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Methionine-choline deficient diet deteriorates DSS-induced murine colitis through disturbance of gut microbes and infiltration of macrophages

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Ulcerative colitis (UC) is associated with changed dietary habits and mainly linked with the gut microbiota dysbiosis, necroptosis of epithelial cells, and mucosal ulcerations. Liver dysfunction and abnormal level of liver metabolism indices were identified in UC patients, suggesting a close interaction between gut and liver disorders. Methionine-choline deficient diet (MCD) has been shown to induce persistent alterations of gut microbiota and metabolome during hepatitis. In this study we further explored the disease phenotypes in UC patients and investigated whether MCD functioned as a trigger for UC susceptibility. After assessing 88 serum specimens from UC patients, we found significant liver dysfunction and dyslipidemia including abnormal ALT, AST, TG, TC, LDL-c and HDL-c. Liver dysfunction and dyslipidemia were confirmed in DSS-induced colitis mice. We fed mice with MCD for 14 days to cause mild liver damage, and then treated with DSS for 7 days. We found that MCD intake significantly exacerbated the pathogenesis of mucosal inflammation in DSS-induced acute, progressive, and chronic colitis, referring to promotion of mucosal ulcers, colon shortening, diarrhea, inflammatory immune cell infiltration, cytokines release, and abnormal activation of inflammatory macrophages in colon and liver specimens. Intraperitoneal injection of clodronate liposomes to globally delete macrophages dramatically compromised the pathogenesis of MCD-triggering colitis. In addition, MCD intake markedly changed the production pattern of short-chain fatty acids (SCFAs) in murine stools, colons, and livers. We demonstrated that MCD-induced colitis pathogenesis largely depended on the gut microbes and the disease phenotypes could be transmissible through fecal microbiota transplantation (FMT). In conclusion, this study supports the concept that intake of MCD predisposes to experimental colitis and enhances its pathogenesis via modulating gut microbes and macrophages in mice.

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Fig. 1: Dyslipidemia and liver inflammation were observed in UC patients and mice.
Fig. 2: MCD exacerbated the disease progression and aggravated the colonic mucosal and liver inflammation in DSS-induced acute colitis.
Fig. 3: MCD exacerbated DSS-induced murine progressive and chronic colitis.
Fig. 4: MCD exacerbated infiltration of inflammatory macrophages in DSS-induced murine UC.
Fig. 5: Macrophage depletion compromised the pathological process of MCD-induced colitis susceptibility.
Fig. 6: Alteration of the metabolites from gut microbes was observed in MCD-treated colitis.
Fig. 7: MCD-induced colitis pathogenesis was largely dependent on gut microbes.
Fig. 8: MCD-induced colitis pathogenesis was reproducible by FMT.
Fig. 9

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Acknowledgements

This work was granted by National Natural Science Foundation of China (No. 82173822).

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  1. These authors contributed equally: Mo-ting Liu, Yao Zhang

Authors and Affiliations

  1. Laboratory of Anti-inflammation and Immunopharmacology, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Mo-ting Liu, Cai-gui Xiang, Tao Yang, Xiao-han Wang, Qiu-kai Lu, Hui-min Lu, Chen Fan, Chun-lan Feng, Xiao-qian Yang, Heng Li & Wei Tang

  2. School of Pharmacy, University of Chinese Academy of Sciences, Beijing, 100049, China

    Mo-ting Liu, Cai-gui Xiang, Tao Yang, Xiao-han Wang, Qiu-kai Lu, Hui-min Lu & Wei Tang

  3. Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Yao Zhang & Duo-wu Zou

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Contributions

MTL and HL designed the research and wrote the manuscript; MTL, CGX, QKL, HML, CF, TY, XHW, CLF, XQY, and HL performed the experiments and data analysis; YZ and DWZ collected the human samples; HL and WT revised the manuscript. DWZ and WT made a substantial contribution to the concept and supervision of the article. All the authors contributed to the interpretation of present data and approved the final manuscript.

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Correspondence to Duo-wu Zou, Heng Li or Wei Tang.

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Liu, Mt., Zhang, Y., Xiang, Cg. et al. Methionine-choline deficient diet deteriorates DSS-induced murine colitis through disturbance of gut microbes and infiltration of macrophages. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01291-y

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