Background Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. As a potential therapeutic target, Nogo-B is needed to determine whether it has an impact on the intestinal microbiome and metabolic pathways.

Objective To explore the protective effect of Nogo-B knockdown on NAFLD and clarify the effects of Nogo-B knockdown on gut microbiota and serum metabolites in NAFLD mice.

Methods Twelve 8-week-old wild type (WT) mice were randomly divided into WT-NCD group and WT-HFD group. Twelve 8-week-old Nogo-B knockout (Nogo-B^-/-) mice were randomly divided into Nogo-B^-/--NCD group and Nogo-B^-/--HFD group. Mice in the WT-HFD and Nogo-B^-/--HFD groups were fed with 60 kal% high-fat diet (HFD) for 12 weeks to construct the NAFLD mouse model, while mice in the WT-NCD and Nogo-B^-/--NCD groups were fed with normal chow diet (NCD) for the same amount of time. Body weight was measured in all four groups. The hepatic triglyceride (TG) and total cholesterol (TC) levels were measured by enzyme-linked immunosorbent assay (ELISA); hematoxylin-eosin (HE) staining was used to evaluate the hepatic pathological features of mice in the four groups; and the gut microbiota and sera metabolites were examined in mice of the WT-HFD and the Nogo-B^-/--HFD groups.

Results At the end of 12-week modeling, the body weight and TC and TG levels in liver tissues of mice in the WT-HFD group were elevated compared with mice in the WT-NCD group (P＜0.01); and the body weight and TC and TG levels in liver tissues of mice in the Nogo-B^-/--HFD group were also elevated compared with those of mice in the Nogo-B^-/--NCD group (P＜0.01); whereas when the Nogo-B was knockout, the body weight and TC and TG levels in liver tissues of mice in the Nogo-B^-/--HFD group decreased compared with those in the WT-HFD group (P＜0.01); intestinal microbiomics showed that Butyricicoccaceae became the dominant species in the gut microbes of Nogo-B knockdown NAFLD mice; serum metabolomics showed that 159 different metabolites were screened between the two groups (WT-HFD group, Nogo-B^-/--HFD group), 79 were up-regulated and 80 were down-regulated, and the metabolic pathways that were extremely significantly enriched (P＜0.001) were the citrate cycle/tricarboxylic acid cycle (TCA cycle), etc., and the major enriched metabolites were citric acid, succinic acid, isocitrate and malic acid.

Conclusion NAFLD mice with Nogo-B knockout show reduced hepatic lipid accumulation, increased beneficial intestinal microbiota, and improved metabolic disorders to some extent. Nogo-B may be a potential target for NAFLD therapy.