Berberine ameliorates collagen-induced arthritis in rats by suppressing Th17 cell responses via inducing cortistatin in the gut

Berberine, an isoquinoline alkaloid, has been reported to ameliorate various autoimmune diseases including rheumatoid arthritis by oral administration. However, its mechanism remains mysterious due to an extremely low bioavailability. The fact that berberine is easy to accumulate in gut, the largest endocrine organ in the body, attracts us to explore its anti-arthritic mechanism in view of the induction of intestinal immunosuppressive neuropeptides. In this study, berberine (200 mg/kg, i.g.) was shown to ameliorate collagen-induced arthritis in rats, which was manifested by the reduction of clinical signs and joint destruction, as well as marked down-regulation of Th17 cell frequency and IL-17 level in blood. In contrast, an intravenous injection of berberine failed to affect the arthritis in rats, implying that its anti-arthritic effect was gut-dependent. Further studies revealed that oral berberine selectively elevated the levels of cortistatin in the intestines and sera of arthritis rats among the five gut-derived neuropeptides tested. The antagonists of GHSR1 (a subtype of cortistatin receptor) almost completely abolished the amelioration of berberine on arthritis and Th17 cell responses in rats. In vitro, berberine showed a moderate ability to promote the expression of cortistatin in nerve cells, which was strengthened when the nerve cells were co-cultured with enteroendocrine cells to induce an autocrine/paracrine environment. In summary, oral berberine exerted anti-arthritic effect through inhibiting Th17 cell response, which was closely associated with the induction of cortistatin generation from gut through augmenting autocrine/paracrine between enteric nerve cells and endocrine cells. This article is protected by copyright. All rights reserved.