Abstract

Scope The overall changes of colon under nonalcoholic fatty liver disease (NAFLD) remain to be further elucidated. Methods and Results This study establishes a mouse model of NAFLD through a long‐term Gubra Amylin‐nonalcoholic steatohepatitis (NASH) diet (GAN diet). The results show that GAN diet significantly induces weight gain, liver steatosis, colonic oxidative stress, and lipid accumulation in blood, liver, and adipose tissue in mice. GAN feeding reduces the diversity of the gut microbiota, alters the composition and abundance of the gut microbiota, and leads to an increase in microbial metabolites such as long‐chain fatty acids (LCFAs) and secondary bile acids (BAs), as well as a decrease in short‐chain fatty acids (SCFAs). The RNA‐seq and immunofluorescence results reveal that the GAN diet alters the expression of proteins and their coding genes involved in oxidative stress, immune response, and barrier function in colon tissue, such as lipocalin‐2 ( Lcn2 , p < 0.05), heme oxygenase‐1 ( HO‐1/Hmox1 , p < 0.05), interferon‐gamma ( IFN‐γ ), and claudin‐3/7 . In addition, correlation analysis indicates a strong correlation between the changes in gut microbiota and lipid biomarkers. Additionally, the expression of immune related genes in colon tissue is related to the LCFAs produced by microbial metabolism. Conclusion GAN‐induced NAFLD is related to microbiota and its metabolic imbalance, oxidative stress, immune disorders, and impaired barrier function in colon.