<i>Medulla Tetrapanacis</i> Water Extract Ameliorates Dextran Sulfate Sodium‐Induced Ulcerative Colitis by Reprogramming Macrophage Polarization and Maintaining Intestinal Barrier Integrity

ABSTRACT Medulla Tetrapanacis (MT) is traditionally consumed as herbal soup to manage mastitis. Although scientific evidence supports its anti‐inflammatory effect, no study has investigated its effect on ulcerative colitis (UC). This study aimed to investigate the effect of MT water extract and its underlying mechanisms both in vitro and in vivo. Dextran sulfate sodium (DSS) was used to induce UC in zebrafish for assessing the effect of MT water extract on oxidative stress, inflammation, and migration of neutrophils. A DSS‐induced UC mouse model was further employed to examine the effect of MT on oxidative stress, inflammation, macrophage phenotype, histopathology, and intestinal barrier integrity. Moreover, bone‐marrow‐derived macrophages (BMDMs) were used to elucidate the actions of MT on regulating polarization and energy metabolism. In vitro results showed that MT water extract significantly suppressed lipopolysaccharide and interferon‐gamma‐induced M1 polarization in BMDMs by reprogramming energy metabolism via suppressing hypoxia‐inducible factor‐1α (HIF‐1α)/glycolysis. In zebrafish, MT water extract remarkably reduced neutrophil intestinal infiltration, reactive oxygen species generation, and expressions of pro‐inflammatory genes (inducible nitric oxide synthase [ iNOS ], cyclooxygenase‐2 [ COX‐2 ], interleukin [ IL ] ‐6 , and IL‐1β ) in DSS‐induced UC. Furthermore, MT treatment alleviated symptoms and histopathological damage in DSS‐induced UC in mice, restored the balance of M1/M2 macrophages in the colon, attenuated inflammation and oxidative stress, and preserved intestinal barrier integrity. In conclusion, MT water extract ameliorated DSS‐induced UC by regulating macrophage polarization through reprogramming of energy metabolism via suppressing HIF‐1α/glycolysis, suppressing oxidative stress, and maintaining intestinal barrier integrity. These findings support the application of MT for managing UC.