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Regional Differences in the Gut Microbiota and Gut-Associated Immunologic Factors in the Ileum and Cecum of Rats With Collagen-Induced Arthritis

ABSTRACT: Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation and a multifactorial etiology. We previously showed that gut microbiota dysbiosis in the rat ileum is involved in the development of collagen-induced arthritis (CIA). The gut microbiota in the distinct gastrointestinal tract (GIT) plays region-specific roles, but information on the different roles of the microbiota in distinct GIT compartments of CIA rats is limited. This study aimed to evaluate the region-specific differences in the gut microbial communities and certain gut-associated immunologic factors in the ileum and cecum of CIA rats. Ileal and cecal digesta were collected from CIA and control rats for microbiome analysis. We determined the microbial richness, diversity and taxa as well as the expression of interleukin (IL)-1? and IL-17A in the epithelium and lamina propria of the ileum and cecum mucosal layers. The CIA-induced microbiota alterations in the ileum differed from those in the cecum. The ileal microbiota were more markedly influenced in CIA, as revealed by sharp reductions in the abundances of the families Enterococcaceae, Lactobacillaceae and Streptococcaceae and the genera Lactobacillus and Lactococcus. Moreover, significant increases in IL-1?, and IL-17A mRNA expression were detected in only the ileal epithelium and lamina propria of the mucosal layer. Therefore, the microbial characteristics in the ileum were consistent with the immune-mediated inflammatory features of CIA, suggesting that the ileal microbiota might better represent the CIA-induced inflammatory responses than the cecal microbiota and that these responses might partially impact the progression of RA by regulating intestinal mucosal immunity.

SUBMITTER: Xu H

PROVIDER: S-EPMC7797777 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:Acarose is an anti-diabetic drug and exhibits anti-arthritic effects. We hypothesized that acarbose influences the gut microbiota to affect the course of arthritis and tested this hypothesis in a collagen-induced arthritis (CIA) murine model. Acarbose in drinking water was administered via gastric gavage started prior to or at the time of CIA induction. Gut microbiota were evaluated with 16S rRNA gene sequencing from fecal pellets collected prior to arthritis induction, during onset of arthritis, and after treatment. Immune response was evaluated by measuring changes in T helper-17 (Th17) and T regulatory (Treg) cells in the spleen and intestine, as well as serum cytokine levels. Before induction of CIA, acarbose significantly reduced the incidence of arthritis and attenuated clinical severity of arthritis. The frequency of Th17 cells was significantly decreased in the intestinal lamina propria in acarbose treated mice. Mice that were treated with acarbose showed significantly increased CD4+CD25+Foxp3+ Treg cells with elevation of Helios and CCR6. A remarkable alteration in microbial community was observed in acarbose treated mice. Bacterial diversity and richness in mice with arthritis were significantly lower than those in acarbose treated groups. The frequency of Firmicutes was significantly reduced after arthritis onset but was restored after treatment with acarbose. The frequency of Lactobacillus, Anaeroplasma, Adlercreutzia, RF39 and Corynebacterium was significantly higher in control groups than in acarbose treated, while Oscillospira, Desulfovibrio and Ruminococcus enriched in acarbose treated group. Miglitol, another α-glucosidase inhibitor showed a similar but less potent anti-arthritic effect to that of acarbose. These data demonstrate that acarbose alleviated CIA through regulation of Th17/Treg cells in the intestinal mucosal immunity, which may have resulted from the impact of acarbose on gut microbial community. Inexpensive antidiabetic drugs with an excellent safety profile are potentially useful for managing rheumatoid arthritis.

Project description:Rheumatoid arthritis (RA) is a common autoimmune disease linked to chronic inflammation. Dysbiosis of the gut microbiota has been proposed to contribute to the risk of RA, and a large number of researchers have investigated the gut-joint axis hypothesis using the collagen-induced arthritis (CIA) rats. However, previous studies mainly involved short-term experiments; very few used the CIA model to investigate changes in gut microbiota over time. Moreover, previous research failed to use the CIA model to carry out detailed investigations of the effects of drug treatments upon inflammation in the joints, hyperplasia of the synovium, imbalance in the ratios of Th1/Th2 and Th17/Treg cells, intestinal cytokines and the gut microbiota following long-term intervention. In the present study, we carried out a 16-week experiment to investigate changes in the gut microbiota of CIA rats, and evaluated the modulatory effect of total glucosides of paeony (TGP), an immunomodulatory agent widely used in the treatment of RA, after 12 weeks of administration. We found that taxonomic differences developed in the microbial structure between the CIA group and the Control group. Furthermore, the administration of TGP was able to correct 78% of these taxonomic differences, while also increase the relative abundance of certain forms of beneficial symbiotic bacteria. By the end of the experiment, TGP had reduced body weight, thymus index and inflammatory cell infiltration in the ankle joint of CIA rats. Furthermore, the administration of TGP had down-regulated the synovial content of VEGF and the levels of Th1 cells and Th17 cells in CIA rats, and up-regulated the levels of Th2 cells and Treg cells. The administration of TGP also inhibited the levels of intestinal cytokines, secretory immunoglobulin A (SIgA) and Interferon-γ (IFN-γ). In conclusion, the influence of TGP on dynamic changes in gut microbiota, along with the observed improvement of indicators related to CIA symptoms during 12 weeks of administration, supported the hypothesis that the microbiome may play a role in TGP-mediated therapeutic effects in CIA rats. The present study also indicated that the mechanism underlying these effects may be related to the regulation of intestinal mucosal immunity remains unknown and deserves further research attention.

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Regional Differences in the Gut Microbiota and Gut-Associated Immunologic Factors in the Ileum and Cecum of Rats With Collagen-Induced Arthritis

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