1. The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong, China.
2. The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, China.
3. Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China.
4. Laboratory of Pathogenic Biology and Immunology, College of Basic Medical, Inner Mongolia Medical University, Hohhot, China.
5. Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, Guangdong, China.
6. Fuwai Hospital, National Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
*These authors contributed equally to this work.
Background: Disulfiram (DSF), a Food and Drug Administration (FDA)-approved drug for chronic alcohol addiction, has anti-inflammatory effects that help prevent various cancers, and Cu2+ can enhance the effects of DSF. Inflammatory bowel diseases (IBD) are characterized by chronic or recurrent relapsing gastrointestinal inflammation. Many drugs targeting the immune responses of IBD have been developed, but their application has many problems, including side effects and high costs. Therefore, there is an urgent need for new drugs. In this study, we investigated the preventive effects of DSF+Cu2+ on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice.
Methods: The anti-inflammatory effects were investigated using the DSS-induced colitis mouse model and lipopolysaccharide (LPS)-induced macrophages. DSS-induced TCRβ-/- mice were used to demonstrate the effect of DSF in conjunction with Cu2+ on CD4+ T cell-secreted interleukin 17 (IL-17). In addition, the effect of DSF+Cu2+ on intestinal flora was studied by 16S rRNA microflora sequencing.
Results: DSF and Cu2+ could significantly reverse the symptom of DSS-induced UC in mice, such as weight loss, disease activity index score, colon length shortening, and reversal of colon pathological changes. DSF and Cu2+ could inhibit colonic macrophage activation by blocking the nuclear factor kappa B (NF-κB) pathway, reducing nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3)-inflammasome-derived interleukin 1 beta (IL-1β) secretion and caspase-1 (CASP1) activation, and decreasing IL-17 secretion by CD4+ T cells. Moreover, the treatment of DSF and Cu2+ could protect the intestinal barrier by reversing the expression of tight junction proteins, zonula occluden-1 (ZO-1), occludin, and mucoprotein-2 (MUC2). Additionally, DSF+Cu2+ could reduce the abundance of harmful bacteria and increase beneficial bacteria in the intestinal tract of mice, effectively improving intestinal microecology.
Conclusion: Our study evaluated the effect of DSF+Cu2+ on the immune system and gut microbiota in colonic inflammation and highlighted its potential to treat UC in the clinic.
Keywords: ulcerative colitis, disulfiram, macrophage, CD4+ T cells, microbiota