Predicting Inchinkoto efficacy, in patients with obstructive jaundice associated with malignant tumors, through pharmacomicrobiomics.

Inchinkoto (ICKT) is a popular choleretic and hepatoprotective herbal medicine that is widely used in Japan. Geniposide, a major ingredient of ICKT, is metabolized to genipin by gut microbiota, which exerts a choleretic effect. This study investigates the relationship between stool genipin-producing activity and diversity of the clinical effect of ICKT in patients with malignant obstructive jaundice. Fifty-two patients with malignant obstructive jaundice who underwent external biliary drainage were included. ICKT was administered as three packets per day (7.5 g/day) for three days and 2.5 g on the morning of the fourth day. Stool samples were collected before ICKT administration and bile flow was monitored on a daily basis. The microbiome, genipin-producing activity, and organic acids in stools were analyzed. The Shannon-Wiener (SW) index was calculated to evaluate gut microbiome diversity. The stool genipin-producing activity showed a significant positive correlation with the SW index. Stool genipin-producing activity positively correlated with the order Clostridia (obligate anaerobes), but negatively correlated with the order Lactobacillales (facultative anaerobes). Moreover, stool genipin-producing activity was positively correlated to the concentration valeric acid, but negatively correlated to the concentration of lactic acid and succinic acid. The change of bile flow at 2 and 3 days after ICKT administration showed significant positive correlation with genipin-producing activity (correlation coefficient, 0.40 and 0.29, respectively, P < 0.05). An analysis of stool profile, including stool genipin-producing activity, may predict the efficacy of ICKT. Modification of the microbiome may be a target to enhance the therapeutic effect of ICKT.

Comprehensive metabolome analysis for the pharmacological action of inchinkoto, a hepatoprotective herbal medicine.

INTRODUCTION: The precise pharmacological action of inchinkoto (ICKT, Yin-Chen-Hao-Tang in Chinese), a hepatoprotective herbal medicine, on total metabolic pathways has not been well investigated. OBJECTIVES: The aim of this study was to explore the serum metabolites reflecting the pharmacological activity of ICKT, and mechanism of action of ICKT using serum metabolome analysis. METHODS: 54 patients with obstructive jaundice due to malignancies were included in this study. ICKT was administered for 3 days. Serum and bile samples were collected before and 1 h after ICKT administration on days 1 and 4. Serum metabolome analysis including ICKT components were performed. RESULTS: The levels of total/direct bilirubin, C-reactive protein, γ-glutamyl transpeptidase, and albumin in the serum were significantly improved after ICKT administration. In the serum metabolome analysis, inosine was the only elevated metabolite on days 1 and 4. Most of the metabolites which were significantly changed after ICKT administration were lipid mediators, and all decreased on day 1. Notably, the levels of many lipid mediators were increased on day 4. The difference in serum aspartic acid 1 h after ICKT administration was significantly correlated with a decrease in the levels of total bilirubin in the serum on day 4. CONCLUSIONS: Using metabolome analysis, we demonstrated several metabolic changes that may be associated with the pharmacological mechanisms of ICKT. The biological implications of these metabolites should be further investigated in basic research studies.