Amelioration of AOM/DSS-Induced Murine Colitis-Associated Cancer by Evodiamine Intervention is Primarily Associated with Gut Microbiota-Metabolism-Inflammatory Signaling Axis

Abstract

Evodiamine (EVO), an indole alkaloid derived from Rutaceae plants Evodia rutaecarpa (Juss.) Benth.、Evodia rutaecarpa (Juss.) Benth. Var. bodinieri (Dode) Huang or Evodia rutaecarpa (Juss.) Benth. Var. officinalis (Dode) Huang, has anti-inflammatory and anti-tumor activities. Our previous study found that EVO attenuates colitis by regulating gut microbiota and metabolites. However, little is known about its effect on colitis-associated cancer (CAC). In this study, the protective effects of EVO on azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis and tumor mice were observed, and the underlying potential mechanism was clarified. The results suggested that EVO ameliorated AOM/DSS-induced colitis by inhibiting the intestinal inflammation and improving mucosal barrier function. And EVO significantly reduced the number and size of AOM/DSS-induced colorectal tumors along with promoted apoptosis and inhibited proliferation of epithelial cell. Moreover, EVO promoted the enrichment of SCFAs-producing bacteria and reduced the levels of the pro-inflammatory bacteria, which contributes to the changes of microbiota metabolism, especially tryptophan metabolism. Furthermore, inflammatory response (like Wnt signaling pathway、Hippo signaling pathway and IL-17 signaling pathway) were effectively alleviated by EVO. Our study demonstrated that the protective therapeutic action of EVO on CAC is to inhibit the development of intestinal inflammation-cancer by regulating gut microbiota metabolites and signaling pathways of colon intestinal epithelial, which may represent a novel agent for colon cancer prevention via manipulation of gut microbiota.

Phycocyanin Ameliorates Colitis-Associated Colorectal Cancer by Regulating the Gut Microbiota and the IL-17 Signaling Pathway

“…The bacterial family Erysipelotrichaceae belongs to the Firmicutes phylum. Studies have revealed the increased abundance of Erysipelotrichaceae in CRC patients and the DMH induced colon cancer animal model [28,42,43], implying that it may be involved in the occurrence and development of CRC. Few research studies have investigated the relationship between Desulfovibrionaceae and CRC, however, many studies reported that it is an endotoxin-producer [44][45][46], endotoxin can promote colorectal cancer cells adhesion and invasion through the regulation of the TLR4/NF-κB pathway [47].…”

“…Some inflammatory cytokines such as IL-1, IL-6, IFNγ and TNFα play an importa role during the development of CAC. Studies showed an increased level of these cyt kines in AOM/DSS induced mice serum or colon [25][26][27][28].…”

The pharmacokinetics profiles, pharmacological properties, and toxicological risks of dehydroevodiamine: A review

“…var. bodinieri (Dode) Huang (Nam et al, 2016;Wang et al, 2021). EF belongs to Rutaceae family, Tetradium ruticarpum (A.…”

“…Dehydroevodiamine (DHE,3':3,4]pyrido[2,1-b]quinazolin-14-ium-13-ide, Figure 1A), molecular formula: C 19 H 15 N 3 O, PubChem CID: 9817839, CAS NO. 67,909-49-3, relative molecular mass: 301.3 (https://pubchem.ncbi.nlm.nih.gov/compound/9817839), is one of the natural bioactive components derived from a widely used traditional Chinese medicine (TCM), Evodiae Fructus (EF, Wuzhuyu in Chinese, Rutaceae family) (Figure 1B) (Park et al, 1996;Nam et al, 2016;Wang et al, 2021). For thousands of years, EF has been widely used as a central agent in classical Chinese herbal prescriptions (Wuzhuyu decoction and Zuojin formula) to treat migraine (known as "Jueyin headache" in ancient China) as well as other diseases (Sun et al, 2020).…”

Gut microbiota: An emerging therapeutic approach of herbal medicine for prevention of colorectal cancer

“…Many herbal medicines, such as Ganoderma Lucidum , American Ginseng, Red Ginseng, Gynostemma Pentaphyllum , and Curcumin, significantly inhibit the growth of pathogenic bacteria such as Clostridium , Escherichia , Staphylicus , Verrucomicrobia but increase the number of probiotic Bifidobacteria and lactobacilli , resulting in the increased diversity of the gut microbiota in DSS-induced CRC mouse model ( Guo et al., 2015 ; McFadden et al., 2015 ; Yu et al., 2015 ; Chen et al., 2016 ; Wang et al., 2016 ; Gong et al., 2019 ; Lv et al., 2019 ; Jiang et al., 2020 ; Shen et al., 2020 ; Sui et al., 2020 ; Sun et al., 2020 ; Zhang et al., 2020 ; Hao et al., 2021 ; Wang et al., 2021 ; Zhang et al., 2021 ; Zhu et al., 2021 ). These anti-CRC profiles of herbal medicine on gut microbiota are summarized as shown in Table 1 .…”