An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis

Abstract

BackgroundThe adaptive immune response in rheumatoid arthritis (RA) is influenced by an interaction between host genetics and environment, particularly the host microbiome. Association of the gut microbiota with various diseases has been reported, though the specific components of the microbiota that affect the host response leading to disease remain unknown. However, there is limited information on the role of gut microbiota in RA. In this study we aimed to define a microbial and metabolite profile that could predict disease status. In addition, we aimed to generate a humanized model of arthritis to confirm the RA-associated microbe.MethodsTo identify an RA biomarker profile, the 16S ribosomal DNA of fecal samples from RA patients, first-degree relatives (to rule out environment/background as confounding factors), and random healthy non-RA controls were sequenced. Analysis of metabolites and their association with specific taxa was performed to investigate a potential mechanistic link. The role of an RA-associated microbe was confirmed using a human epithelial cell line and a humanized mouse model of arthritis.ResultsPatients with RA exhibited decreased gut microbial diversity compared with controls, which correlated with disease duration and autoantibody levels. A taxon-level analysis suggested an expansion of rare taxa, Actinobacteria, with a decrease in abundant taxa in patients with RA compared with controls. Prediction models based on the random forests algorithm suggested that three genera, Collinsella, Eggerthella, and Faecalibacterium, segregated with RA. The abundance of Collinsella correlated strongly with high levels of alpha-aminoadipic acid and asparagine as well as production of the proinflammatory cytokine IL-17A. A role for Collinsella in altering gut permeability and disease severity was confirmed in experimental arthritis.ConclusionsThese observations suggest dysbiosis in RA patients resulting from the abundance of certain rare bacterial lineages. A correlation between the intestinal microbiota and metabolic signatures could determine a predictive profile for disease causation and progression.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0299-7) contains supplementary material, which is available to authorized users.

The role of the gastrointestinal tract in the pathogenesis of rheumatic diseases

“…In this study, three genera, Collinsella, Eggerthella, and Faecalibacterium, were found to be associated with RA; abundance of Collinsella was strongly correlated with the production of the proinflammatory cytokine IL-17A [16]. The role of Collinsella in altering gut permeability and disease severity has been confirmed in experimental arthritis [16]. A more recent study evaluated human fecal Lactobacillus community and its relationship with RA [17].…”

“…On the one hand, there is much evidence that supports the association between RA and the intestinal microbiota; bacteria such as Mycoplasma fermentans [12], Escherichia coli [13], and Proteus mirabilis [14] have been reported to initiate the disease. On the other hand, it has been demonstrated that gastrointestinal and urogenital infections are associated with a significantly lowered risk of RA [15] and that patients with RA exhibit decreased gut microbial diversity compared with controls [16]. In particular, it has been proved that expansion of rare taxa such as Actinobacteria along with decrease in abundant taxa occur in patients with RA compared with controls [16].…”

“…On the other hand, it has been demonstrated that gastrointestinal and urogenital infections are associated with a significantly lowered risk of RA [15] and that patients with RA exhibit decreased gut microbial diversity compared with controls [16]. In particular, it has been proved that expansion of rare taxa such as Actinobacteria along with decrease in abundant taxa occur in patients with RA compared with controls [16]. In this study, three genera, Collinsella, Eggerthella, and Faecalibacterium, were found to be associated with RA; abundance of Collinsella was strongly correlated with the production of the proinflammatory cytokine IL-17A [16].…”

“…In particular, it has been proved that expansion of rare taxa such as Actinobacteria along with decrease in abundant taxa occur in patients with RA compared with controls [16]. In this study, three genera, Collinsella, Eggerthella, and Faecalibacterium, were found to be associated with RA; abundance of Collinsella was strongly correlated with the production of the proinflammatory cytokine IL-17A [16]. The role of Collinsella in altering gut permeability and disease severity has been confirmed in experimental arthritis [16].…”

The human gut microbiome as source of innovation for health: Which physiological and therapeutic outcomes could we expect?

“…This was the case for instance in obesity, COPD, pancreatitis, chronic inflammatory arthritis and non alcoholic fatty liver disease (NAFLD) [53][54][55][56][57]. In this last disease, the presence of selected bacterial DNA, identified through gut MWAS, was retrieved in patient blood samples and is a way to get a simple and less invasive disease biomarker to replace liver biopsies [58].…”