) is associated with dysbiosis - i.e., disturbed gut microbiota composition - which may contribute to disease pathogenesis. Whether gut dysbiosis exists in SpA and could contribute to disease development or be a bystander consequence of chronic inflammation is a question of major interest. RECENT FINDINGS: Several metagenomic studies have been performed in SpA. Most of them concerned faecal samples and showed dysbiosis consisting in a reduction of microbial biodiversity in a way similar to what has been described in IBD. They also highlighted changes in microbial taxa composition that could contribute to the inflammatory process. Likewise, healthy carriers of human leukocyte antigen (HLA)-B27 exhibited gut dysbiosis, indicating that this predisposing allele could exert its pathogenic effect by influencing microbiota composition, and possibly by driving antigen-specific cross-reactive immune response. On the other hand, SpA treatments were associated with a reduction of dysbiosis, showing that it is at least in part a consequence of inflammation. SUMMARY: Recent insights from metagenomic studies warrant further investigations to identify the mechanisms by which microbial dysbiosis could contribute to SpA development. This would bring novel therapeutic opportunities aiming at correcting detrimental changes.

Lessons on SpA pathogenesis from animal models.

Understanding the complex mechanisms underlying a disorder such as spondyloarthritis (SpA) may benefit from studying animal models. Several suitable models have been developed, in particular to investigate the role of genetic factors predisposing to SpA, including HLA-B27, ERAP1, and genes related to the interleukin (IL)-23/IL-17 axis. One of the best examples of such research is the HLA-B27 transgenic rat model that fostered the emergence of original theories regarding HLA-B27 pathogenicity, including dysregulation of innate immunity, contribution of the adaptive immune system to chronic inflammation, and influence of the microbiota on disease development. Very recently, a new model of HLA-B27 transgenic Drosophila helped to expand further some of those theories in an unexpected direction involving the TGFß/BMP family of mediators. On the other hand, several spontaneous, inducible, and/or genetically modified mouse models-including SKG mouse, TNFΔARE mouse and IL-23-inducible mouse model of SpA-have highlighted the importance of TNFα and IL-23/IL-17 axis in the development of SpA manifestations. Altogether, those animal models afford not only to study disease mechanism but also to investigate putative therapeutic targets.

Rodent Models of Spondyloarthritis Have Decreased White and Bone Marrow Adipose Tissue Depots.

Bone marrow adipose tissue (BMAT) has recently been recognized as a distinct fat depot with endocrine functions. However, if and how it is regulated by chronic inflammation remains unknown. Here, we investigate the amount of white fat and BMAT in HLA-B27 transgenic rats and curdlan-challenged SKG mice, two well-established models of chronic inflammatory spondyloarthritis (SpA). Subcutaneous and gonadal white adipose tissue and BMAT was reduced by 65-70% and by up to 90% in both experimental models. Consistently, B27 rats had a 2-3-fold decrease in the serum concentrations of the adipocyte-derived cytokines adiponectin and leptin as well as a 2-fold lower concentration of triglycerides. The bone marrow of B27 rats was further characterized by higher numbers of neutrophils, lower numbers of erythroblast precursors, and higher numbers of IL-17 producing CD4+ T cells. IL-17 concentration was also increased in the serum of B27 rats. Using a cell culture model, we show that high levels of IL-17 in the serum of B27 rats negatively impacted adipogenesis (-76%), an effect that was reversed in the presence of neutralizing anti-IL-17 antibody. In summary, these findings show BMAT is severely reduced in two experimental models of chronic inflammatory SpA and suggest that IL-17 is involved in this process.

Valvular and infection-associated risk factors as criteria to guide the use of echocardiography in patients with native joint infections.

BACKGROUND: Native joint and bone infections (NJBI) are associated with infective endocarditis (IE) in 15% of cases. There are no studies analyzing the use of cardiac imaging in cases of NJBI. The objective of this study was to identify factors associated with echocardiography suggestive of IE in patients with NJBI. METHODS: This medical records review was conducted in patients hospitalized for NJBI between 2007 and 2017 in Rheumatology and Infectious Diseases departments of 2 university hospitals. Patients included had a microbiologically proven NJBI during their hospitalization. RESULTS: In this cohort of 546 patients, median age 66 years, echocardiography was suggestive of IE in 66 (12%). In multivariate analysis, factors associated with echocardiography suggestive of IE were 2 or more positive blood cultures (OR 11.55 (CI95% 3.24-74.20)), cardiac conditions with a high risk of IE (OR 7.34 (CI95% 2.95-18.61)), unknown heart murmur (OR 4.59 (CI95% 1.79-11.74)), multifocal infection (OR 2.26 (CI95% 1.21-4.23)) and an infection due to S. bovis (OR 3.52 (CI95% 1.26-9.79)). The factor associated with the absence of an echocardiography evocative of IE was infection due to unconventional bacteria for IE (OR 0.13 (CI95% 0.01-0.76)). According to the factors associated with echocardiography evocative of IE, we propose the Normandy score based on three kinds of data: cardiac condition, bacterial strain and NJBI mechanism. Echocardiography should be realized when this score, whose negative predictive value is 100% CI95% (98-100%) for prescription of echocardiography, is more than zero. CONCLUSIONS: A score based on valvular condition, bacterial strain and NJBI mechanism could guide clinicians in prescribing echocardiography during NJBI with an excellent negative predictive value.

The microbiome in spondyloarthritis.

A causal link between the wealth of microbes that populate our body surfaces, designated as microbiota, and inflammatory disorders, including ankylosing spondylitis and the related spondyloarthritis (SpA) has been suspected for decades. This specially concerns the gut microbiota that became only recently accessible to thorough description thanks to massive sequencing methods or metagenomics. Here, we review evidences supporting the existence of microbiota imbalance or dysbiosis in the context of SpA. We also discuss currently existing evidences for a causal relationship between such dysbiosis and disease development, as well as putative therapeutic implications.