Effect of Korea red ginseng on nonalcoholic fatty liver disease: an association of gut microbiota with liver function

Abstract

Background: Korea Red Ginseng (KRG) has been used as remedies with hepato-protective effects in liver-related condition. Microbiota related gut-liver axis plays key roles in the pathogenesis of chronic liver disease. We evaluated the effect of KRG on gut-liver axis in patients with nonalcoholic statohepatitis by the modulation of gut-microbiota.

Methods: A total of 94 patients (KRG: 45 and placebo: 49) were prospectively randomized to receive KRG (2,000 mg/day, ginsenoside Rg1+Rb1+Rg3 4.5mg/g) or placebo during 30 days. Liver function test, cytokeraton 18, and fatigue score were measured. Gut microbiota was analyzed by MiSeq systems based on 16S rRNA genes.

Results: In KRG group, the mean levels (before vs. after) of aspartate aminotransferase (53 ± 19 vs. 45 ± 23 IU/L), alanine aminotransferase (75 ± 40 vs. 64 ± 39 IU/L) and fatigue score (33 ± 13 vs. 26 ± 13) were improved (p < 0.05). In placebo group, only fatigue score (34 ± 13 vs. 31 ± 15) was ameliorated (p < 0.05). The changes of phyla were not statistically significant on both groups. In KRG group, increased abundance of Lactobacillus was related with improved alanine aminotransferase level and increased abundance of Clostridium and Intestinibacter was associated with no improvement after KRG supplementation. In placebo group, increased abundance of Lachnospiraceae could be related with aggravation of liver enzyme (p < 0.05).

Conclusion: KRG effectively improved liver enzymes and fatigue score by modulating gut-microbiota in patients with fatty liver disease. Further studies are needed to understand the mechanism of improvement of nonalcoholic steatohepatitis.

Clnicaltrialsgov: NCT03945123 (www.ClinicalTrials.gov).

Keywords: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK18, cytokeratin 18; KRG, Korea Red Ginseng; LEfSe, Linear Discriminant Analysis Effect Size; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; OTUs, operational taxonomic units; PCoA, principal coordinate analysis; fatty liver; ginseng; gut microbiota; nonalcoholic fatty liver disease.

Fig. 1

Flow chart and study design. NAFLD, nonalcoholic fatty liver disease; KRG, Korean Red Ginseng.

Fig. 2

Comparison of diversity indices and total bacterial amounts between before and after ingestion of KRG (n = 35) and placebo (n = 30) groups. (A) The number of observed OTUs, Shannon diversity indices, and total bacterial amounts were compared between before and after ingestion of KRG and placebo. (B) The difference of gut microbiota was analyzed in PCoA plot. The inter-variation and intra-variation of gut microbiota were compared in both of KRG and placebo group based on unweighted UniFrac distance. ∗p value < 0.05.

Fig. 3

Different members of gut microbiota between KRG (n = 35) and placebo (n = 30) groups. (A) Comparison of gut microbiota composition between before and after ingestion in both of KRG and placebo group at phylum and genus level. (B) Different taxa of gut microbiota between KRG and placebo group before and after ingestion detected in LefSe analysis.

Fig. 4

Significantly different genera between before and after ingestion in both of KRG and placebo sub-groups. Subjects in each treatment group were divided into three subgroups (improve, no change, and aggravate) according to ALT changed values. ∗p value < 0.05. Two groups were divided into three subgroups (improve [improved by 10 IU/L or more], no change [changed less than 10 IU/L], and aggravate [worsened by 10 or more]) according to ALT change.

Fig. 5

Correlated genera with the values of AST and ALT in both of KRG (n = 35) and placebo (n = 30) groups. The correlation was determined by the Spearman's rank correlation using the proportions of genus in gut microbiota of each group and the values of AST and ALT. ∗p value < 0.05.