Analysis of Gut Microbiota in Rheumatoid Arthritis Patients: Disease-Related Dysbiosis and Modifications Induced by Etanercept

Andrea Picchianti-Diamanti,Maria Sorgi,Roberta Di Rosa,Fulvia Terracciano,Concetta Panebianco,Simonetta Salemi,Gerardo Salerno,Valerio Pazienza,Mayla Sgrulletti,Alessandro Tropea,Bruno Laganà,Raffaele D’Amelio

doi:10.3390/ijms19102938

Abstract

A certain number of studies were carried out to address the question of how dysbiosis could affect the onset and development of rheumatoid arthritis (RA), but little is known about the reciprocal influence between microbiota composition and immunosuppressive drugs, and how this interaction may have an impact on the clinical outcome. The aim of this study was to characterize the intestinal microbiota in a groups of RA patients treatment-naïve, under methotrexate, and/or etanercept (ETN). Correlations between the gut microbiota composition and validated immunological and clinical parameters of disease activity were also evaluated. In the current study, a 16S analysis was employed to explore the gut microbiota of 42 patients affected by RA and 10 healthy controls. Disease activity score on 28 joints (DAS-28), erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, anti-cyclic citrullinated peptides, and dietary and smoking habits were assessed. The composition of the gut microbiota in RA patients free of therapy is characterized by several abnormalities compared to healthy controls. Gut dysbiosis in RA patients is associated with different serological and clinical parameters; in particular, the phylum of Euryarchaeota was directly correlated to DAS and emerged as an independent risk factor. Patients under treatment with ETN present a partial restoration of a beneficial microbiota. The results of our study confirm that gut dysbiosis is a hallmark of the disease, and shows, for the first time, that the anti-tumor necrosis factor alpha (TNF-α) ETN is able to modify microbial communities, at least partially restoring a beneficial microbiota.

Highlights

The human intestinal microbiota is a complex microcosm composed of more than 1000 different bacterial species, archaea, fungi, and viruses [1]
A certain number of studies were carried out to address the question of how dysbiosis could affect the onset and development of rheumatoid arthritis (RA), but little is known about the reciprocal influence between microbiota composition and immunosuppressive drugs, and how this interaction may have an impact on the clinical outcome
The assessment of the Shannon index in each sample revealed that α-diversity was neither changed in naïve patients compared with the healthy subjects were used as controls (HCs), nor in each treatment group relative to patients free of therapy (Figure 1A)

Summary

Introduction

The human intestinal microbiota is a complex microcosm composed of more than 1000 different bacterial species, archaea, fungi, and viruses [1]. Recent advances in sequencing technologies led to a deep characterization of the human gut microbiota in healthy subjects. This enabled the investigation of modifications in the structure of gut commensal communities (called dysbiosis), which could be involved in the onset and maintenance of different chronic autoimmune diseases, such as inflammatory bowel diseases (IBD) and arthritis [5,6]. Dysbiosis could lead to alterations in the intestinal epithelial cell layer with an increased exposure to a variety of bacteria and bacterial products leading to a chronic antigenic stimulation, spreading of inflammatory mediators, and T cell activation [7,8]. It was recently demonstrated that different environmental factors are involved in the development of both intestinal/oral dysbiosis and arthritis onset and outcome, among which the most relevant are diet, smoking, infections, and drugs [9,10,11,12]

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