Tumor-targeting engineered probiotic Escherichia coli Nissle 1917 inhibits colorectal tumorigenesis and modulates gut microbiota homeostasis in miceopen access
- Authors
- Tang, Haibo; Zhou, Tuoyu; Jin, Weilin; Zong, Simin; Mamtimin, Tursunay; Salama, El-Sayed; Jeon, Byong-Hun; Liu, Pu; Han, Huawen; Li, Xiangkai
- Issue Date
- Jul-2023
- Publisher
- PERGAMON-ELSEVIER SCIENCE LTD
- Keywords
- Engineered probiotic; Escherichia coli Nissle 1917; AOM; DSS model; Tumor-targeting treatment; Gut microbiota
- Citation
- LIFE SCIENCES, v.324, pp.1 - 13
- Indexed
- SCIE
SCOPUS
- Journal Title
- LIFE SCIENCES
- Volume
- 324
- Start Page
- 1
- End Page
- 13
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/186373
- DOI
- 10.1016/j.lfs.2023.121709
- ISSN
- 0024-3205
- Abstract
- Aims: Preliminary studies have identified the use of probiotics as a potential treatment strategy against colorectal cancer (CRC). However, natural probiotics lack direct tumor-targeting and tumor-killing activity in the intestine. This study aimed to construct a tumor-targeting engineered probiotic to combat CRC. Main methods: Standard adhesion assay was performed to analyze the adherence ability of tumor-binding protein HlpA to CT26 cells. CCK-8 assay, Hoechst 33258 staining and flow cytometry analysis were used for examining cytotoxicity of tumoricidal protein azurin toward CT26 cells. An engineered probiotic Ep-AH harboring azurin and hlpA genes was developed using Escherichia coli Nissle 1917 (EcN) chassis. Antitumor effects of Ep-AH were evaluated in the azoxymethane (AOM) and dextran sodium sulfate salt (DSS)-induced CRC mice. Moreover, analysis of gut microbiota was conducted via fecal 16S rRNA gene sequencing and shotgun metagenomic sequencing. Key findings: Azurin caused a dose-dependent increase of apoptosis in CT26 cells. Ep-AH treatment reversed weight loss (p < 0.001), fecal occult blood (p < 0.01), and shortening of colon length (p < 0.001) than model group, as well as reducing tumorigenesis by 36 % (p < 0.001). Both Ep-H and Ep-A (EcN expressing HlpA or azurin) were less effective than Ep-AH. Furthermore, Ep-AH enriched the members of beneficial bacteria (e.g., Blautia and Bifidobacterium) and reversed abnormal changes of genes associated with several metabolic pathways (e.g., lipopolysaccharide biosynthesis). Significance: These results demonstrated that Ep-AH had excellent therapeutic benefits on cancer remission and gut microbiota modulation. Our study provides an effective strategy for anti-CRC treatment.
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