Abstract
Imbalances in intestinal bacteria correlate with colitis-associated colorectal cancer (CAC). Traditional Chinese medicines have been used to adjust the gut microbiota, and isoliquiritigenin (ISL), a flavonoid extracted from licorice, has shown antitumor efficacy. In this study, the effects of ISL on CAC development and the gut microbiota were evaluated using an azoxymethane and dextran sulphate sodium (AOM/DSS)-induced mouse model of CAC (CACM). Histopathological analysis suggested that ISL reduced tumor incidence in vivo. Moreover, high-throughput sequencing and terminal restriction fragment length polymorphism (T-RFLP) studies of the bacterial 16S rRNA gene revealed that the structure of the gut microbial community shifted significantly following AOM/DSS treatment, and that effect was alleviated by treatment with high-dose ISL (150 mg/kg). Compared to the microbiota in the control mice (CK), the levels of Bacteroidetes decreased and the levels of Firmicutes increased during CAC development. ISL reversed the imbalance at the phylum level and altered the familial constituents of the gut microbiota. Specifically, the abundance of Helicobacteraceae increased after treatment with high-dose ISL, while the abundance of Lachnospiraceae and Rikenellaceae decreased. At the genus level, ISL reduced the abundance of opportunistic pathogens (Escherichia and Enterococcus), and increased the levels of probiotics, particularly butyrate-producing bacteria (Butyricicoccus, Clostridium, and Ruminococcus). Thus, ISL protects mice from AOM/DSS-induced CAC, and ISL and the gut microbiota may have synergistic anti-cancer effects.
Highlights
Colorectal cancer (CRC) is a relatively common cancer that has a high mortality [1]
High-throughput sequencing and terminal restriction fragment length polymorphism (T-RFLP) studies of the bacterial 16S rRNA gene revealed that the structure of the gut microbial community shifted significantly following AOM/dextran sodium sulfate (DSS) treatment, and that effect was alleviated by treatment with high-dose ISL (150 mg/kg)
AOM/DSS induced CAC treatment (CACM) caused a significant loss of body weight, which was rescued by ISL treatment (AOM/DSS + 150 mg/kg ISL, CIH; AOM/DSS + 75 mg/kg ISL, CIM; AOM/DSS + 30 mg/kg ISL, CIL)
Summary
Prolonged periods of chronic colitis significantly increase the risk of CRC and early metastasis [2,3]. CRC occurs in the intestinal tract, which is often described as the “neglected endocrine organ” where more than 1014 microbes live. Using quantitative PCR, Sobhani et al demonstrated that the ratio of Bacteroides to Prevotella was significantly www.impactjournals.com/oncotarget increased in CRC patients [8]. Bacteria induce carcinogenesis, but can produce metabolites that influence CRC progression [11]. Propionate, and butyrate may inhibit CRC while deoxycholic acid and lithocholic acid were shown to directly promote carcinogenesis [12]. Butyrate, can suppress inflammation and prevent CRC through several signaling pathways [13]
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