Berberine alleviates DSS-induced colitis by modulating macrophage phenotype via PPAR-γ/ mTOR/HIF-1α signaling pathway

Berberine (BBR), an isoquinoline alkaloid derived from Chinese herbal drugs of Coptis chinensis Franch. and Phellodendron chinense C.K. Schneid., has been traditionally extensively utilized in treating acute or chronic diarrhea and distension. In modern medical practice, BBR has also been developed to remit diarrhea of ulcerative colitis (UC). However, the potential mechanism remains not been fully elucidated.

The present study aimed to explore the modulation effect of BBR on M2 macrophage polarization and elucidate the underlying mechanism.

Mice with colitis were induced by dextran sulfate sodium (DSS) and administrated with BBR. The distribution of M2-like phenotype of macrophage in colon tissues was determined by flow cytometry and immunofluorescence. Additionally, the Seahorse real-time cell metabolic analysis was applied to measure the oxygen consumption rate on RAW264.7 cells cultured under M2 macrophage polarization conditions. Protein levels were measured using western blotting and immunohistochemistry. Finally, the GW9662 was used for reverse validation experiments.

BBR notably alleviated colitis and resettled inflammatory macrophages toward M2 phenotype in a mouse model. Additionally, BBR significantly promoted peroxisome proliferator-activated receptor gamma (PPAR-γ) expression in mice with colitis. In vitro findings demonstrated BBR significantly enhanced M2 macrophage polarization and increased the oxygen consumption and ATP production of RAW 264.7 cells cultured in M2 macrophage polarization condition. BBR also exerted a negative regulatory effect on the mTOR/HIF-1α signaling pathway. Nevertheless, the modulation efficiency of BBR on M2 macrophage polarization and mTOR/HIF-1α pathway were abrogated upon the application of GW9662 both in vivo and in vitro.

BBR significantly contribute to drive M2 macrophage polarization via the PPAR-γ/mTOR/HIF-1α axis, and further confirmed the considerable approach of BBR for the clinical treatment of UC.