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. 2020 Mar 26;15(3):e0230200.
doi: 10.1371/journal.pone.0230200. eCollection 2020.

An in vitro evaluation of the effects of different statins on the structure and function of human gut bacterial community

Changhui Zhao  1   2 , Yunfei Hu  2 , Huahai Chen  2 , Baiyuan Li  2 , Linyan Cao  2 , Jinlan Xia  1 , Yeshi Yin  2
Affiliations

An in vitro evaluation of the effects of different statins on the structure and function of human gut bacterial community

Changhui Zhao et al. PLoS One. .

Abstract

Statins, a class of drugs that can effectively remove cholesterol from serum, are used to regulate plasma total cholesterol and reduce the risk of cardiovascular diseases, but it is still unclear whether the drug are modulated by gut microbiota or the structures of gut microbiota are shaped by statins. We investigated the interactions between statins and the human gut microbiota during the in vitro fermentation process by 16S rRNA gene sequencing, gas chromatography (GC), and high-performance liquid chromatography (HPLC) analyses. The presence of fluvastatin (FLU2) specifically promoted the growth of Escherichia/Shigella, Ruminococcaceae UCG 014, and Sutterella. However, the composition of the gut bacterial microbiota remained relatively static in samples treated with rosuvastatin (ROS), simvastatin (SIM), and atorvastatin (ATO). The PICRUSt program predicted moderate differences in the functional categories related to the biosynthesis of other secondary metabolites, cellular processes and signaling, and signal transduction in the FLU2 fermentation samples. Our study revealed substantial variation in the structure and function of microbiomes from the FLU2-treated samples. In addition, short-chain fatty acids (SCFAs) were also significantly decreased in FLU2-treated samples compared with the samples treated with other stains. Statins can be degraded by the human gut microbiota in vitro, and the degradation rate was approximately 7%-30% and 19%-48% after fermentation was allowed to proceed for 24 h and 48 h, respectively. Generally, FLU2 could largely shape the composition and function of human gut microbiota, which resulted in changes in the production of SCFAs. In turn, all statins could be degraded or modified by the gut microbiota. Our study paves the way for elucidating statin-gut microbiota interactions in vitro towards the improvement of the host health and personalized medicine.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Principal coordinates analysis (PCoA) plot.
PCoA plot of the gut microbiota based on the unweighted UniFrac metric. Basic analysis of sequenced data. Con, A1, A2, F1, F2, R1, R2, S1, and S2 represent the gut microbiota of fermented samples using the media plus DMSO and different statins at 20 μM and colon concentration. The p value of A, F, R, and S is 0.951, 0.006, 1, and 0.999, respectively, which was obtained by permanova.
Fig 2
Fig 2. Analysis of the different abundant bacterial taxa using LEfSe.
The bacterial percentage of the fermented samples was used for LEfSe analysis. The P-value <0.05 was identified as being significantly different between groups. Significantly enriched bacterial phyla, classes, orders, families, and genera are listed next to the histogram. Con, FLU1, and FLU2 represent samples collected after cultured using VI media with DMSO, 20 μM, and colon concentration of FLU. A Significantly different bacteria between FLU1 and FLU2. B Significantly different bacteria between groups of FLU2 and DMSO.
Fig 3
Fig 3. Relative abundance of individual gut microbiota composition at different taxonomic rank.
Heatmap visualizes logarithm (base-10) of ratios (p<0.05). A Phyla found to be statistically different among the three groups. B Genera found to be statistically different among the three groups.
Fig 4
Fig 4. KEGG categories present in the human gut microbiota.
The KEGG pathways in box A were not affected by FLU2; the KEGG pathways in boxes B and C were affected significantly by FLU2 compared with other statins (Box A p>0.05; Box B: p<0.05, 0.05
Fig 5
Fig 5. Functional analysis of the proteins involved in biosynthesis of xenobiotics biodegradation and metabolism.
** means significantly different between F2 and some other samples except for A2 (p<0.05; FDR<0.05); * means significantly different between F2 and some other samples except for A2 (p<0.05; 0.05<FDR<0.1).
Fig 6
Fig 6. Effect of statins on SCFA production after fermentation.
Acetic, propionic, isobutyric, butyric, isovaleric, and valeric acid were detected using GC in this paper. Each sample was measured in triplicate. Figures were generated using GraphPad Prism version 5.01. The figure shows total SCFA, acetic, propionic, and butyric acid concentration of the following samples: (1: 20 μM; 2: colon concentration; A: ATO; S: SIM; R: ROS; F: FLU).
Fig 7
Fig 7. Degradation of statins.
Different statins were detected by HPLC, and the degradation was obtained by the original percentage subtracted measurable percentage. Each statin sample was measured in duplicate.
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This work was supported by the National Natural Science Foundation of China (No. 31741109) to HC and the Hunan Natural Science Foundation (No. 2018JJ3200) to YY, and the construct program of applied characteristic discipline in Hunan University of Science and Engineering to YY.