The change of plasma metabolic profile and gut microbiome dysbiosis in patients with rheumatoid arthritis

Abstract

ObjectiveRheumatoid arthritis (RA) is a chronic inflammatory joint disease, which is associated with progressive disability, systemic complications, and early death. But its etiology and pathogenesis are not fully understood. We aimed to investigate the alterations in plasma metabolite profiles, gut bacteria, and fungi and their role of them in the pathogenesis of RA.MethodsMetabolomics profiling of plasma from 363 participants including RA (n = 244), systemic lupus erythematosus (SLE, n = 50), and healthy control (HC, n = 69) were performed using the ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry. The differentially expressed metabolites were selected among groups and used to explore important metabolic pathways. Gut microbial diversity analysis was performed by 16S rRNA sequencing and ITS sequencing (RA = 195, HC = 269), and the specific microbial floras were identified afterward. The diagnosis models were established based on significant differential metabolites and microbial floras, respectively.ResultsThere were 63 differential metabolites discovered between RA and HC groups, mainly significantly enriched in the arginine and proline metabolism, glycine, serine, and threonine metabolism, and glycerophospholipid metabolism between RA and HC groups. The core differential metabolites included L-arginine, creatine, D-proline, ornithine, choline, betaine, L-threonine, LysoPC (18:0), phosphorylcholine, and glycerophosphocholine. The L-arginine and phosphorylcholine were increased in the RA group. The AUC of the predictive model was 0.992, based on the combination of the 10 differential metabolites. Compared with the SLE group, 23 metabolites increased and 61 metabolites decreased in the RA group. However, no significant metabolic pathways were enriched between RA and SLE groups. On the genus level, a total of 117 differential bacteria genera and 531 differential fungal genera were identified between RA and HC groups. The results indicated that three bacteria genera (Eubacterium_hallii_group, Escherichia-Shigella, Streptococcus) and two fungal genera (Candida and Debaryomyces) significantly increased in RA patients. The AUC was 0.80 based on a combination of six differential bacterial genera and the AUC was 0.812 based on a combination of seven differential fungal genera. Functional predictive analysis displayed that differential bacterial and differential fungus both were associated with KEGG pathways involving superpathway of L-serine and glycine biosynthesis I, arginine, ornithine, and proline interconversion.ConclusionThe plasma metabolism profile and gut microbe profile changed markedly in RA. The glycine, serine, and threonine metabolism and arginine and proline metabolism played an important role in RA.

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“…Desulfurizing bacteria, Bacteroides, and Streptococcus still play dangerous roles, as discussed earlier. In the results of this study, the Eubacterium hallii group is considered a risk factor for AD, which has been proven in many autoimmune diseases such as Hashimoto’s thyroiditis ( 62 ), clear cell renal cell carcinoma ( 63 ), rheumatoid arthritis (RA) ( 64 ). Eubacterium hallii group and Lachnospiraceae UCG001 belong to the Lachnospiraceae family and can both produce butyrate and participate in the metabolism of amino acids and lipids.…”

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“…Findings from studies in vitro and in vivo further suggest that choline metabolism is activated in RA fibroblast-like synoviocytes under proinflammatory conditions and that selective blocking of choline kinase might be beneficial in inflammatory arthritis (27). Contrasting these observations, levels of serum choline have been reported to be inversely related with RA disease activity defined by DAS28 (28) and associated with beneficial response to MTX (29).…”

Inflammation and Organic Cation Transporters Novel (OCTNs)

“…Conversely, other studies conducted using rats with Collagen-Induced Arthritis (CIA), an autoimmune disease model that shares features with RA, showed reduced levels of choline in CIA rats compared to the control [128]. A decrease in plasma or blood choline levels was also described in studies that recruited human RA patients [129,130]. Choline decrease may be due to an increased choline uptake and consumption by the inflamed synovium [130,131].…”