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  3. Genetically engineered bacteria expressing IL-34 alleviate DSS-induced experimental colitis by promoting tight junction protein expression in intestinal mucosal epithelial cells

Genetically engineered bacteria expressing IL-34 alleviate DSS-induced experimental colitis by promoting tight junction protein expression in intestinal mucosal epithelial cells

  • Mol Immunol. 2025 Feb:178:64-75. doi: 10.1016/j.molimm.2025.01.008.
Weijie Chen 1,  Tongtong Zhou 2,  Yicun Liu 3,  Leilei Luo 4,  Yujing Ye 5,  Lixian Wei 6,  Jian Chen 7,  Zhaolian Bian 8
Affiliations

Affiliations

  • 1 Medical School, Nantong University, Nantong, Jiangsu Province 226001, China. Electronic address: ntchenwj@163.com.
  • 2 Medical School, Nantong University, Nantong, Jiangsu Province 226001, China. Electronic address: zhoutongtong9702@163.com.
  • 3 Department of Gastroenterology and Hepatology, Nantong Third People's Hospital, Affiliated Nantong Hospital 3 of Nantong University, Nantong, Jiangsu Province 226006, China. Electronic address: liuyicun94@163.com.
  • 4 Department of Gastroenterology and Hepatology, Nantong Third People's Hospital, Affiliated Nantong Hospital 3 of Nantong University, Nantong, Jiangsu Province 226006, China. Electronic address: luoleileintsy@163.com.
  • 5 Medical School, Nantong University, Nantong, Jiangsu Province 226001, China. Electronic address: yyj000426@163.com.
  • 6 Department of Gastroenterology and Hepatology, Nantong Third People's Hospital, Affiliated Nantong Hospital 3 of Nantong University, Nantong, Jiangsu Province 226006, China. Electronic address: Ruthwei87@163.com.
  • 7 Department of Gastroenterology and Hepatology, Nantong Third People's Hospital, Affiliated Nantong Hospital 3 of Nantong University, Nantong, Jiangsu Province 226006, China. Electronic address: mudchen@139.com.
  • 8 Department of Gastroenterology and Hepatology, Nantong Third People's Hospital, Affiliated Nantong Hospital 3 of Nantong University, Nantong, Jiangsu Province 226006, China. Electronic address: bianzhaolian1998@163.com.
PMID: 39864284 DOI: 10.1016/j.molimm.2025.01.008
Abstract

Background: The intestinal mucosa of ulcerative colitis patients expresses high levels of interleukin 34, and mice lacking IL-34 have more severe DSS-induced experimental colitis. There are no studies on the effects of directly upregulating intestinal IL-34 on experimental colitis in mice.

Methods: The bacteria EcN/CSF-1 and EcN/IL-34, which express CSF-1 and IL-34, respectively, were genetically engineered from Escherichia coli Nissle 1917 (EcN). Colitis mice received daily gavage of sterile PBS buffer, empty plasmid E. coli (EcN/WT), EcN/CSF-1, or EcN/IL-34. Each group of mice was assessed for body mass, clinical signs, DAI, intestinal mucosal permeability, pathological, and immunohistological changes. In vitro, NCM460 cells were treated with CSF-1 or IL-34 recombinant proteins in the presence of signaling pathway inhibitors to evaluate tight junction protein expression. Additionally, intestinal mucosal epithelial cells isolated from active UC patients were analyzed for IL-34 and tight junction protein levels.

Results: DSS-induced colitis mice are protected by EcN/IL-34 gavage. Pathological results showed that EcN/IL-34 group colonic histological injury was significantly improved and tight junction protein ZO-1 and Occludin expression increased. In NCM460 cells, IL-34 also increased tight junction protein expression. More importantly, expression of IL-34 was positively correlated with the level of tight junction protein expression in epithelial cells of UC patients.

Conclusion: EcN/IL-34 can directly act on damaged intestinal mucosa, up-regulate IL-34 expression, and promote tight junction protein expression in intestinal mucosal epithelial cells to alleviate experimental colitis in mice. IL-34 may be a potential therapeutic target for ulcerative colitis, and genetically engineered bacteria carrying the cytokine may offer new ideas for treating UC.

Keywords

Escherichia coli Nissle1917; Genetically engineered bacteria; Inflammatory bowel disease; Interleukin-34; Intestinal mucosal barrier; Tight junction protein.

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