Combination Therapy with Indigo and Indirubin for Ulcerative Colitis via Reinforcing Intestinal Barrier Function

Abstract

Indigo and indirubin, the active molecules of traditional Chinese medicine indigo naturalis, exert therapeutic activity for ulcerative colitis (UC). Indigo and indirubin are isomers and have distinctive profiles in anti-inflammation, immune regulation, intestinal microbiota regulation, oxidative stress regulation, and intestinal mucosal repair for UC treatment. Thus, exploring its combined administration’s integrated advantages for UC is critical. This study is aimed at clarifying the effect and mechanisms of the combined administration of indigo and indirubin on colitis mouse models. The results showed that all the treatment groups could improve the disease symptoms, and the combined administration showed the best effect. Additionally, compared with indigo and indirubin alone, the combination group could significantly reinforce intestinal barrier function by increasing the expression of E-cadherin, occludin, ZO-1, and MUC2 and improving intestinal permeability. The treatment groups significantly improved the expression of cytokines, including TNF-α, IFN-γ, IL-12, IL-23, and IL-17A, and indirubin presented the most potent anti-inflammatory effect. Furthermore, all the treatment groups reduced the infiltration of the immune cells in intestinal lamina propria and the production of ROS/RNS. Notably, indigo exhibited a more substantial capacity to regulate natural killer (NK) cells, ILC3, neutrophils, and dendritic cells, followed by the combination group and indirubin alone. Finally, all the treatment groups modulated intestinal microbiota composition, increased the proportion of beneficial microbiota, and decreased the proportion of microbiota. Our results indicated that indigo and indirubin synergistically reinforced the intestinal barrier function, which may be associated with integrating the indirubin anti-inflammatory and intestinal microbiota regulating strength and indigo immune and ROS/RNS regulation advantage.

Improved Therapeutic Efficacy of MT102, a New Anti-Inflammatory Agent, via a Self-Microemulsifying Drug Delivery System, in Ulcerative Colitis Mice

“…Given that (i) MT-102 is an herbal extract including multiple active ingredients, and (ii) SMEDDS-F1 may improve the dissolution of other active and auxiliary substances, SMEDD-F1 may be advantageous for achieving more synergistic effects in therapeutic efficacy compared to isolated indirubin. Xie et al [ 28 ] also support the synergistic effect of multiple components in treating ulcerative colitis. They showed that combined use of indirubin and indigo was more effective in ameliorating DSS-induced colitis by improving the intestinal barrier function compared to indirubin or indigo alone.…”

Anti-diabetic effect of Ornithogalum caudatum Jacq. polysaccharides via the PI3K/Akt/GSK-3β signaling pathway and regulation of gut microbiota

“…At the genus level, OCPs intervention increased the relative abundances of Muribaculaceae_norank, Prevotellaceae _UCG-001, and Alloprevotella . Muribaculaceae_norank, inhibited harmful bacteria and oxidative stress, and improved the inflammation of the intestinal mucosa [ 29 ]. The presence of Prevotellaceae_UCG-001 indicates that there is a close relationship between mediating glucose and lipid metabolism and energy metabolism-related signal regulation [ 30 ].…”

Repairing the intestinal mucosal barrier of traditional Chinese medicine for ulcerative colitis: a review

“…[Caprifoliaceae; lonicerae japonicae flos], might restore the diversity of gut microbiota, reduce the abundance of Firmicutes and Bacteroidetes , and markedly increase the proportion of Akkermansia ( Zhang et al, 2017 ). Combination therapy with indigo and indirubin was demonstrated to be effective on increasing the amounts of beneficial bacteria, like norank_f_Muribaculaceae and Lactobacillus ( Xie et al, 2023 ).…”

“…It was shown that indirubin alone, or combined with isatin, could significantly inhibit DSS-induced CD4 + T cell infiltration in mouse colon, and promote the generation of Foxp3 - expressing regulatory T cells ( Gao et al, 2016 ; Gao et al, 2018 ). Xie et al (2023) showed that combination of indigo and indirubin could reduce the populations of neutrophils, macrophages, and dendritic cells in the lamina propria, and significantly increase the relative quantity of CD335+CD11b+ NK cells.…”