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Cited by 325Gut microbiota and healthDrug Transport and Resistance MechanismsBerberine and alkaloids research

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Bile acid is a significant host factor shaping the gut microbiome of diet-induced obese mice

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Zheng, Xiaojiao, Huang, Fengjie, Zhao, Aihua, Lei, Sha, Zhang, Yunjing, Xie, Guoxiang, Chen, Tianlu, Qu, Chun, Rajani, Cynthia, Dong, Bing, Li, Defa, Jia, Wei·2017·BMC Biology
DOI 10.1186/s12915-017-0462-7PMC PMC5731064
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Abstract

BACKGROUND: Intestinal bacteria are known to regulate bile acid (BA) homeostasis via intestinal biotransformation of BAs and stimulation of the expression of fibroblast growth factor 19 through intestinal nuclear farnesoid X receptor (FXR). On the other hand, BAs directly regulate the gut microbiota with their strong antimicrobial activities. It remains unclear, however, how mammalian BAs cross-talk with gut microbiome and shape microbial composition in a dynamic and interactive way. RESULTS: We quantitatively profiled small molecule metabolites derived from host-microbial co-metabolism in mice, demonstrating that BAs were the most significant factor correlated with microbial alterations among all types of endogenous metabolites. A high-fat diet (HFD) intervention resulted in a rapid and significant increase in the intestinal BA pool within 12 h, followed by an alteration in microbial composition at 24 h, providing supporting evidence that BAs are major dietary factors regulating gut microbiota. Feeding mice with BAs along with a normal diet induced an obese phenotype and obesity-associated gut microbial composition, similar to HFD-fed mice. Inhibition of hepatic BA biosynthesis under HFD conditions attenuated the HFD-induced gut microbiome alterations. Both inhibition of BAs and direct suppression of microbiota improved obese phenotypes. CONCLUSIONS: Our study highlights a liver-BA-gut microbiome metabolic axis that drives significant modifications of BA and microbiota compositions capable of triggering metabolic disorders, suggesting new therapeutic strategies targeting BA metabolism for metabolic diseases.

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Fig. 1 The correlation between metabolite types and gut microbial phyla, and BA alterations with HFD intervention. a Principal component analysis was performed on each metabolite type and each phylum of gut microbiome. The t values of the first principal component (PC1) among the samples from control (n = 5) and HFD (n = 5) groups were selected as representative of each dataset. The heatmaps depict Spearman correlation of metabolite types and microbial phyla. Red and green cells indicate positive and negative correlations, respectively; *P < 0.05. b The concentrations of total, primary, and secondary BAs in caecal content in control (n = 7) and HFD (n = 7) groups. Data are expressed as mean ± SEM. Differences were assessed by the Mann–Whitney U test. Significance is established at adjusted P < 0.05 (*P < 0.05, **P < 0.01) with a false discovery rate (FDR) of 0.05. c The fold change ratios of the average concentrations of identified BA species in the HFD group (n = 7) to that in the control group (n = 7). Differences are assessed by the Mann–Whitney U test. Significance is established at adjusted P < 0.05 with FDR = 0.05
Fig. 1 The correlation between metabolite types and gut microbial phyla, and BA alterations with HFD intervention. a Principal component analysis was performed on each metabolite type and each phylum of gut microbiome. The t values of the first principal component (PC1) among the samples from control (n = 5) and HFD (n = 5) groups were selected as representative of each dataset. The heatmaps depict Spearman correlation of metabolite types and microbial phyla. Red and green cells indicate positive and negative correlations, respectively; *P < 0.05. b The concentrations of total, primary, and secondary BAs in caecal content in control (n = 7) and HFD (n = 7) groups. Data are expressed as mean ± SEM. Differences were assessed by the Mann–Whitney U test. Significance is established at adjusted P < 0.05 (*P < 0.05, **P < 0.01) with a false discovery rate (FDR) of 0.05. c The fold change ratios of the average concentrations of identified BA species in the HFD group (n = 7) to that in the control group (n = 7). Differences are assessed by the Mann–Whitney U test. Significance is established at adjusted P < 0.05 with FDR = 0.05CC BY · PubMed Central
