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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

AHR-dependent inflammation in mice after dietary exposure to vehicle or TCDF (24 μg/kg). (A) qPCR analysis of inflammatory cytokine (IL-1β, TNF-α, IL-10, Saa1, and Saa3) mRNA expression in the ileum of Ahr+/+ mice. (B) IL-1β and Tnf-α expression in the ileum of Ahr–/– mice. (C) qPCR analysis of Lcn-2 mRNA expression in the ileum of Ahr+/+ and Ahr–/– mice. (D) Quantification of fecal LCN2 in Ahr+/+ mice by ELISA. (E) qPCR analysis of Myosin Vb and Ptprh mRNA in the ileum of Ahr+/+ mice after TCDF treatment. (F) Quantification of serum LPS in Ahr+/+ mice. (G) Quantification of IgA in Ahr+/+ mice by ELISA. Data are presented as mean ± SD; n = 5/group. NS, not significant.*p < 0.05, **p < 0.01, and ***p < 0.001, by two-tailed Student’s t-test.
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f3: AHR-dependent inflammation in mice after dietary exposure to vehicle or TCDF (24 μg/kg). (A) qPCR analysis of inflammatory cytokine (IL-1β, TNF-α, IL-10, Saa1, and Saa3) mRNA expression in the ileum of Ahr+/+ mice. (B) IL-1β and Tnf-α expression in the ileum of Ahr–/– mice. (C) qPCR analysis of Lcn-2 mRNA expression in the ileum of Ahr+/+ and Ahr–/– mice. (D) Quantification of fecal LCN2 in Ahr+/+ mice by ELISA. (E) qPCR analysis of Myosin Vb and Ptprh mRNA in the ileum of Ahr+/+ mice after TCDF treatment. (F) Quantification of serum LPS in Ahr+/+ mice. (G) Quantification of IgA in Ahr+/+ mice by ELISA. Data are presented as mean ± SD; n = 5/group. NS, not significant.*p < 0.05, **p < 0.01, and ***p < 0.001, by two-tailed Student’s t-test.

Mentions: Inflammatory signaling and immune responses. TCDF led to a significant increase in mRNAs that encode factors in the ileum involved in inflammatory signaling, such as Il-1β, Il-10, Tnf-α, Saa1, and Saa3 (Figure 3A); these changes were AHR dependent (Figure 3B). Lcn-2 mRNA, encoding lipocalin-2, a sensitive biomarker for intestinal inflammation (Chassaing et al. 2012), was dramatically increased in the ileum (Figure 3C) and in the feces (Figure 3D) of mice exposed to TCDF. No significant change in Lcn-2 mRNA (Figure 3C) was observed in the ileum of Ahr–/– mice after TCDF treatment. Dietary TCDF resulted in a significant elevation of serum lipopolysaccharide (LPS) (Figure 3F) and fecal IgA (Figure 3G), and also resulted in decreased Myosin Vb and Ptprh in the ileum (Figure 3E), both of which are closely associated with gut permeability and the host immune system. Taken together, these results suggest that dietary TCDF triggers robust intestinal inflammation and inflammatory signaling in mice in an AHR-dependent manner.


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)

AHR-dependent inflammation in mice after dietary exposure to vehicle or TCDF (24 μg/kg). (A) qPCR analysis of inflammatory cytokine (IL-1β, TNF-α, IL-10, Saa1, and Saa3) mRNA expression in the ileum of Ahr+/+ mice. (B) IL-1β and Tnf-α expression in the ileum of Ahr–/– mice. (C) qPCR analysis of Lcn-2 mRNA expression in the ileum of Ahr+/+ and Ahr–/– mice. (D) Quantification of fecal LCN2 in Ahr+/+ mice by ELISA. (E) qPCR analysis of Myosin Vb and Ptprh mRNA in the ileum of Ahr+/+ mice after TCDF treatment. (F) Quantification of serum LPS in Ahr+/+ mice. (G) Quantification of IgA in Ahr+/+ mice by ELISA. Data are presented as mean ± SD; n = 5/group. NS, not significant.*p < 0.05, **p < 0.01, and ***p < 0.001, by two-tailed Student’s t-test.
© Copyright Policy - public-domain
Related In: Results  -  Collection

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

f3: AHR-dependent inflammation in mice after dietary exposure to vehicle or TCDF (24 μg/kg). (A) qPCR analysis of inflammatory cytokine (IL-1β, TNF-α, IL-10, Saa1, and Saa3) mRNA expression in the ileum of Ahr+/+ mice. (B) IL-1β and Tnf-α expression in the ileum of Ahr–/– mice. (C) qPCR analysis of Lcn-2 mRNA expression in the ileum of Ahr+/+ and Ahr–/– mice. (D) Quantification of fecal LCN2 in Ahr+/+ mice by ELISA. (E) qPCR analysis of Myosin Vb and Ptprh mRNA in the ileum of Ahr+/+ mice after TCDF treatment. (F) Quantification of serum LPS in Ahr+/+ mice. (G) Quantification of IgA in Ahr+/+ mice by ELISA. Data are presented as mean ± SD; n = 5/group. NS, not significant.*p < 0.05, **p < 0.01, and ***p < 0.001, by two-tailed Student’s t-test.
Mentions: Inflammatory signaling and immune responses. TCDF led to a significant increase in mRNAs that encode factors in the ileum involved in inflammatory signaling, such as Il-1β, Il-10, Tnf-α, Saa1, and Saa3 (Figure 3A); these changes were AHR dependent (Figure 3B). Lcn-2 mRNA, encoding lipocalin-2, a sensitive biomarker for intestinal inflammation (Chassaing et al. 2012), was dramatically increased in the ileum (Figure 3C) and in the feces (Figure 3D) of mice exposed to TCDF. No significant change in Lcn-2 mRNA (Figure 3C) was observed in the ileum of Ahr–/– mice after TCDF treatment. Dietary TCDF resulted in a significant elevation of serum lipopolysaccharide (LPS) (Figure 3F) and fecal IgA (Figure 3G), and also resulted in decreased Myosin Vb and Ptprh in the ileum (Figure 3E), both of which are closely associated with gut permeability and the host immune system. Taken together, these results suggest that dietary TCDF triggers robust intestinal inflammation and inflammatory signaling in mice in an AHR-dependent manner.

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