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Persistent Organic Pollutants Modify Gut Microbiota-Host Metabolic Homeostasis in Mice Through Aryl Hydrocarbon Receptor Activation.

Zhang L, Nichols RG, Correll J, Murray IA, Tanaka N, Smith PB, Hubbard TD, Sebastian A, Albert I, Hatzakis E, Gonzalez FJ, Perdew GH, Patterson AD - Environ. Health Perspect. (2015)

Bottom Line: Six-week-old male wild-type and Ahr-/- mice on the C57BL/6J background were treated with 24 μg/kg TCDF in the diet for 5 days.TCDF-treated mouse cecal contents were enriched with Butyrivibrio spp. but depleted in Oscillobacter spp. compared with vehicle-treated mice.Further, dietary TCDF inhibited the farnesoid X receptor (FXR) signaling pathway, triggered significant inflammation and host metabolic disorders as a result of activation of bacterial fermentation, and altered hepatic lipogenesis, gluconeogenesis, and glycogenolysis in an AHR-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA.

ABSTRACT

Background: Alteration of the gut microbiota through diet and environmental contaminants may disturb physiological homeostasis, leading to various diseases including obesity and type 2 diabetes. Because most exposure to environmentally persistent organic pollutants (POPs) occurs through the diet, the host gastrointestinal tract and commensal gut microbiota are likely to be exposed to POPs.

Objectives: We examined the effect of 2,3,7,8-tetrachlorodibenzofuran (TCDF), a persistent environmental contaminant, on gut microbiota and host metabolism, and we examined correlations between gut microbiota composition and signaling pathways.

Methods: Six-week-old male wild-type and Ahr-/- mice on the C57BL/6J background were treated with 24 μg/kg TCDF in the diet for 5 days. We used 16S rRNA gene sequencing, 1H nuclear magnetic resonance (NMR) metabolomics, targeted ultra-performance liquid chromatography coupled with triplequadrupole mass spectrometry, and biochemical assays to determine the microbiota compositions and the physiological and metabolic effects of TCDF.

Results: Dietary TCDF altered the gut microbiota by shifting the ratio of Firmicutes to Bacteroidetes. TCDF-treated mouse cecal contents were enriched with Butyrivibrio spp. but depleted in Oscillobacter spp. compared with vehicle-treated mice. These changes in the gut microbiota were associated with altered bile acid metabolism. Further, dietary TCDF inhibited the farnesoid X receptor (FXR) signaling pathway, triggered significant inflammation and host metabolic disorders as a result of activation of bacterial fermentation, and altered hepatic lipogenesis, gluconeogenesis, and glycogenolysis in an AHR-dependent manner.

Conclusion: These findings provide new insights into the biochemical consequences of TCDF exposure involving the alteration of the gut microbiota, modulation of nuclear receptor signaling, and disruption of host metabolism.

No MeSH data available.


Related in: MedlinePlus

Host metabolism and the bacterial fermentation process in Ahr+/+ mice after dietary exposure to vehicle or TCDF (24 μg/kg). OPLS-DA scores (left) and coefficient-coded loadings plots for the models (right) from NMR spectra of aqueous fecal (A), cecal content (B), and liver extracts (C), discriminating between the vehicle (black circles) and TCDF-treated mice (red squares). These models are cross-validated with CV-ANOVA: p = 1.64 × 10–3, p = 0.033, and p = 0.0018 for feces, cecal content, and liver, respectively. Metabolite assignment is shown in Supplemental Material, Figure S5 and Table S4, and correlation coefficient values for the significantly changed metabolites are shown in Supplemental Material, Table S3.
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f5: Host metabolism and the bacterial fermentation process in Ahr+/+ mice after dietary exposure to vehicle or TCDF (24 μg/kg). OPLS-DA scores (left) and coefficient-coded loadings plots for the models (right) from NMR spectra of aqueous fecal (A), cecal content (B), and liver extracts (C), discriminating between the vehicle (black circles) and TCDF-treated mice (red squares). These models are cross-validated with CV-ANOVA: p = 1.64 × 10–3, p = 0.033, and p = 0.0018 for feces, cecal content, and liver, respectively. Metabolite assignment is shown in Supplemental Material, Figure S5 and Table S4, and correlation coefficient values for the significantly changed metabolites are shown in Supplemental Material, Table S3.