Fig. 2 HFD-induced microbial composition changes in mouse caecum. a Principle coordinate analysis (PCOA) plot is generated using OTU metrics based on the Bray–Curtis similarity for the samples in control (n = 5) and HFD (n = 5) groups. The center point coordinate of the ellipse is the mean value of PC1 and PC2, respectively, in the corresponding group. The length of the semi-major and semi-minor axes of the ellipse is 1.5-fold SD of PC1 and PC2, respectively. The ellipse is rotated to the direction of largest variation of the corresponding group. The values of PC1 and PC2 are shown in bar plots. Data are expressed as mean ± SEM. Differences are assessed by the Mann–Whitney U test. Significance is established at P < 0.05 (***P < 0.001). b Hierarchical clustering based on the Bray–Curtis similarity of caecal content microbial composition in control (n = 5) and HFD (n = 5) groups. c The mean percentage of the total population at phylum levels in the caecal microbiota in control (n = 5) and HFD (n = 5) groups. Differences are assessed by the Mann–Whitney U test. Significance is established at P < 0.05 (*P < 0.05, **P < 0.01). d Linear discriminant analysis (LDA) effect size method was performed to compare taxa between control (red; n = 5) and HFD (green; n = 5) groups. The bar plot lists the significantly differential taxa based on effect size (LDA score (log 10) > 2). Enriched taxa in controls (negative LDA score), and enriched taxa in HFD (positive LDA score). e Spearman correlations of the relative abundance of differential microbial species selected by the LDA effect size method and the concentrations of BAs among the samples from control (n = 5) and HFD (n = 5) groups. The r values are represented by gradient colors, where red and green cells indicate positive and negative correlations, respectively; *P < 0.05
Fig. 2 HFD-induced microbial composition changes in mouse caecum. a Principle coordinate analysis (PCOA) plot is generated using OTU metrics based on the Bray–Curtis similarity for the samples in control (n = 5) and HFD (n = 5) groups. The center point coordinate of the ellipse is the mean value of PC1 and PC2, respectively, in the corresponding group. The length of the semi-major and semi-minor axes of the ellipse is 1.5-fold SD of PC1 and PC2, respectively. The ellipse is rotated to the direction of largest variation of the corresponding group. The values of PC1 and PC2 are shown in bar plots. Data are expressed as mean ± SEM. Differences are assessed by the Mann–Whitney U test. Significance is established at P < 0.05 (***P < 0.001). b Hierarchical clustering based on the Bray–Curtis similarity of caecal content microbial composition in control (n = 5) and HFD (n = 5) groups. c The mean percentage of the total population at phylum levels in the caecal microbiota in control (n = 5) and HFD (n = 5) groups. Differences are assessed by the Mann–Whitney U test. Significance is established at P < 0.05 (*P < 0.05, **P < 0.01). d Linear discriminant analysis (LDA) effect size method was performed to compare taxa between control (red; n = 5) and HFD (green; n = 5) groups. The bar plot lists the significantly differential taxa based on effect size (LDA score (log 10) > 2). Enriched taxa in controls (negative LDA score), and enriched taxa in HFD (positive LDA score). e Spearman correlations of the relative abundance of differential microbial species selected by the LDA effect size method and the concentrations of BAs among the samples from control (n = 5) and HFD (n = 5) groups. The r values are represented by gradient colors, where red and green cells indicate positive and negative correlations, respectively; *P < 0.05CC BY · PubMed Central
