Abstract:
:Previously, we reported that oral administration of madecassoside, the main active triterpene in Centella asiatica L., exerted anti-arthritis effect by inducing the generation of regulatory T (Treg) cells in small intestine. This study investigates the action site and mechanism of madecassoside to induce Treg cells. In collagen-induced arthritis (CIA) of rats, oral administration of madecassoside significantly alleviated arthritis symptoms, but its main metabolite madecassic acid did not, suggesting that madecassoside functions in the parent form. Madecassoside was shown to increase the number of Treg cells and promote the expression of Foxp3 and IL-10 in rat ileum rather than duodenum and jejunum, as detected using the immunohistochemistry assay and quantitative PCR assay, respectively. Unexpectedly, madecassoside was absent of significant effect on in vitro Treg cell differentiation and the expression of Foxp3 and IL-10. A combined use of broad-spectrum antibiotics resulted in significant reduction of the anti-arthritis effect of madecassoside in CIA rats. The 16S rRNA gene sequence showed that madecassoside could reverse the changes of gut microbiota under arthritis condition, and enrich several bacteria such as Lachnospiraceae, Butyricicoccus, Faecalibacterium, Butyricicoccus pullicaecorum and so on. GC-MS assay showed that madecassoside elevated the levels of acetic acid and butyric acid, but not other short chain fatty acids (SCFAs) in the cecum contents of CIA rats. Butyric acid rather than acetic acid could induce the in vitro differentiation of Treg cells and the expression of Foxp3 and IL-10. Accordingly, when madecassoside was co-administered with heptanoyl CoA, the competitive inhibitor of butyrate synthase, its effect on butyric acid production, Treg cell proportion and arthritis nearly disappeared. These findings indicate that oral madecassoside induces the generation of Treg cells and therefore displays anti-arthritis effect in the parent form but not metabolites, and the ileum is the main action site. The mechanism of madecassoside can be summarized as: expansion of the richness of butyrate-producing bacteria-up-regulation of intestinal butyrate level-induction of Treg cell differentiation and IL-10 expression.
journal_name
Int Immunopharmacoljournal_title
International immunopharmacologyauthors
Qiao S,Lian X,Yue M,Zhang Q,Wei Z,Chen L,Xia Y,Dai Ydoi
10.1016/j.intimp.2020.107047subject
Has Abstractpub_date
2020-12-01 00:00:00pages
107047issue
Pt Aeissn
1567-5769issn
1878-1705pii
S1567-5769(20)33086-1journal_volume
89pub_type
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