Polyphenolics from Mango (Mangifera indica L.) and Pomegranate (Punica granatum L.) Suppress Inflammation in in vivo and in vitro Models for Colitis

Abstract

Ulcerative colitis is a chronic inflammation of the large intestine, and it may increase risk of human colorectal cancer. Polyphenolics from mango and pomegranate have been shown to have potent anti-inflammatory properties, thus they could be the potential therapeutic agents for colitis. However, the mechanism underlying these effects of polyphenolics has not yet been elucidated.

To determine the anti-inflammatory effects and possible mechanisms of polyphenolics from mango (gallic acid and gallotannins), and pomegranate (ellagic acid and ellagitannins) in dextran sodium sulfate (DSS)-induced colitis in rats, Sprague Dawley rats were administered control, mango, or pomegranate juice, and were exposed to three cycles of 3% DSS followed by 2-week recovery period. Colon inflammation and injury scores were assessed, and cell proliferation was evaluated by immunohistochemical detection of Ki-67. The mRNA and protein expressions involved in the inflammatory response and the mTOR pathway were analyzed by qRT-PCR, low density arrays, western blot analysis and multiplex bead assay. The involvement of miRNAs was additionally investigated with the antagomiR-126 and antagomiR-145 in lipopolysaccharide (LPS)-treated CCD-18Co, non-cancer colon fibroblasts cell lines.

Both mango and pomegranate showed anti-inflammatory properties in vitro and in vivo. Mango and pomegranate juice reduced DSS-induced colon inflammation score (41% and 50%) and cell proliferative index (38% and 36%) during chronic colitis in rats compared to control juice. Mango and pomegranate juice significantly attenuated the pro-inflammatory cytokines, CRP, TNF-alpha, IL-1beta, GM-CSF, and IL-6 levels in colonic tissues. In addition, mango and pomegranate juice suppressed COX-2 and iNOS mRNA and protein expressions. Mango juice suppressed HIF-1alpha by decreasing the PI3K(p85beta)/AKT-mTOR signaling axis via up-regulation of miR-126, while pomegranate decreased p70S6K and HIF-1alpha by up-regulating miR-145. The interactions of mango with miR-126/PI3K(p85beta) and pomegranate with miR-145/p70S6K1 were additionally identified in CCD-18Co cells, where mango and pomegranate extract reversed the effect of the antagomiR.

In addition, the modulation of microbiota composition (Blautia, Fusobacterium, and Ruminococcaceae) by pomegranate and short-chain fatty acids (SCFA; Isovalerate and valerate) production by mango may be involved in at least in part the anti-inflammatory effects of polyphenolics.

These results suggest that both mango and pomegranate polyphenolics seem to have potential in the prevention and mitigation of colon inflammation.