Fig. 3 The time-dependent alteration of BAs and microbe species in response to HFD. a Alteration of BAs shown by trajectories based on t values of principal component 1 (PC1) and PC2 of partial least squares discriminant analysis (PLS-DA). The red lines from D0 to D0.5 and D0.5 to D1 highlight when the most dramatic changes occurred. b Alteration of microbiota shown by trajectories based on t values of PC1 and PC2 of PLS-DA. The red lines from D1 to D2 and D2 to D3 highlight when the most dramatic changes occurred. c The concentration of each BA and the abundance of microbe species were compared between control (n = 5) and HFD (n = 5) groups at the corresponding time points. The BAs and microbes were recorded when they were significantly altered at the earliest time point. The number of recorded BAs and microbes is shown in the line charts, and the peaks of the two lines are highlighted in red. d The BAs and microbes selected in Fig. 4c are listed along the timeline, where red and green indicate high and low concentrations, respectively, in the HFD group relative to the control group at each corresponding time point
Fig. 3 The time-dependent alteration of BAs and microbe species in response to HFD. a Alteration of BAs shown by trajectories based on t values of principal component 1 (PC1) and PC2 of partial least squares discriminant analysis (PLS-DA). The red lines from D0 to D0.5 and D0.5 to D1 highlight when the most dramatic changes occurred. b Alteration of microbiota shown by trajectories based on t values of PC1 and PC2 of PLS-DA. The red lines from D1 to D2 and D2 to D3 highlight when the most dramatic changes occurred. c The concentration of each BA and the abundance of microbe species were compared between control (n = 5) and HFD (n = 5) groups at the corresponding time points. The BAs and microbes were recorded when they were significantly altered at the earliest time point. The number of recorded BAs and microbes is shown in the line charts, and the peaks of the two lines are highlighted in red. d The BAs and microbes selected in Fig. 4c are listed along the timeline, where red and green indicate high and low concentrations, respectively, in the HFD group relative to the control group at each corresponding time pointCC BY · PubMed Central
Fig. 4 The concentrations of BAs, physiological changes, and microbial composition after HFD feeding or BA supplementation. a The concentrations of total BAs, primary BAs, and secondary BAs in caecal content in control, control + BA, and HFD groups (n = 7 per group). Data are expressed as mean ± SEM. Differences were assessed by the Mann–Whitney U test. Significance was established at adjusted P < 0.05 (*P < 0.05, **P < 0.01) with FDR = 0.05. b Heatmaps of BA alteration, microbiome alteration, and their correlations. The two heatmaps with gradient colors of white to orange illustrate the mean concentration of BAs and the mean abundance of microbes in control, HFD, and control + BA groups. The heatmaps with gradient colors of green, white, and red illustrate the Spearman correlations of the relative abundance of microbes and the concentrations of BAs among the samples from the control (n = 5) and control + BA (n = 5) groups. The r values are represented by gradient colors, where red and green cells indicate positive and negative correlations, respectively; *P < 0.05. c Body weight, abdomen adipose tissue weight, liver weight, and the concentration of serum total cholesterol in control, control + BA, and HFD groups (n = 7 per group). Differences are assessed by the Mann–Whitney U test. Significance is established at adjusted P < 0.05 (*P < 0.05) with FDR = 0.05. d Principle coordinate analysis (PCOA) plot is generated using OTU metrics based on the Bray–Curtis similarity for the samples in control, control + BA, and HFD groups (n = 5 per group). The center point coordinate of the ellipse is the mean value of PC1 and PC2, respectively, in the corresponding group. The length of the semi-major axis and semi-minor axes of the ellipse is 1.5-fold SD of PC1 and PC2, respectively. The ellipse is rotated to the direction of largest variation of the corresponding group. The values of PC1 and PC2 are shown in bar plots. Data are expressed as mean ± SEM. Differences were assessed by the Mann–Whitney U test. Significance was established at P < 0.05 (***P < 0.001). e Hierarchical clustering based on the Bray–Curtis similarity for the microbial composition of caecal content of each sample in control, control + BA, and HFD groups (n = 5 per group). f The mean percentage of the total population at phylum levels in the caecal microbiota in control, control + BA, and HFD groups (n = 5 per group). Differences were assessed by the Mann–Whitney U test. Significance was established at P < 0.05 (*P < 0.05, **P < 0.01)
