Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects the joints. Microbial infection is considered a crucial inducer of RA. Alterations in the composition of intestinal bacteria in individuals with preclinical and established RA suggest a vital role of the gut microbiota in immune dysfunction characteristic of RA. However, the mechanisms by which gut dysbiosis contributes to RA are not fully understood. Furthermore, multiple therapies commonly used to treat RA may alter gut microbiota diversity, suggesting that modulating the gut microbiota may help prevent or treat RA. Hence, a better understanding of the changes in the gut microbiota that accompany RA should aid the development of novel therapeutic approaches. This mini-review discusses the impact of gut dysbiosis in the pathogenesis of RA, the selection of gut microbiota-related biomarkers for diagnosing RA, and provides examples of cross-modulation between the gut microbiota and some drugs commonly used to treat RA. Some suggestions and outlooks are also raised, which may help guide future research efforts.

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Gut microbiota and rheumatoid arthritis: From pathogenesis to novel therapeutic opportunities

Abstract Metabolic abnormalities lead to the dysfunction of metabolic pathways and metabolite accumulation or deficiency which is well-recognized hallmarks of diseases. Metabolite signatures that have close proximity to subject’s phenotypic informative dimension, are useful for predicting diagnosis and prognosis of diseases as well as monitoring treatments. The lack of early biomarkers could lead to poor diagnosis and serious outcomes. Therefore, noninvasive diagnosis and monitoring methods with high specificity and selectivity are desperately needed. Small molecule metabolites-based metabolomics has become a specialized tool for metabolic biomarker and pathway analysis, for revealing possible mechanisms of human various diseases and deciphering therapeutic potentials. It could help identify functional biomarkers related to phenotypic variation and delineate biochemical pathways changes as early indicators of pathological dysfunction and damage prior to disease development. Recently, scientists have established a large number of metabolic profiles to reveal the underlying mechanisms and metabolic networks for therapeutic target exploration in biomedicine. This review summarized the metabolic analysis on the potential value of small-molecule candidate metabolites as biomarkers with clinical events, which may lead to better diagnosis, prognosis, drug screening and treatment. We also discuss challenges that need to be addressed to fuel the next wave of breakthroughs. 

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Small molecule metabolites: discovery of biomarkers and therapeutic targets

Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint destruction, synovitis, and pannus formation. Gut microbiota dysbiosis may exert direct pathogenic effects on gut homeostasis. It may trigger the host’s innate immune system and activate the “gut–joint axis”, which exacerbates the RA. However, although the importance of the gut microbiota in the development and progression of RA is widely recognized, the mechanisms regulating the interactions between the gut microbiota and the host immune system remain incompletely defined. In this review, we discuss the role of gut microbiota-derived biological mediators, such as short-chain fatty acids, bile acids, and tryptophan metabolites, in maintaining intestinal barrier integrity, immune balance and bone destruction in RA patients as the bridge of the gut–joint axis.

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The bridge of the gut–joint axis: Gut microbial metabolites in rheumatoid arthritis

Pregnancy-related complications in systemic lupus erythematosus.

Gut microbiota in pre-clinical rheumatoid arthritis: From pathogenesis to preventing progression.

The relationship among the gut microbiome, global fecal metabolites and rheumatoid arthritis (RA) has not been systematically evaluated. In this study, we performed 16S rDNA sequencing and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based nontargeted metabolomic profiling on feces of 26 untreated RA patients and 26 healthy controls. Twenty-six genera and forty-one MS2-identified metabolites were significantly altered in the RA patients. Klebsiella, Escherichia, Eisenbergiella and Flavobacterium were more abundant in the RA patients, while Fusicatenibacter, Megamonas and Enterococcus were more abundant in the healthy controls. Function prediction analysis demonstrated that the biosynthesis pathways of amino acids, such as L-arginine and aromatic amino acids, were depleted in the RA group. In the metabolome results, fecal metabolites including glycerophospholipids (PC(18:3(9Z,12Z,15Z)/16:1(9Z)), lysoPE 19:1, lysoPE 18:0, lysoPC(18:0/0:0)), sphingolipids (Cer(d18:0/16:0), Cer(d18:0/12:0), Cer(d18:0/14:0)), kynurenic acid, xanthurenic acid and 3-hydroxyanthranilic acid were remarkably altered between the RA patients and healthy controls. Dysregulation of pathways, such as tryptophan metabolism, alpha-linolenic acid metabolism and glycerophospholipid metabolism, may contribute to the development of RA. Additionally, we revealed that the gut microbiome and metabolites were interrelated in the RA patients, while Escherichia was the core genus. By depicting the overall landscape of the intestinal microbiome and metabolome in RA patients, our study could provide possible novel research directions regarding RA pathogenesis and targeted therapy.

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The Gut Microbiome and Metabolites Are Altered and Interrelated in Patients With Rheumatoid Arthritis

Nuclear-factor, interleukin 3 regulated (NFIL3) is an immune regulator that plays an essential role in autoimmune diseases. However, the relationship between rheumatoid arthritis (RA) and NFIL3 remains largely unknown. In this study, we examined NFIL3 expression in RA patients and its potential molecular mechanisms in RA. Increased NFIL3 expression levels were identified in peripheral blood mononuclear cells (PBMCs) from 62 initially diagnosed RA patients and 75 healthy controls (HCs) by quantitative real-time PCR (qRT-PCR). No correlation between NFIL3 and disease activity was observed. In addition, NFIL3 expression was significantly upregulated in RA synovial tissues analyzed in the Gene Expression Omnibus (GEO) dataset (GSE89408). Then, we classified synovial tissues into NFIL3-high (≥75%) and NFIL3-low (≤25%) groups according to NFIL3 expression levels. Four hundred five differentially expressed genes (DEGs) between the NFIL3-high and NFIL3-low groups were screened out using the “limma” R package. Enrichment analysis showed that most of the enriched genes were primarily involved in the TNF signaling pathway via NFκB, IL-17 signaling pathway, and rheumatoid arthritis pathways. Then, 10 genes (IL6, IL1β, CXCL8, CCL2, PTGS2, MMP3, MMP1, FOS, SPP1, and ADIPOQ) were identified as hub genes, and most of them play a key role in RA. Positive correlations between the hub genes and NFIL3 were revealed by qRT-PCR in RA PBMCs. An NFIL3-related protein–protein interaction (PPI) network was constructed using the STRING database, and four clusters (mainly participating in the inflammatory response, lipid metabolism process, extracellular matrix organization, and circadian rhythm) were constructed with MCODE in Cytoscape. Furthermore, 29 DEGs overlapped with RA-related genes from the RADB database and were mainly enriched in IL-17 signaling pathways. Thus, our study revealed the elevated expression of NFIL3 in both RA peripheral blood and synovial tissues, and the high expression of NFIL3 correlated with the abnormal inflammatory cytokines and inflammatory responses, which potentially contributed to RA progression.

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Shaobiao Pan

Papers

The Gut Microbiome and Metabolites Are Altered and Interrelated in Patients With Rheumatoid Arthritis

NFIL3 and its immunoregulatory role in rheumatoid arthritis patients