Abstract
Gut microbiota and their influence on metabolites are receiving increasing attentions in autoimmune diseases including rheumatoid arthritis (RA). Probiotics become a promising manipulator to prevent or attenuate the progression of arthritis, some evidences suggesting that lactobacilli treatment influence the responses to RA therapy but the underlying mechanisms are limited. By using a collagen-induced arthritis (CIA) rats, the study assessed the effects of two L. casei strains (CCFM1074, CCFM1075) on the immune responses, gut microbiota and plasma metabolites via an integrated cross-omics approach including fecal 16S rRNA high-throughput sequencing and plasma metabolomics. The genome of the two strains was analyzed and compared using whole-genome sequencing approach to further confirm biology functions. CCFM1074 reduced arthritic symptoms while CCFM1075 did not, though both strains down-regulated the plasma IL-6 and Th17 cells proportion. CCFM1074 enhanced the proportion of Treg cells in mesenteric lymph nodes which was significantly associated with SCFAs upregulation, as well as with genomic evidence that CCFM1074 possesses more functional genes involved in carbohydrate metabolism. Moreover, CCFM1074 regulated the gut microbiota, including modulating community structure, decreasing the abundance of Alistipes and Parabacteroides and increasing the abundance of Oscillibacter. The differential metabolites modulated by CCFM1074 including eicosapentaenoic acid and docosapentaenoic acid which involved in unsaturated fatty acids metabolism. Furthermore, alterations of gut microbial community were correlated with the plasma metabolome. In summary, L. casei CCFM1074 alleviated arthritis via rebalancing gut microbiota, immune responses and plasma metabolites.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune-mediated inflammatory disorder characterized by synovitis and joint destruction
After 8-week intervention, the rats orally administered with CCFM1074 or MTX revealed less aggravated redness and swollen in paw, while rats in CCFM1075 group showed an indistinctive phenotype comprised with those in model group, in the changes of body weight
The results of micro-CT showed that both CCFM1074 and CCFM1075 reduced the bone erosion in ankles, the micro-CT image showed an intact joint architecture and smooth bone surface in CCFM1074 and CCFM1075 treated rats, whereas the joint in collagen-induced arthritis (CIA) rats presents with compromised joint integrity (Figure 1E)
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune-mediated inflammatory disorder characterized by synovitis and joint destruction. In addition to genetic and environmental factors responsible for the development of RA, there is clear and strong evidence for an involvement of gut microbiota in RA progression. This is supported by facts that dysbiosis of gut microbiota preceded RA symptoms, Prevotella copri strongly correlated with disease, and the perturbation was normalized after methotrexate treatment [1,2,3]. Transplantation of fecal microbiota from RA patients aggravates arthritis in collagen-induced arthritis (CIA) mice, further demonstrating that dysbiosis in gut microbiota are a result of the disease, and a reason for the progression of RA [5]. Investigations on gut microbiota suggest probiotics might be an alternative therapeutic target to prevent or attenuate arthritis
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