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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

Effects of dietary TCDF on the morphology, population, and composition of gut microbiota of mice; animals were treated for 5 days with vehicle or TCDF (24 μg/kg) and sampled on day 7. (A) Weighted UniFrac principal coordinate analysis of the total population of the gut microbiome of cecal content from Ahr+/+ and Ahr–/– mice. (B) 16S rRNA gene sequencing analysis of the cecal content of Ahr+/+ mice at the phylum level. (C) 16S rRNA gene sequencing analysis of cecal contents of Ahr+/+ mice at the class and genus levels. (D) Scanning electron microscopy images of ileum (bars = 50 μm) and (E) qPCR analysis of ileum SFB from Ahr+/+ and Ahr–/– mice. Images in (D) represent replicates from two mice in each group. Data are presented as mean ± SD; n = 5 or 6/group. NS, not significant by two-tailed Student’s t-test or Mann-Whitney test.
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f2: Effects of dietary TCDF on the morphology, population, and composition of gut microbiota of mice; animals were treated for 5 days with vehicle or TCDF (24 μg/kg) and sampled on day 7. (A) Weighted UniFrac principal coordinate analysis of the total population of the gut microbiome of cecal content from Ahr+/+ and Ahr–/– mice. (B) 16S rRNA gene sequencing analysis of the cecal content of Ahr+/+ mice at the phylum level. (C) 16S rRNA gene sequencing analysis of cecal contents of Ahr+/+ mice at the class and genus levels. (D) Scanning electron microscopy images of ileum (bars = 50 μm) and (E) qPCR analysis of ileum SFB from Ahr+/+ and Ahr–/– mice. Images in (D) represent replicates from two mice in each group. Data are presented as mean ± SD; n = 5 or 6/group. NS, not significant by two-tailed Student’s t-test or Mann-Whitney test.

Mentions: Effects of dietary TCDF on the morphology, population, and composition of gut microbiota. Given recent evidence that the AHR is important for regulating gut homeostasis (Monteleone et al. 2013), and that in gut microbiota changed after oral dietary exposure to POPs (Snedeker and Hay 2012), we examined this relationship. Weighted UniFrac principal coordinate analysis (for assessing changes in abundance) of 16S rRNA sequencing results indicated that dietary TCDF induced a remarkable change in the overall population of gut microbiota (Figure 2A). Firmicutes and Bacteroidetes exhibited significant changes, with reduction of Firmicutes/Bacteroidetes ratio after dietary TCDF exposure (Figure 2B; see also Supplemental Material, Figure S2). Furthermore, cecal contents from TCDF-treated mice were enriched with Butyrivibrio spp. but depleted in Oscillobacter spp., compared with those from vehicle-treated mice (Figure 2C). Further, we observed an increase in the class Flavobacteria but a decrease in the class Clostridia. SEM images showed that dense segmented filamentous bacteria (SFB) formed a network of segmented filaments in the ileum of vehicle-treated mice, whereas they were dramatically depleted in the ileum of TCDF-treated mice (Figure 2D). qPCR analyses revealed that dietary TCDF significantly reduced SFB levels in the ileum, with no significant changes observed between TCDF-treated Ahr–/– mice and vehicle-treated Ahr–/– mice (Figure 2E).


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)

Effects of dietary TCDF on the morphology, population, and composition of gut microbiota of mice; animals were treated for 5 days with vehicle or TCDF (24 μg/kg) and sampled on day 7. (A) Weighted UniFrac principal coordinate analysis of the total population of the gut microbiome of cecal content from Ahr+/+ and Ahr–/– mice. (B) 16S rRNA gene sequencing analysis of the cecal content of Ahr+/+ mice at the phylum level. (C) 16S rRNA gene sequencing analysis of cecal contents of Ahr+/+ mice at the class and genus levels. (D) Scanning electron microscopy images of ileum (bars = 50 μm) and (E) qPCR analysis of ileum SFB from Ahr+/+ and Ahr–/– mice. Images in (D) represent replicates from two mice in each group. Data are presented as mean ± SD; n = 5 or 6/group. NS, not significant by two-tailed Student’s t-test or Mann-Whitney test.
© Copyright Policy - public-domain
Related In: Results  -  Collection

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

f2: Effects of dietary TCDF on the morphology, population, and composition of gut microbiota of mice; animals were treated for 5 days with vehicle or TCDF (24 μg/kg) and sampled on day 7. (A) Weighted UniFrac principal coordinate analysis of the total population of the gut microbiome of cecal content from Ahr+/+ and Ahr–/– mice. (B) 16S rRNA gene sequencing analysis of the cecal content of Ahr+/+ mice at the phylum level. (C) 16S rRNA gene sequencing analysis of cecal contents of Ahr+/+ mice at the class and genus levels. (D) Scanning electron microscopy images of ileum (bars = 50 μm) and (E) qPCR analysis of ileum SFB from Ahr+/+ and Ahr–/– mice. Images in (D) represent replicates from two mice in each group. Data are presented as mean ± SD; n = 5 or 6/group. NS, not significant by two-tailed Student’s t-test or Mann-Whitney test.
Mentions: Effects of dietary TCDF on the morphology, population, and composition of gut microbiota. Given recent evidence that the AHR is important for regulating gut homeostasis (Monteleone et al. 2013), and that in gut microbiota changed after oral dietary exposure to POPs (Snedeker and Hay 2012), we examined this relationship. Weighted UniFrac principal coordinate analysis (for assessing changes in abundance) of 16S rRNA sequencing results indicated that dietary TCDF induced a remarkable change in the overall population of gut microbiota (Figure 2A). Firmicutes and Bacteroidetes exhibited significant changes, with reduction of Firmicutes/Bacteroidetes ratio after dietary TCDF exposure (Figure 2B; see also Supplemental Material, Figure S2). Furthermore, cecal contents from TCDF-treated mice were enriched with Butyrivibrio spp. but depleted in Oscillobacter spp., compared with those from vehicle-treated mice (Figure 2C). Further, we observed an increase in the class Flavobacteria but a decrease in the class Clostridia. SEM images showed that dense segmented filamentous bacteria (SFB) formed a network of segmented filaments in the ileum of vehicle-treated mice, whereas they were dramatically depleted in the ileum of TCDF-treated mice (Figure 2D). qPCR analyses revealed that dietary TCDF significantly reduced SFB levels in the ileum, with no significant changes observed between TCDF-treated Ahr–/– mice and vehicle-treated Ahr–/– mice (Figure 2E).

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