Poncirin and its metabolite ponciretin attenuate colitis in mice by inhibiting LPS binding on TLR4 of macrophages and correcting Th17/Treg imbalance.
ETHNOPHARMACOLOGICAL RELEVANCE
The fruit of Poncirus trifoliate, which contains poncirin as a main constituent, is frequently used in the traditional Chinese medicine for inflammation, asthma, and infection diseases.


AIM OF THE STUDY
To examine anti-colitic effects of poncirin and ponciretin, a metabolite of poncirin by gut microbiota.


MATERIALS AND METHODS
Colitis was induced in mice by the intrarectal injection of 2,4,6-trinitrobenzenesulfonic acid (TNBS). Inflammatory markers were analyzed by enzyme-linked immunosorbent assay, immunoblotting, quantitative polymerase chain reaction, confocal microscopy, and flow cytometry. Peritoneal macrophages were isolated from mice stimulated with 4% thioglycolate.


RESULTS
Poncirin was metabolized to ponciretin in vitro and in vivo by gut microbiota of mice. Orally administered poncirin and ponciretin suppressed TNBS-induced colitis in mice: these inhibited colon shortening, myeloperoxidase activity, NF-κB activation, and Th17 cell differentiation, but increased occludin, claudin-1, and ZO-1 expressions and Treg cell differentiation. Poncirin and ponciretin suppressed the differentiation of splenocytes into Th17 cells and expression of IL-17 and Foxp3 in vitro, as well as the activation of macrophages stimulated with lipopolysaccharide (LPS) by inhibiting the binding of LPS on TLR4 of macrophages. These increased the differentiation of splenocytes into Treg cells. The ant-inflammatory effect of ponciretin was superior to that of poncirin.


CONCLUSION
Orally administered poncirin is metabolized to ponciretin by gut microbiota and poncirin and ponciretin attenuates colitis by suppressing NF-κB activation through the inhibition of LPS binding on macrophages and correcting Th17/Treg cell imbalance.
['Kang|Geum-Dan|GD|', 'Kim|Dong-Hyun|DH|']
D000284:Administration, Oral D000818:Animals D000893:Anti-Inflammatory Agents D001419:Bacteria D001711:Biotransformation D002478:Cells, Cultured D003092:Colitis D003106:Colon D004195:Disease Models, Animal D004305:Dose-Response Relationship, Drug D004365:Drugs, Chinese Herbal D005419:Flavonoids D005765:Gastrointestinal Agents D000069196:Gastrointestinal Microbiome D018836:Inflammation Mediators D008070:Lipopolysaccharides D008262:Macrophage Activation D017737:Macrophages, Peritoneal D008297:Male D008810:Mice, Inbred C57BL D016328:NF-kappa B D015398:Signal Transduction D013154:Spleen D050378:T-Lymphocytes, Regulatory D058504:Th17 Cells D013997:Time Factors D051197:Toll-Like Receptor 4 D014302:Trinitrobenzenesulfonic Acid
Poncirin Ponciretin Colitis Macrophages Th17 cells