2. Academic Validation
  3. Host ALDH2 deficiency aggravates nonalcoholic steatohepatitis through gut-liver axis

Host ALDH2 deficiency aggravates nonalcoholic steatohepatitis through gut-liver axis

  • Pharmacol Res. 2023 Aug 30;106902. doi: 10.1016/j.phrs.2023.106902.
Zhan-Ming Li 1,  Chao-Yue Kong 2,  Yu-Qin Mao 3,  Hui-Ling Chen 4,  Shi-Long Zhang 5,  Jia-Ting Huang 6,  Jin-Qing Yao 7,  Pei-Ran Cai 8,  Nuo Xie 9,  Bing Han 10,  Li-Shun Wang 11
Affiliations

Affiliations

  • 1 Center for traditional Chinese medicine and gut microbiota, Minhang Hospital, Fudan University, 201199 Shanghai, China; Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, 201199 Shanghai, China. Electronic address: zhanmingli123@163.com.
  • 2 Center for traditional Chinese medicine and gut microbiota, Minhang Hospital, Fudan University, 201199 Shanghai, China; Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, 201199 Shanghai, China. Electronic address: kongchaoyue@163.com.
  • 3 Center for traditional Chinese medicine and gut microbiota, Minhang Hospital, Fudan University, 201199 Shanghai, China; Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, 201199 Shanghai, China. Electronic address: myq110813@163.com.
  • 4 Center for traditional Chinese medicine and gut microbiota, Minhang Hospital, Fudan University, 201199 Shanghai, China; Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, 201199 Shanghai, China. Electronic address: chenhuil@163.com.
  • 5 Center for traditional Chinese medicine and gut microbiota, Minhang Hospital, Fudan University, 201199 Shanghai, China; Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, 201199 Shanghai, China. Electronic address: 15211210048@fudan.edu.cn.
  • 6 Center for traditional Chinese medicine and gut microbiota, Minhang Hospital, Fudan University, 201199 Shanghai, China; Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, 201199 Shanghai, China. Electronic address: 18211360005@fudan.edu.cn.
  • 7 Center for traditional Chinese medicine and gut microbiota, Minhang Hospital, Fudan University, 201199 Shanghai, China; Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, 201199 Shanghai, China. Electronic address: 772448451@qq.com.
  • 8 Center for traditional Chinese medicine and gut microbiota, Minhang Hospital, Fudan University, 201199 Shanghai, China; Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, 201199 Shanghai, China. Electronic address: caipr@163.com.
  • 9 Center for traditional Chinese medicine and gut microbiota, Minhang Hospital, Fudan University, 201199 Shanghai, China; Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, 201199 Shanghai, China. Electronic address: hb054080108@126.com.
  • 10 Center for traditional Chinese medicine and gut microbiota, Minhang Hospital, Fudan University, 201199 Shanghai, China; Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, 201199 Shanghai, China. Electronic address: lishunwang@fudan.edu.cn.
  • 11 Center for traditional Chinese medicine and gut microbiota, Minhang Hospital, Fudan University, 201199 Shanghai, China; Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, 201199 Shanghai, China. Electronic address: binghan_@fudan.edu.cn.
PMID: 37657657 DOI: 10.1016/j.phrs.2023.106902
Abstract

Nonalcoholic steatohepatitis (NASH) is the major cause of liver dysfunction. Animal and population studies have shown that mitochondrial aldehyde dehydrogenase (ALDH2) is implicated in fatty liver disease. However, the role of ALDH2 in NASH and the underlying mechanisms remains unclear. To address this issue, ALDH2 knockout (ALDH2-/-) mice and wild-type littermate mice were fed a methionine-and choline-deficient (MCD) diet to induce a NASH model. Fecal, serum, and liver samples were collected and analyzed to investigate the impact of the gut microbiota and bile acids on this process. We found that MCD-fed ALDH2-/- mice exhibited increased serum pro-inflammation cytokines, hepatic inflammation and fat accumulation than their wild-type littermates. MCD-fed ALDH2-/- mice exhibited worsened MCD-induced intestinal inflammation and barrier damage, and gut microbiota disorder. Furthermore, mice receiving microbiota from MCD-fed ALDH2-/- mice had increased severity of NASH compared to those receiving microbiota from MCD-fed wild-type mice. Notably, the intestinal Lactobacillus was significantly reduced in MCD-fed ALDH2-/- mice, and gavage with Lactobacillus cocktail significantly improved MCD-induced NASH. Finally, we found that ALDH2-/- mice had reduced levels of bile salt hydrolase and specific bile acids, especially lithocholic acid (LCA), accompanied by downregulated expression of the intestinal FXR-FGF15 pathway. Supplementation of LCA in ALDH2-/- mice upregulated intestinal FXR-FGF15 pathway and alleviated NASH. In summary, ALDH2 plays a critical role in the development of NASH through modulation of gut microbiota and bile acid. The findings suggest that supplementing with Lactobacillus or LCA could be a promising therapeutic approach for treating NASH exacerbated by ALDH2 deficiency.

Keywords

ALDH2; LCA; Lactobacillus; gut microbiota; non-alcoholic steatohepatitis.

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