Background: Nonalcoholic fatty liver disease (NAFLD) is characterized by an abnormal accumulation of lipids in the liver tissue. Aim: This study aims to evaluate the potential therapeutic effect of oral Lycium barbarum polysaccharide (LBP) capsules in patients with NAFLD. Methods: A pre–post-intervention clinical trial involving 13 participants, aged 28–50 years, was conducted at a community health center. Participants underwent abdominal ultrasound and laboratory tests, including alanine aminotransferase level measurements. During the 12-week intervention period, participants received a daily oral LBP supplement capsule (300 mg). We collected blood and stool samples at baseline and postintervention, which were for 16S rRNA gene sequencing and metabolomics analysis. Results: Postintervention, significant reductions (p < 0.05) were observed in gamma-glutamyltransferase (GGT), ALB, TP, and D-BIL levels. There were 125 upregulated and 65 downregulated metabolites. LBP supplementation increased Gemmiger abundance. Microbiota diversity, analyzed through 16S rRNA sequencing, showed altered phylum distribution in fecal samples, with PICRUSt2 indicating effects on linoleic acid metabolism. Changes in negative correlations between specific lipid metabolites, such as Her2Cer(d14:0_22:6), and enzyme activities like GGT, were also noted. Conclusion: Lycium barbarum polysaccharide intervention may enhance GGT, ALB, TP, and D-BIL levels, demonstrating beneficial effects on critical biochemical parameters in NAFLD patients. Correlation analysis showed LBP alters the relationship between specific lipid metabolites and enzyme activity, notably between GGT and Her2Cer(d14:0_22:6), laying groundwork for further research on LBP's impact on NAFLD. Trial registration: Chinese Clinical Trial Registry, ChiCTR2000034740, and Institutional Ethics Committee of Ningxia Medical University, 2019-329.
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