Abstract
The imbalance between Th17 and Treg cells substantially contributes to the intestinal immune disturbance and subsequent tissue injury in ulcerative colitis. The triterpenoid-rich fraction of Centella asiatica was able to ameliorate dextran sulfate sodium-induced colitis in mice. Here we explored its active ingredient and underlying mechanism with a focus on restoring the Th17/Treg balance. The four main triterpenoids occurring in C. asiatica were shown to attenuate colitis in mice by oral administration. The most effective ingredient madecassoside lost anti-colitis effect when applied topically in the colon, and madecassic acid was recognized to be the active form of madecassoside. Oral administration of madecassic acid decreased the percentage of Th17 cells and downregulated the expression of RORγt, IL-17A, IL-17F, IL-21 and IL-22 and increased the percentage of Treg cells and the expression of Foxp3 and IL-10 in the colons of mice with colitis, but it did not affect Th1 and Th2 cells. Under Th17-polarizing conditions, madecassic acid downregulated ACC1 expression and enhanced the shift of Th17 cells toward Treg cells, but it did not affect the differentiation of Treg cells under Treg-polarizing conditions. Both compound C and AMPK siRNA inhibited the madecassic acid-mediated downregulation of ACC1 expression and shift of Th17 cells to Treg cells under Th17-polarizing conditions. GW9662, T0070907 and PPARγ siRNA blocked the effect of madecassic acid on AMPK activation, ACC1 expression and shift of Th17 cells to Treg cells. Furthermore, madecassic acid was identified as a PPARγ agonist, as it promoted PPARγ transactivation. The correlation between activation of PPARγ and AMPK, downregulation of ACC1 expression, restoration of Th17/Treg balance and attenuation of colitis by madecassic acid was validated in mice with DSS-induced colitis. In conclusion, madecassic acid was the active form of madecassoside in ameliorating colitis by restoring the Th17/Treg balance via regulating the PPARγ/AMPK/ACC1 pathway.
Highlights
Ulcerative colitis (UC) is a debilitating syndrome characterized by colonic mucosal ulceration, abdominal pain and intestinal barrier dysfunction.[1,2] Immune system dysfunction, an imbalance of Th17 cells and Treg cells, contributes substantially to the occurrence and development of UC.[3,4,5] An excess of Th17 cells and insufficient Treg cells result in persistent immune dysfunction and sustained intestinal inflammation.[6,7,8] restoring the balance of Th17/ Treg cells may be a practical therapeutic strategy for treating UC
To clarify the active ingredients for the anticolitis effect of C. asiatica, four major pentacyclic triterpenes isolated from the plant and cyclosporin A were orally administered to dextran sulfate sodium (DSS)-treated mice for 10 days
These findings revealed that the primary active ingredient madecassoside acted through the intestinal metabolite madecassic acid in ameliorating colitis in mice
Summary
Ulcerative colitis (UC) is a debilitating syndrome characterized by colonic mucosal ulceration, abdominal pain and intestinal barrier dysfunction.[1,2] Immune system dysfunction, an imbalance of Th17 cells and Treg cells, contributes substantially to the occurrence and development of UC.[3,4,5] An excess of Th17 cells and insufficient Treg cells result in persistent immune dysfunction and sustained intestinal inflammation.[6,7,8] restoring the balance of Th17/ Treg cells may be a practical therapeutic strategy for treating UC. Centella asiatica (L.) Urban, a perennial herbaceous plant with pleiotropic bioactivities, mainly consists of pentacyclic triterpenes, including the glycosides madecassoside and asiaticoside as well as their corresponding aglycones madecassic acid and asiatic acid.[9,10,11] Our previous studies demonstrated that the triterpenoid-rich fraction of this herb could ameliorate dextran sulfate sodium (DSS)-induced colitis in mice (unpublished data). Madecassoside, the most abundant triterpene in this herb, was shown to regulate the balance of Th17/Treg cells in a collagen-induced arthritis in rats.[12] Whether it functions as the primary active ingredient of C. asiatica in ameliorating colitis by restoring the Th17/Treg balance remains to be determined. The present study aimed to identify the primary active ingredient of C. asiatica and explore its underlying mechanisms for anti-UC potential with an emphasis on the Th17/Treg balance
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