Anti‐inflammatory effect of Rhein on ulcerative colitis via inhibiting PI3K/Akt/mTOR signaling pathway and regulating gut microbiota

Abstract

This study aimed to analyze the therapeutic effect of Rhein on ulcerative colitis (UC) in mice and its possible mechanism. LPS‐induced UC cell model and DSS‐induced UC mouse model were used to analyze the antiinflammatory effect of Rhein on UC in vitro and in vivo, respectively. Network pharmacology analysis was conducted to identify potential signaling pathways involved in Rhein treating UC, and the results were further confirmed through western blotting assay. 16sRNA sequencing was performed to study the regulatory effect of Rhein on gut microbiota in UC mice. As indicated by the results, Rhein could significantly inhibit the production of pro‐inflammatory cytokines (e.g., TNF‐α, IL‐6 and IL‐1β) in vivo and in vitro, and alleviate DSS‐induced UC‐associated symptoms in mice (e.g., colon shortening, weight loss, diarrhea and hematochezia). The PI3K/Akt/mTOR signaling pathway was predicted as the potential interacting protein of Rhein in the treatment of UC through network pharmacology analysis. It was found through western blotting assay that the Rhein treatment could significantly inhibit the PI3K/Akt/mTOR signaling pathway by decreasing the phosphorylated protein levels of PI3K, Akt, mTOR and p70S6K1. By 16sRNA gene sequencing analysis, Rhein administration could partially reverse the gut dysbacteriosis of mice induced by DSS and decrease pathogenic bacteria (e.g., Enterobacteriaceae and Turicibacter). It was positively correlated with the production of pro‐inflammatory cytokines above, whereas the increase in probiotics (e.g., Unspecified‐S24‐7 and Rikenellaceae) was negatively correlated with the production of pro‐inflammatory cytokines. In conclusion, Rhine had anti‐UC efficacy, which was demonstrated by mitigating the UC symptoms and reducing intestinal inflammation by inhibiting the PI3K/Akt/mTOR signaling pathway and modulating gut microbiota.

Integrated Metabonomics and Network Pharmacology to Reveal the Action Mechanism Effect of Shaoyao Decoction on Ulcerative Colitis

“… 41 Besides, a study elucidated that MiR-223 can trigger cell apoptosis and inflammation in UC by up-regulating the PI3K/AKT-mTOR signaling pathway. 63 In addition, this study revealed that SYD may exert its therapeutic effect on UC by inhibiting PI3K/Akt-mTOR pathway, and other Chinese medicine-related studies have also produced similar results, 25 , 29 , 64 , 65 which all clarify that Chinese medicine treatment against UC may mainly produce efficacy through regulating PI3K/Akt pathway. Compared with single-drug research, compound drug research can reveal the synergistic mechanism between drugs.…”

MPST deficiency promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via AKT

“…The role of PI3K-AKT in IBD is multiplex. They can regulate epithelium inflammation, epithelium apoptosis, cell proliferation and dendritic cells maturation by regulating different downstream targeted genes [ 42 ], such as NF-κB [ 43 , 44 ], mTOR [ 45 , 46 ], FOXO1, BAD and caspase. Early studies revealed that PI3K-AKT phosphorylation is a key event in the progression of colitis via the activation of inflammatory signaling by regulating NF-κB or mTOR.…”

Traditional Chinese Medicine and Natural Products: Potential Approaches for Inflammatory Bowel Disease

“…In UC mice, Rhein downregulates NF-κB and NLRP3 activity in macrophages and activates the Nrf2/HO-1/NQO1 pathway, inhibits NOX2 subunit expression, and translocation, downregulates protein expression levels of IL-6, IL-1β, TNF-α, iNOS, and COX-2, significantly reduces NO production. Rhein can increase the number of beneficial bacteria, decrease the proportion of pathogenic bacteria, alter the composition of the intestinal microbiota, and thus improve dysbiosis, which may be related to the inhibition of the PI3K/Akt/mTOR signaling pathway ( Dong et al, 2022 ). Rhein can also indirectly regulate the level of uric acid metabolism in the intestine by increasing the fermentation products of Lactobacillus and restoring the barrier function of the intestine by decreasing intestinal permeability by increasing the expression of claudin-1, E-cadherin, and the secretion of mucus ( Wu J. et al, 2020 ).…”