Mentions: Effects of dietary TCDF on the host metabolome. 1H NMR–based metabolomics coupled with multivariate statistical analysis was employed to evaluate the metabolic changes induced by TCDF exposure. Typical 1H NMR spectra of liver, fecal, and cecal content extracts obtained from vehicle- and TCDF-treated Ahr+/+ mice are presented in Supplemental Material, Figure S5A–F. Metabolite assignments were carried out as described previously (Tian et al. 2012; Wu et al. 2010) and confirmed with a series of 2D NMR experiments (see Supplemental Material, Table S4). To obtain the metabolic variations associated with different biological sample from vehicle- and TCDF-treated mice, we performed pair-wise OPLS-DA of data obtained from feces (Figure 5A), cecal contents (Figure 5B), liver (Figure 5C), and gut tissues, including duodenum, jejunum, ileum, and cecum (see Supplemental Material, Figure S6A–D). The model quality indicators (R2X and Q2; see Supplemental Material, Table S3) clearly showed that the extracts obtained from the biological matrices were distinctive in terms of their metabolite profiles. However, the Q2 values (0.007, –0.12, and 0.29 for the models of feces, cecal contents, and liver samples, respectively) of the OPLS-DA models of data from Ahr–/– mice revealed no significant differences between TCDF and vehicle treatment (see Supplemental Material, Figure S6E–G and Table S5). These observations were further supported by results from the model evaluation with analysis of variance of the cross-validated residuals (CV-ANOVA) (p < 0.05) and permutation test for the OPLS-DA models (see Supplemental Material, Figure S7 and Table S5). The metabolites with statistically significant contributions between TCDF- and vehicle-treated groups are identified in the corresponding color-coded coefficient plots (Figure 5A–C; see also Supplemental Material, Figure S6A–D), and the correlation coefficient values were also tabulated (see Supplemental Material, Table S3). Compared with the vehicle-treated mice, dietary TCDF significantly elevated the levels of the short chain fatty acids (SCFAs) propionate and n-butyrate, but significantly decreased the levels of oligosaccharides and glucose in feces and cecal contents (Figure 5A,B; see also Supplemental Material, Table S3). Reliable assignments of n-butyrate and propionate were further confirmed by 2D 1H-1H total correlation spectroscopy (TOCSY) NMR spectroscopy (see Supplemental Material, Figure S8). Similar changes in SCFAs and oligosaccharides were also obtained from calculating their relative concentration from the NMR peaks integration to internal standard (sodium 3-trimethylsilyl [2,2,3,3-d4] propionate; TSP-d4) in feces and cecal contents of the TCDF-treated wild-type mice against those from the respective controls (see Supplemental Material, Figure S9A,B). However, no significant differences in the levels of SCFAs and oligosaccharides were observed in feces and cecal content between TCDF-treated and vehicle-treated Ahr–/– mice (see Supplemental Material, Figure S9A,B), supporting the dependence on AHR status. Significant increases in the expression of the G-protein–coupled receptors (Gpr41 and Gpr43) were found in the colons of TCDF-treated mice (see Supplemental Material, Figure S10A).


Persistent Organic Pollutants Modify Gut Microbiota-Host Metabolic Homeostasis in Mice Through Aryl Hydrocarbon Receptor Activation.

Zhang L, Nichols RG, Correll J, Murray IA, Tanaka N, Smith PB, Hubbard TD, Sebastian A, Albert I, Hatzakis E, Gonzalez FJ, Perdew GH, Patterson AD - Environ. Health Perspect. (2015)

Host metabolism and the bacterial fermentation process in Ahr+/+ mice after dietary exposure to vehicle or TCDF (24 μg/kg). OPLS-DA scores (left) and coefficient-coded loadings plots for the models (right) from NMR spectra of aqueous fecal (A), cecal content (B), and liver extracts (C), discriminating between the vehicle (black circles) and TCDF-treated mice (red squares). These models are cross-validated with CV-ANOVA: p = 1.64 × 10–3, p = 0.033, and p = 0.0018 for feces, cecal content, and liver, respectively. Metabolite assignment is shown in Supplemental Material, Figure S5 and Table S4, and correlation coefficient values for the significantly changed metabolites are shown in Supplemental Material, Table S3.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492271&req=5