Fig. 4 The concentrations of BAs, physiological changes, and microbial composition after HFD feeding or BA supplementation. a The concentrations of total BAs, primary BAs, and secondary BAs in caecal content in control, control + BA, and HFD groups (n = 7 per group). Data are expressed as mean ± SEM. Differences were assessed by the Mann–Whitney U test. Significance was established at adjusted P < 0.05 (*P < 0.05, **P < 0.01) with FDR = 0.05. b Heatmaps of BA alteration, microbiome alteration, and their correlations. The two heatmaps with gradient colors of white to orange illustrate the mean concentration of BAs and the mean abundance of microbes in control, HFD, and control + BA groups. The heatmaps with gradient colors of green, white, and red illustrate the Spearman correlations of the relative abundance of microbes and the concentrations of BAs among the samples from the control (n = 5) and control + BA (n = 5) groups. The r values are represented by gradient colors, where red and green cells indicate positive and negative correlations, respectively; *P < 0.05. c Body weight, abdomen adipose tissue weight, liver weight, and the concentration of serum total cholesterol in control, control + BA, and HFD groups (n = 7 per group). Differences are assessed by the Mann–Whitney U test. Significance is established at adjusted P < 0.05 (*P < 0.05) with FDR = 0.05. d Principle coordinate analysis (PCOA) plot is generated using OTU metrics based on the Bray–Curtis similarity for the samples in control, control + BA, and HFD groups (n = 5 per group). The center point coordinate of the ellipse is the mean value of PC1 and PC2, respectively, in the corresponding group. The length of the semi-major axis and semi-minor axes of the ellipse is 1.5-fold SD of PC1 and PC2, respectively. The ellipse is rotated to the direction of largest variation of the corresponding group. The values of PC1 and PC2 are shown in bar plots. Data are expressed as mean ± SEM. Differences were assessed by the Mann–Whitney U test. Significance was established at P < 0.05 (***P < 0.001). e Hierarchical clustering based on the Bray–Curtis similarity for the microbial composition of caecal content of each sample in control, control + BA, and HFD groups (n = 5 per group). f The mean percentage of the total population at phylum levels in the caecal microbiota in control, control + BA, and HFD groups (n = 5 per group). Differences were assessed by the Mann–Whitney U test. Significance was established at P < 0.05 (*P < 0.05, **P < 0.01)CC BY · PubMed Central
Fig. 5 The concentrations of BAs, physiological changes, and microbial composition after HFD, HFD + GW4064, and HFD + rifaximin feeding. a The concentrations of total BAs, primary, and secondary BAs in caecal content in control, HFD, HFD + GW4064, and HFD + rifaximin groups (n = 7 per group). Data are expressed as mean ± SEM. Differences were assessed by the Mann–Whitney U test. Significance was established at adjusted P < 0.05 (*P < 0.05, **P < 0.01) with a false discovery rate (FDR) of 0.05. b Body weight, abdomen adipose tissue weight, liver weight, and concentration of total serum cholesterol in control, HFD, HFD + GW4064, and HFD + rifaximin groups (n = 7 per group). Data are expressed as mean ± SEM. Differences were assessed by Mann–Whitney U test. Significance was established at adjusted P < 0.05 (*P < 0.05) with FDR = 0.05. c Principle coordinate analysis (PCOA) plot generated using OTU metrics based on the Bray–Curtis similarity for control, HFD, and HFD + GW4064 groups (n = 5 per group). The center