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Emerging evidence indicates that Akkermansia muciniphila (AKK) may be a potential probiotic agent for ameliorating colorectal cancer (CRC). Thus, we utilized the azoxymethane (AOM)/ dextran sodium sulfate (DSS)-induced mouse model of colorectal cancer to evaluate the intervention effect of AKK PROBIO. The results showed that AKK PROBIO significantly improved mouse colon health, decreased the serum pro-inflammatory cytokines levels, as well as downregulated the mRNA levels of p50, p52, p65, and IκBβ, upregulated the expressions of Bid, Bim, and caspase-9 in the colon. In addition, AKK PROBIO modulated the gut microbiota composition, as characterized by the increased abundance of Muribaculaceae and Akkermansia and the decreased levels of Bacteroides, and Parasutterella. Notably, the high-dosage group was better than that of low-dosage. In conclusion, AKK PROBIO has the potential to modulate colorectal cancer by alleviating intestinal inflammation through the NF-κB pathway and promoting cell apoptosis, thereby intervening in the development of colorectal tumors.

Chronic inflammation-induced oxidative stress is an important driving force for developing colitis-associated cancer (CAC). 4-hydroxynonenal (4-HNE) is a highly reactive aldehyde derived from lipid peroxidation of ω-6 polyunsaturated fatty acids that contributes to colorectal carcinogenesis. Glutathione S-transferase alpha 4 (Gsta4) specifically conjugates glutathione to 4-HNE and thereby detoxifies 4-HNE. The correlation of these oxidative biomarkers with the pathological changes in CAC is, however, unclear. In this study, we investigated the expression of Gsta4 and 4-HNE adducts in azoxymethane/dextran sulfate sodium (AOM/DSS)-induced murine CAC, and analyzed the correlations of 4-HNE and Gsta4 with inflammatory cytokines and the pathological scores in the colon biopsies. Real-time quantitative PCR showed that expression of IL6, TNFα, and Gsta4 sequentially increased in colon tissues for mice treated with DSS for 1, 2, and 3 cycles, respectively. Moreover, immunohistochemical staining showed remarkably increased expression of 4-HNE adducts, Gsta4, TNFα, and IL6 in the colon biopsies after 3 cycles of DSS treatment. Correlation analysis demonstrated that 4-HNE adducts in the colon biopsies were positively correlated with Gsta4 expression. Additionally, the expression of Gsta4 and 4-HNE adducts were strongly correlated with the pathological changes of colon, as well as the expression of TNFα and IL6 in colon tissues. These results provide evidence for the association of oxidative biomarkers Gsta4 and 4-HNE with the pathological changes of CAC and may help developing novel histopathological biomarkers and prevention targets for CAC.

Sodium butyrate (NaB) is a by-product of dietary fiber that has an anti-tumor effect on colorectal cancer (CRC). The aim of this study was to explore the effect of NaB on tumor and colitis using a colitis-associated colorectal cancer (CAC) model. CAC model was induced in mice by administration of azoxymethane (AOM) and dextran sulfate sodium salt (DSS). 0.1 M NaB in drinking water, or intraperitoneal injection of NaB (1 g/kg body weight) was given during the study period. NLRP3 inflammasome-related molecules were detected. The composition and taxonomy of colorectal microbiota were analyzed. NaB increased spleen index decreased by AOM/DSS. NaB attenuated tumors by reducing tumor load and tumor size in AOM/DSS-induced mice. NaB protected mice from CAC by improving colitis and inhibiting expression of NLRP3 and IL-1β. NaB regulated gut microbiota dysbiosis induced by AOM/DSS. In conclusion, NaB inhibited CAC by ameliorating the gut microbiota dysbiosis and inhibiting colitis.

The oral bioavailability and efficacy of citrus polymethoxyflavone, tangeretin, was attenuated by its poor aqueous solubility. An emulsion-based delivery system was utilized to enhance the anti-tumourigenesis activity of tangeretin. The in vitro anti-proliferative activity of tangeretin was first evaluated using methyl thiazol tetrazolium bromide (MTT) test on colonic carcinoma cell lines, HCT116 and HT29. The utilization of emulsion system significantly improved the efficacy of tangeretin at dosing concentrations at 12.5 and 25 µM. The effectiveness of the emulsion system in enhancing the in vivo oral efficacy of tangeretin against colorectal cancer development was also evaluated by azoxymethane/dextran sodium sulphate (AOM/DSS)-induced colitis related colon tumourigenesis model. The tumour incidence, multiplicity, and pathological signs of colorectal adenoma were significantly reduced when tangeretin emulsion was applied. The regulation on tumourigenesis related protein expression was more effective in mice treated with tangeretin emulsion than unformulated suspension. Our finding indicated that emulsion-based delivery system was an effective means to increase the oral efficacy of tangeretin. This study is the first successful demonstration of the effect of delivery system on the oral efficacy of nutraceutical using long-term animal model.

Aims: Cetuximab improves the survival of patients with advanced colorectal cancer (CRC). However, how cetuximab affects the tumor microenvironment has not been sufficiently understood. This study was to investigate whether cetuximab could inhibit the pro-tumor function of tumor-associated macrophages (TAMs) by suppressing the EGFR/IL-6 pathway., Main Methods: The azoxymethane/dextran sodium sulfate (AOM/DSS) and tumor xenograft mouse models were used to assess the effect of cetuximab on TAMs. Flow cytometry, Western blotting, RT-qPCR, and ELISA were used to assess the prevalence of M2 and M1 phenotypes. Publicly available datasets of CRC patients were used to assess the relevance of EGFR and IL-6 expression as prognostic indicators., Key Findings: The two mouse models showed that cetuximab could attenuate the pro-tumor function of TAMs and decrease tumor burden. Cetuximab repolarized TAMs from M2-like to M1-like phenotypes, mainly by suppressing the IL-6 expression through NFκB and STAT3 pathways. Analysis of public scRNA-seq data indicated EGFR was mainly expressed on the surface of macrophage infiltration into tumor microenvironment. The public transcriptomics datasets showed that the expression level of IL-6 was positively correlated with EGFR in CRC patients, and PROGgeneV2 analysis indicated that IL-6 and CD206 both predicted poor recurrence-free and overall survival of CRC patients. Furthermore, the inhibition efficacy of cetuximab was significantly attenuated in IL-6 knockout CRC mice model., Significance: These results indicate a new macrophage-based molecular mechanism explaining the effect of cetuximab in treatment of colorectal cancer., (Copyright © 2020. Published by Elsevier Inc.)