f5: Host metabolism and the bacterial fermentation process in Ahr+/+ mice after dietary exposure to vehicle or TCDF (24 μg/kg). OPLS-DA scores (left) and coefficient-coded loadings plots for the models (right) from NMR spectra of aqueous fecal (A), cecal content (B), and liver extracts (C), discriminating between the vehicle (black circles) and TCDF-treated mice (red squares). These models are cross-validated with CV-ANOVA: p = 1.64 × 10–3, p = 0.033, and p = 0.0018 for feces, cecal content, and liver, respectively. Metabolite assignment is shown in Supplemental Material, Figure S5 and Table S4, and correlation coefficient values for the significantly changed metabolites are shown in Supplemental Material, Table S3.
Mentions: Effects of dietary TCDF on the host metabolome. 1H NMR–based metabolomics coupled with multivariate statistical analysis was employed to evaluate the metabolic changes induced by TCDF exposure. Typical 1H NMR spectra of liver, fecal, and cecal content extracts obtained from vehicle- and TCDF-treated Ahr+/+ mice are presented in Supplemental Material, Figure S5A–F. Metabolite assignments were carried out as described previously (Tian et al. 2012; Wu et al. 2010) and confirmed with a series of 2D NMR experiments (see Supplemental Material, Table S4). To obtain the metabolic variations associated with different biological sample from vehicle- and TCDF-treated mice, we performed pair-wise OPLS-DA of data obtained from feces (Figure 5A), cecal contents (Figure 5B), liver (Figure 5C), and gut tissues, including duodenum, jejunum, ileum, and cecum (see Supplemental Material, Figure S6A–D). The model quality indicators (R2X and Q2; see Supplemental Material, Table S3) clearly showed that the extracts obtained from the biological matrices were distinctive in terms of their metabolite profiles. However, the Q2 values (0.007, –0.12, and 0.29 for the models of feces, cecal contents, and liver samples, respectively) of the OPLS-DA models of data from Ahr–/– mice revealed no significant differences between TCDF and vehicle treatment (see Supplemental Material, Figure S6E–G and Table S5). These observations were further supported by results from the model evaluation with analysis of variance of the cross-validated residuals (CV-ANOVA) (p < 0.05) and permutation test for the OPLS-DA models (see Supplemental Material, Figure S7 and Table S5). The metabolites with statistically significant contributions between TCDF- and vehicle-treated groups are identified in the corresponding color-coded coefficient plots (Figure 5A–C; see also Supplemental Material, Figure S6A–D), and the correlation coefficient values were also tabulated (see Supplemental Material, Table S3). Compared with the vehicle-treated mice, dietary TCDF significantly elevated the levels of the short chain fatty acids (SCFAs) propionate and n-butyrate, but significantly decreased the levels of oligosaccharides and glucose in feces and cecal contents (Figure 5A,B; see also Supplemental Material, Table S3). Reliable assignments of n-butyrate and propionate were further confirmed by 2D 1H-1H total correlation spectroscopy (TOCSY) NMR spectroscopy (see Supplemental Material, Figure S8). Similar changes in SCFAs and oligosaccharides were also obtained from calculating their relative concentration from the NMR peaks integration to internal standard (sodium 3-trimethylsilyl [2,2,3,3-d4] propionate; TSP-d4) in feces and cecal contents of the TCDF-treated wild-type mice against those from the respective controls (see Supplemental Material, Figure S9A,B). However, no significant differences in the levels of SCFAs and oligosaccharides were observed in feces and cecal content between TCDF-treated and vehicle-treated Ahr–/– mice (see Supplemental Material, Figure S9A,B), supporting the dependence on AHR status. Significant increases in the expression of the G-protein–coupled receptors (Gpr41 and Gpr43) were found in the colons of TCDF-treated mice (see Supplemental Material, Figure S10A).

Bottom Line: Six-week-old male wild-type and Ahr-/- mice on the C57BL/6J background were treated with 24 μg/kg TCDF in the diet for 5 days.TCDF-treated mouse cecal contents were enriched with Butyrivibrio spp. but depleted in Oscillobacter spp. compared with vehicle-treated mice.Further, dietary TCDF inhibited the farnesoid X receptor (FXR) signaling pathway, triggered significant inflammation and host metabolic disorders as a result of activation of bacterial fermentation, and altered hepatic lipogenesis, gluconeogenesis, and glycogenolysis in an AHR-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA.

ABSTRACT

Background: Alteration of the gut microbiota through diet and environmental contaminants may disturb physiological homeostasis, leading to various diseases including obesity and type 2 diabetes. Because most exposure to environmentally persistent organic pollutants (POPs) occurs through the diet, the host gastrointestinal tract and commensal gut microbiota are likely to be exposed to POPs.

Objectives: We examined the effect of 2,3,7,8-tetrachlorodibenzofuran (TCDF), a persistent environmental contaminant, on gut microbiota and host metabolism, and we examined correlations between gut microbiota composition and signaling pathways.

Methods: Six-week-old male wild-type and Ahr-/- mice on the C57BL/6J background were treated with 24 μg/kg TCDF in the diet for 5 days. We used 16S rRNA gene sequencing, 1H nuclear magnetic resonance (NMR) metabolomics, targeted ultra-performance liquid chromatography coupled with triplequadrupole mass spectrometry, and biochemical assays to determine the microbiota compositions and the physiological and metabolic effects of TCDF.

Results: Dietary TCDF altered the gut microbiota by shifting the ratio of Firmicutes to Bacteroidetes. TCDF-treated mouse cecal contents were enriched with Butyrivibrio spp. but depleted in Oscillobacter spp. compared with vehicle-treated mice. These changes in the gut microbiota were associated with altered bile acid metabolism. Further, dietary TCDF inhibited the farnesoid X receptor (FXR) signaling pathway, triggered significant inflammation and host metabolic disorders as a result of activation of bacterial fermentation, and altered hepatic lipogenesis, gluconeogenesis, and glycogenolysis in an AHR-dependent manner.

Conclusion: These findings provide new insights into the biochemical consequences of TCDF exposure involving the alteration of the gut microbiota, modulation of nuclear receptor signaling, and disruption of host metabolism.

No MeSH data available.


Related in: MedlinePlus