Faculty Bibliography

Background: Rheumatoid arthritis (RA) is a complex, autoimmune disease in which several genetic and environmental factors play a role. Recent data suggest that the gut and oral microbiome might potentially contribute to an aberrant systemic immune response characteristic of RA. Among recently studied microbiota, both P. gingivalis in the oral cavity1 and P. copri2 in the gut have been implicated. Imaging abnormalities seen in RA patients and also in at-risk individuals for the development of disease3 along with the presence of autoantibodies in the airways4 implicates the lung as yet another site of autoimmunity generation in RA. Objectives: To test whether the RA lung microbiome contains distinct taxonomic features that associate with local and/or systemic autoimmunity Methods: Bronchoalveolar lavage (BAL) samples from 20 subjects with RA and 10 with sarcoidosis were obtained by research bronchoscopy. 16S rDNA sequencing was performed to define microbiota composition. Levels of arginine/citrulline were measured in BAL fluid using GC-MS for all samples. Autoantibodies, including anti-CCP, RF and ACPAs were also measured in RA subjects in BAL and serum. Statistical analysis was performed using wilcoxon test and Spearman correlation. Results: There were no differences in demographic or clinical characteristics (including smoking status) between the groups. 16S sequencing data show similar alpha and beta diversity based on UniFrac between groups. Taxonomic comparison between RA and sarcoidosis was performed using LEfSe, which revealed several significant differences (LDA score>2). While RA BAL samples were enriched with Sphingobacteria, sarcoidosis BAL was enriched with Bacteroidia, Rhizobiales, Nitrospirales, and Campylobacter. GC-MS showed similar levels of arginine and citrulline in BAL for the sarcoidosis and RA groups. Raoultella and Barnesiella correlated with CCP2 levels in BAL (rho=0.49 and 0.47; p-value=0.026 and 0.032 respectively). Serum levels of CCP-IgA had a negative correlation with Massilia and Tannerella (rho= -0.63 and 0.53; p-value 0.003 and 0.016, respectively), and a positive correlation with Vagococcus and Lactobacillus (rho=0.59 and 0.54; p-value 0.006 and 0.014, respectively). Unclas-Lactobacillales also had a positive correlation with serum levels of RF-IgA (rho=0.71; p-value <0.001). Serum levels of anti-CCP2 antibodies had a negative correlation with Escherichia and Bdellovibrio (rho=-0.47 and 0.45, p-value=0.03 and 0.04 respectively), and a positive correlation with Porphyromonas, Rahnella and Chryseobacterium (rho=0.46, 0.46 and 0.45; p-value=0.03, 0.03 and 0.04 respectively). Conclusions: Despite the relatively small number of samples analyzed, several taxonomic differences were noted between RA and Sarcoidosis. Correlations between relative abundance of specific taxa in BAL with serum autoantibodies (i.e., anti-CCP) support an association between the lung microbiome and the host immune phenotype in RA. Further evaluation of functional aspects of this microbiome may provide further insights into its possible contribution to RA

Humans and other mammals are not (and have never been) alone. From the moment we are born, millions of microorganisms populate our bodies and coexist with us rather peacefully for the rest of our lives. This massive anitgenic load derived from microorganisms (and their genomes) define the human microbiome. Micro-organisms living in or on us have evolved to extract the energy they require to survive, and in exchange they support the physiological, nutritional, metabolic and immune functions that have contributed to our evolutionary success. Although currently categorized as autoimmune disorders and regarded as complex genetic disease, the ultimate cause of rheumatoid arthritis (RA), psoriatic arthirits (PsA), and related conditions remain elusive. It seems that interplay between predisposing genetic factors and environmental triggers is required for disease manifestations. New insights from DNA sequence- based analyses of gut and skin microbial communities and a renewed interest in mucosal immunology suggest that the microbiome represents an important environmental factor that can modulate inflammation and autoimmune disease manifestations. Multiple animal models and novel human studies suggest a possible role for a disruption in the microbiome composition (dysbiosis) in the pathogenesis of inflammatory arthritis, presumably through activation of proinflammatory T-cells via antigenic molecules and/or bacterial-derived metabolites

The human microbiome, which represents the total collection of microorganisms (and their genes) inhabiting the human body, has increasingly been recognized as a potential key factor in the development of autoimmune disease. Multiple studies suggest that the microbiome has significant influence on immune homeostasis, while disruptions in local microbiome composition can result in a heightened systemic inflammatory response. The intestinal microbiome, in particular, harbors the densest assembly of bacteria and appears to influence the immune system in the context of inflammatory arthropathies. Although studies are still sparse, this review will examine the role of the microbiome in the pathogenesis of spondyloarthritis (SpA), particularly in enteropathic arthritis (EA), reactive arthritis (ReA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA).

OBJECTIVE: To characterize the diversity and taxonomic relative abundance of the gut microbiota in patients with never-treated, recent-onset psoriatic arthritis (PsA). METHODS: High-throughput 16S ribosomal RNA pyrosequencing was utilized to compare the community composition of gut microbiota in patients with PsA (n = 16), patients with psoriasis of the skin (n = 15), and healthy, matched control subjects (n = 17). Samples were further assessed for the presence and levels of fecal and serum secretory IgA (sIgA), proinflammatory proteins, and fatty acids. RESULTS: The gut microbiota observed in patients with PsA and patients with skin psoriasis was less diverse when compared to that in healthy controls. This could be attributed to the reduced presence of several taxa. Samples from both patient groups showed a relative decrease in abundance of Coprococcus species, while samples from PsA patients were also characterized by a significant reduction in Akkermansia, Ruminococcus, and Pseudobutyrivibrio. Supernatants of fecal samples from PsA patients revealed an increase in sIgA levels and decrease in RANKL levels. Analysis of fatty acids revealed low fecal quantities of hexanoate and heptanoate in both patients with PsA and patients with psoriasis. CONCLUSION: Patients with PsA and patients with skin psoriasis had a lower relative abundance of multiple intestinal bacteria. Although some genera were concomitantly decreased in both conditions, PsA samples had a lower abundance of reportedly beneficial taxa. This gut microbiota profile in PsA was similar to that previously described in patients with inflammatory bowel disease and was associated with changes in specific inflammatory proteins unique to this group, and distinct from that in patients with skin psoriasis and healthy controls. Thus, the role of the gut microbiome in the continuum of psoriasis-PsA pathogenesis and the associated immune response merits further study.