Impaired intestinal akkermansia muciniphila and aryl hydrocarbon receptor ligands contribute to nonalcoholic fatty liver disease in mice

Zunji Shi, Hehua Lei, Gui Chen, Peihong Yuan, Zheng Cao, Hooi Leng Ser, Xuehang Zhu, Fang Wu, Caixiang Liu, Manyuan Dong, Yuchen Song, Yangyang Guo, Chuan Chen, Kexin Hu, Yifan Zhu, Xin An Zeng, Jinlin Zhou, Yujing Lu, Andrew D. Patterson, Limin Zhang

Research output: Contribution to journalArticlepeer-review

43 Scopus citations


Noncaloric artificial sweeteners (NAS) are extensively introduced into commonly consumed drinks and foods worldwide. However, data on the health effects of NAS consumption remain elusive. Saccharin and sucralose have been shown to pass through the human gastrointestinal tract without undergoing absorption and metabolism and directly encounter the gut microbiota community. Here, we aimed to identify a novel mechanism linking intestinal Akkermansia muciniphila and the aryl hydrocarbon receptor (AHR) to saccharin/sucralose-induced nonalcoholic fatty liver disease (NAFLD) in mice. Saccharin/sucralose consumption altered the gut microbial community structure, with significant depletion of A. muciniphila abundance in the cecal contents of mice, resulting in disruption of intestinal permeability and a high level of serum lipopolysaccharide, which likely contributed to systemic inflammation and caused NAFLD in mice. Saccharin/sucralose also markedly decreased microbiota-derived AHR ligands and colonic AHR expression, which are closely associated with many metabolic syndromes. Metformin or fructo-oligosaccharide supplementation significantly restored A. muciniphila and AHR ligands in sucralose-consuming mice, consequently ameliorating NAFLD. IMPORTANCE Our findings indicate that the gut-liver signaling axis contributes to saccharin/sucralose consumption-induced NAFLD. Supplementation with metformin or fructo-oligosaccharide is a potential therapeutic strategy for NAFLD treatment. In addition, we also developed a new nutritional strategy by using a natural sweetener (neohesperidin dihydrochalcone [NHDC]) as a substitute for NAS and free sugars.

Original languageEnglish (US)
Article numbere00985-20
Issue number1
StatePublished - 2021

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Physiology
  • Biochemistry
  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Molecular Biology
  • Genetics
  • Computer Science Applications


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