Pre-Administration of Berberine Exerts Chemopreventive Effects in AOM/DSS-Induced Colitis-Associated Carcinogenesis Mice via Modulating Inflammation and Intestinal Microbiota

Abstract

Inflammatory activation and intestinal flora imbalance play an essential role in the development and progression of colorectal cancer (CRC). Berberine (BBR) has attracted great attention in recent years due to its heath-related benefits in inflammatory disorders and tumors, but the intricate mechanisms have not been fully elucidated. In this study, the effects and the mechanism of BBR on colon cancer were investigated in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated carcinogenesis mice model. Our results showed that pre-administration of BBR showed a decrease in weight loss, disease activity index (DAI) score, and the number of colon tumors in mice, compared with the model group. The evidence from pathological examination indicated that the malignancy of intestinal tumors was ameliorated after pre-administration of BBR. Additionally, pre-administration with BBR suppressed the expression of pro-inflammatory factors (interleukin (IL)-6, IL-1β, cyclooxygenase (COX)-2 and tumor necrosis factor (TNF)-α) and the cell-proliferation marker Ki67, while expression of the tight junction proteins (ZO-1 and occludin) were increased in colon tissue. Moreover, the levels of critical pathway proteins involved in the inflammatory process (p-STAT3 and p-JNK) and cell cycle regulation molecules (β-catenin, c-Myc and CylinD1) exhibited lower expression levels. Besides, 16S rRNA sequence analysis indicated that pre-administration of BBR increased the ratio of Firmicutes/Bacteroidetes (F:M) and the relative abundance of potentially beneficial bacteria, while the abundance of cancer-related bacteria was decreased. Gavage with Lactobacillus rhamnosus can improve the anti-tumor effect of BBR. Overall, pre-administration of BBR exerts preventive effects in colon carcinogenesis, and the mechanisms underlying these effects are correlated with the inhibition of inflammation and tumor proliferation and the maintenance of intestinal homeostasis.

Therapeutic Mechanisms of Berberine to Improve the Intestinal Barrier Function via Modulating Gut Microbiota, TLR4/NF-κ B/MTORC Pathway and Autophagy in Cats

“…We treated IBD cats with BBr and found that their gut microbiota was roughly the same as healthy cats. Firmicutes and Bacteroidetes are the major bacterial phyla in the gastrointestinal tract, and the Firmicutes/Bacteroidetes (F/B) ratio associating with maintaining homeostasis (Deng et al, 2022). Our results are consistent with previous studies showing a reduced F/B ratio in IBD cats compared to the CON group.…”

“…Enterotoxins produced by pathogenic bacteria can destroy villous effacement and dysfunction the mucosal barrier (Suchodolski, 2016;Deng et al, 2022). The physical barrier of intestinal epithelial cells and tight junction proteins is part of the intestinal barrier (Stojanov et al, 2020).…”

Anticancer Effects and Mechanisms of Berberine from Medicinal Herbs: An Update Review

“…Bile acids (BAs) upregulation is a risk factor for colorectal cancer, and berberine downregulated BAs via modulating intestine bacteria [ 92 , 93 ]. Moreover, berberine could exert an anticancer effect by increasing the ratio of Firmicutes / Bacteroidetes , thus decreasing the abundance of cancer-related bacteria and improving intestinal barrier function [ 94 ]. Furthermore, berberine could inhibit the development of azoxymethane/dextran sodium sulfate-induced precancerous lesions, such as crypt destruction, inflammatory cell infiltration, and tumor formation, which indicated that berberine could prevent the occurrence of colorectal cancer [ 94 ].…”

“…Moreover, berberine could exert an anticancer effect by increasing the ratio of Firmicutes / Bacteroidetes , thus decreasing the abundance of cancer-related bacteria and improving intestinal barrier function [ 94 ]. Furthermore, berberine could inhibit the development of azoxymethane/dextran sodium sulfate-induced precancerous lesions, such as crypt destruction, inflammatory cell infiltration, and tumor formation, which indicated that berberine could prevent the occurrence of colorectal cancer [ 94 ]. Furthermore, berberine in combination with some other natural products might synergistically promote the anti-tumorigenic properties in CRC.…”

Berberine as a Potential Agent for the Treatment of Colorectal Cancer

“…At the same time, BBR could decrease the permeability of intestinal mucosa by modulating zonula occludens-1 (ZO1) and occludin (OCLN) ( 176 ). More recently, Deng and coauthors found that preadministration of BBR suppressed CRC development by inhibiting inflammation and proliferation and maintaining intestinal homeostasis ( 145 ).…”