Alteration of Gut Microbiota in Individuals at High‐Risk for Rheumatoid Arthritis Associated With Disturbed Metabolome and the Initiation of Arthritis Through the Triggering of Mucosal Immunity Imbalance

Abstract

ObjectiveWe aimed to decipher the gut microbiome (GM) and serum metabolic characteristic of individuals at high risk for rheumatoid arthritis (RA) and to investigate the causative effect of GM on the mucosal immune system and its involvement in the pathogenesis of arthritis.DesignFecal samples were collected from 38 healthy individuals (HCs) and 53 high‐risk RA individuals with anti‐citrullinated protein antibody (ACPA)‐positivity (PreRA), 12 of 53 PreRA developed RA within 5 years of follow‐up. The differences in intestinal microbial composition between the HC and PreRA individuals or among PreRA subgroups were identified by 16S rRNA sequencing. The serum metabolite profile and its correlation with GM were also explored. Moreover, antibiotic‐pretreated mice received GM from the HC or PreRA groups were then evaluated for intestinal permeability, inflammatory cytokines and immune cell populations. Collagen‐induced arthritis (CIA) was also applied to test the effect of fecal microbiota transplantation (FMT) from PreRA individuals on arthritis severity in mice.ResultsStool microbial diversity was lower in PreRA individuals than in HCs. The bacterial community structure and function significantly differed between HC and PreRA individuals. Although there were to some extent differences in the bacterial abundance among the PreRA subgroups, no robust functional differences were observed. The metabolites in the serum of the PreRA group were dramatically different from those in the HC group, with KEGG pathway enrichment of amino acid and lipid metabolism. Moreover, intestinal bacteria from the PreRA group increased intestinal permeability in FMT mice and ZO‐1 expression in the small intestine and Caco‐2 cells. Moreover, Th17 cells in the mesenteric lymph nodes and Peyer's patches were also increased in mice receiving PreRA feces compared to HC. The changes in intestinal permeability and Th17‐cell activation prior to arthritis induction enhanced CIA severity in PreRA‐FMT mice compared with HC‐FMT mice.ConclusionGut microbial dysbiosis and metabolome alterations already occur in individuals at high risk for RA. FMT from preclinical individuals triggers intestinal barrier dysfunction and changes mucosal immunity, further contributing to arthritis development.

Research Progress of Intestinal Flora and Related Diseases

“…The intestinal permeability and expression of ZO-2 in the small intestine and Caco-1 cells of mice transplanted with intestinal flora from high-risk RA patients were increased. Th17 cells in mesenteric lymph nodes and Peyer's plaques increased, which further contributed to the development of arthritis, 6 and structurally and functionally altered gut microbiota in RA patients, 79 and the gut microbiota structure was altered after oral administration of Porphyromonas gingivalis in mice, aggravating collagen-induced arthritis. 80 And RA model mice can exert its protective effect on RA mice by maintaining the normal intestinal microbiota of arthritis mice after taking tuftsin-phosphocholine.…”

Research

“…Although it differs slightly from the usual paper on orthopaedic conditions, this fascinating piece of research from Sichuan (China) provided valuable insights into the pathogenesis of bone and joint diseases. 1 Generally, such inflammatory diseases are known to develop due to an autoimmune disorder. The gut microbiome (GM) is known to have a profound immunoregulatory effect.…”

Microbiota-dependent indole production is required for the development of collagen-induced arthritis

“…Except for a small, but significant, difference in IL-1β at CIA day 14 in the TL+Indole group compared to TL+Vehicle (Figure 4A), there were no significant differences between groups in any of the cytokines measured at CIA days 14 and 21 (prior to arthritis onset). However, by the plateau of disease (CIA day [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50], the TL+Vehicle diet resulted in a significant reduction in IL-1β and IL-6, with significantly increased IL-10 compared to mice on the TS+Vehicle diet at CIA day 35+, but not at earlier timepoints (days 14 and 21) (Figure 4A-C).…”

“…However, the mechanism(s) by which the microbiome drives these inflammatory processes have not been identified. Observations of altered bacterial metabolomes have been described in both murine models of autoimmunity and in patients with autoimmunity [35][36][37][38][39], leading us to hypothesize that certain (yet unidentified) intestinal microbial metabolite(s) would play a key role in the development of CIA. We identified alterations in Tryptophan (Trp) metabolism in CIA in a microbiome-dependent manner, with a significant increase in indole (a bacterial-derived Trp metabolite) production in mice with CIA compared to unimmunized mice and antibioticprotected CIA mice.…”