point coordinate of the ellipse is the mean value of PC1 and PC2, respectively, in the corresponding group. The length of the semi-major and semi-minor axes of the ellipse is 1.5-fold SD of PC1 and PC2, respectively. The ellipse is rotated to the direction of largest variation of the corresponding group. The values of PC1 and PC2 are shown in bar plots. Data are expressed as mean ± SEM. Differences were assessed by the Mann–Whitney U test. Significance was established at P < 0.05 (*P < 0.05, ***P < 0.001). d Mean percentage of the total population at phylum levels in the caecal microbiota in control, HFD, and HFD + GW4064 groups (n = 5 per group). Differences were assessed by the Mann–Whitney U test. Significance was established at P < 0.05 (control vs. HFD: *P < 0.05, ** P < 0.01; HFD vs. HFD + GW4064: #P < 0.05)
Fig. 5 The concentrations of BAs, physiological changes, and microbial composition after HFD, HFD + GW4064, and HFD + rifaximin feeding. a The concentrations of total BAs, primary, and secondary BAs in caecal content in control, HFD, HFD + GW4064, and HFD + rifaximin groups (n = 7 per group). Data are expressed as mean ± SEM. Differences were assessed by the Mann–Whitney U test. Significance was established at adjusted P < 0.05 (*P < 0.05, **P < 0.01) with a false discovery rate (FDR) of 0.05. b Body weight, abdomen adipose tissue weight, liver weight, and concentration of total serum cholesterol in control, HFD, HFD + GW4064, and HFD + rifaximin groups (n = 7 per group). Data are expressed as mean ± SEM. Differences were assessed by Mann–Whitney U test. Significance was established at adjusted P < 0.05 (*P < 0.05) with FDR = 0.05. c Principle coordinate analysis (PCOA) plot generated using OTU metrics based on the Bray–Curtis similarity for control, HFD, and HFD + GW4064 groups (n = 5 per group). The center point coordinate of the ellipse is the mean value of PC1 and PC2, respectively, in the corresponding group. The length of the semi-major and semi-minor axes of the ellipse is 1.5-fold SD of PC1 and PC2, respectively. The ellipse is rotated to the direction of largest variation of the corresponding group. The values of PC1 and PC2 are shown in bar plots. Data are expressed as mean ± SEM. Differences were assessed by the Mann–Whitney U test. Significance was established at P < 0.05 (*P < 0.05, ***P < 0.001). d Mean percentage of the total population at phylum levels in the caecal microbiota in control, HFD, and HFD + GW4064 groups (n = 5 per group). Differences were assessed by the Mann–Whitney U test. Significance was established at P < 0.05 (control vs. HFD: *P < 0.05, ** P < 0.01; HFD vs. HFD + GW4064: #P < 0.05)CC BY · PubMed Central

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Authors
Zheng, X., Huang, F., Zhao, A., Lei, S., Zhang, Y., Xie, G., Chen, T., Qu, C., Rajani, C., Dong, B., Li, D., & Jia, W.
Affiliations
  • Shanghai Jiao Tong University (CN)
  • University of Hawaii Cancer Center (US)
  • China Agricultural University (CN)
Corresponding author
Jia, Wei
ORCID
Venue
BMC Biology
Publisher
Springer Science and Business Media LLC
Published
2017-12
Volume
15
Issue
1
Pages
120-120
ISSN
1741-7007 (ISSN-L)
DOI
10.1186/s12915-017-0462-7
PMC
PMC5731064
OpenAlex
W2774287749
Cited by
323
References
40
Citations by year
2026: 18 · 2025: 36 · 2024: 40 · 2023: 61 · 2022: 44 · 2021: 47 · 2020: 36 · 2019: 29 · 2018: 12
FWCI
8.83
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • BMC Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (31500954)
  • Science and Technology Committee of Shanghai Municipality Government (15YF1409100)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Pharmacology (medical) › Berberine and alkaloids research
Keywords
bile acids, gut microbiota, diet-induced obesity, high-fat diet, bile acid synthesis, FGF19, farnesoid X receptor, small molecule metabolites, metabolic disorders
MeSH terms
Gastrointestinal Microbiome, Receptor, Farnesoid X-Activated, Animals, Bile Acids and Salts, Isoxazoles, Male, Mice, Inbred C57BL, Mice, Obese, Signal Transduction, Receptors, Cytoplasmic and Nuclear, Mice, Diet, High-Fat

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