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. 2017 Sep 6;12(9):e0182467.
doi: 10.1371/journal.pone.0182467. eCollection 2017.

In vivo therapeutic effect of combination treatment with metformin and Scutellaria baicalensis on maintaining bile acid homeostasis

Kyungsun Han  1   2 , Shambhunath Bose  3 , Jing-Hua Wang  1 , Soo-Kyoung Lim  1 , Young-Won Chin  4 , Young-Mi Kim  4 , Han-Seok Choi  5 , Hojun Kim  1
Affiliations
Free PMC article

In vivo therapeutic effect of combination treatment with metformin and Scutellaria baicalensis on maintaining bile acid homeostasis

Kyungsun Han et al. PLoS One. .
Free PMC article

Abstract

The radix of Scutellaria baicalensis (SB) is a herb widely used in traditional Chinese medicine to treat metabolic diseases. Several main components, including baicalin and wogonoside, possess anti-dyslipidemia, anti-obesity and anti-diabetic effects. We hypothesized that co-administration of SB extract and metformin exerts a better effect on obesity-induced insulin resistance and lipid metabolism than treatment with metformin alone. We compared the effect of metformin (100 mg/10 mL/kg/day) alone with co-administration of metformin (100 mg/5 mL/kg/day) and SB extract (200 mg/5 mL/kg/day) on Otsuka Long Evans Tokushima Fatty rats, a useful model of type II diabetes with obesity, and used Long-Evans Tokushima Otsuka rats as a control. Weight, fasting glucose, oral glucose tolerance test, intraperitoneal insulin tolerance test, and serum total cholesterol were measured after 12 weeks of drug administration. We observed a synergetic effect of metformin and SB on lowering cholesterol level by excretion of bile acid through feces. We found that this accompanied activation of FXR, CYP7A1 and LDLR genes and repression of HMGCR in the liver. Although there were no significant changes in BSH-active gut microbiota due to high variability, functional prediction with 16S sequences showed increased primary and secondary bile acid biosynthesis in the combination treatment group. Further study is needed to find the specific strains of bacteria which contribute to FXR-related cholesterol and bile acid regulations.

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Conflict of interest statement

Competing Interests: Shambhunath Bose is affiliated with Applied Surface Technology, Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Quality control of Scutellaria baicalensis(SB).
Detection of main components of SB extract by Ultra-Performance Liquid Chromatography (UPLC) analysis. Main compounds were confirmed by comparison of the retention time, UV chromatogram(A) and MASS chromatogram(B) with those of the standards. The major compound was identified as baicalin.
Fig 2
Fig 2. Effect of metformin and metformin plus Scutellaria baicalensis (SB) extract on the glucose homeostasis and insulin sensitivity in OLETF rats.
(A, B) Oral glucose tolerance test (OGTT) and (C, D) intraperitoneal insulin tolerance test (IPITT). #: p < 0.05 compared to LETO group. *: p <0.05 compared to OLETF group. **: p <0.001 compared to OLETF group. MetSB: Metformin co-administered with Scutellaria baicalensis extract.
Fig 3
Fig 3. Principal Component Analysis (PCA) analyses of 84 gene sets of related to insulin resistance and fatty liver.
Vectors indicate the strength and direction of each gene expressions to the overall distribution. Red plots correspond to each experimental groups in this study.
Fig 4
Fig 4. Western blot analysis of CYP7A1, HMG CoA reductase, LDL receptor and FXR in liver tissues.
MetSB: Metformin co-administered with Scutellaria baicalensis extract. Each protein samples are obtained by pooling liver tissues from each group. Numbers denotes fold changes compared to LETO group. Y-axis denotes fold changes compared to LETO group.
Fig 5
Fig 5. Quantitative analysis of total cholesterol and total bile acids in feces and liver.
Values are means ± Standard deviations. #: p < 0.05 compared to LETO group. *: p <0.05 compared to OLETF group. **: p < 0.001 compared to OLETF group. MetSB: Metformin co-administered with Scutellaria baicalensis extract. Liver and fecal samples were obtained from individual rats from each group.
Fig 6
Fig 6. Relative abundance of intestinal microbial community after 12 weeks of drug intervention shown at the phylum level and family level.
MetSB: Metformin co-administered with Scutellaria baicalensis extract. Data are from stool samples from 5 rats/group.
Fig 7
Fig 7. Relative abundance of intestinal microbiota with bile salt hydrolase (BSH) activity.
Relative abundance of intestinal microbiota related to bile acid deconjugation was analyzed with fecal samples. There was no significant difference between groups. MetSB: Metformin co-administered with Scutellaria baicalensis extract. Data are from stool samples from 5 rats/group.
Fig 8
Fig 8. Functional composition of metagenome related to metabolism was predicted with PICRUSt algorithm.
#: p < 0.05 compared to LETO group. MetSB: Metformin co-administered with Scutellaria baicalensis extract.
Fig 9
Fig 9. Predicted functional composition of metagenome related to primary and secondary bile acid biosynthesis was analyzed with PICRUSt algorithm.
There was no significant difference between groups. MetSB: Metformin co-administered with Scutellaria baicalensis extract.
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Grants and funding

This work was supported by the grant of Convergence of Conventional Medicine and Traditional Korean Medicine R&D program funded by the Ministry of Health and Welfare through the KHIDI (Korea Health Industry Development Institute, HI14C0558). Author Shambhunath Bose receives a salary from Applied Surface Technology, Inc. The specific roles of this author are articulated in the ‘author contributions’ section. The funders did not play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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