Limits...
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: 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.

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

Xenobiotic responses in mice after dietary exposure to vehicle or TCDF (24 μg/kg). Light microscopic examination of H&E-stained liver sections from Ahr+/+ (A) and Ahr–/– (B) mice; arrows indicate inflammatory foci (bars = 200 μm). (C) Serum concentrations of ALT (left) and ALP (right) from Ahr+/+ and Ahr–/– mice. (D) Percent change in body weight of Ahr+/+ mice recorded every other day during the adaptation and treatment periods. (E) Cyp1a1, Cyp1a2, Cyp2e1, and Cyp2a1 expression in the liver (left) and Cyp1a1 mRNA expression in the intestine (right) of Ahr+/+ mice. (F) Cyp1a1 and Cyp1a2 mRNA expression in the liver of Ahr–/– mice. Data are presented as mean ± SD; n = 5 or 6/group. NS, not significant.*p < 0.05, and **p < 0.01 by two-tailed Student’s t-test or Mann-Whitney test.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492271&req=5

f1: Xenobiotic responses in mice after dietary exposure to vehicle or TCDF (24 μg/kg). Light microscopic examination of H&E-stained liver sections from Ahr+/+ (A) and Ahr–/– (B) mice; arrows indicate inflammatory foci (bars = 200 μm). (C) Serum concentrations of ALT (left) and ALP (right) from Ahr+/+ and Ahr–/– mice. (D) Percent change in body weight of Ahr+/+ mice recorded every other day during the adaptation and treatment periods. (E) Cyp1a1, Cyp1a2, Cyp2e1, and Cyp2a1 expression in the liver (left) and Cyp1a1 mRNA expression in the intestine (right) of Ahr+/+ mice. (F) Cyp1a1 and Cyp1a2 mRNA expression in the liver of Ahr–/– mice. Data are presented as mean ± SD; n = 5 or 6/group. NS, not significant.*p < 0.05, and **p < 0.01 by two-tailed Student’s t-test or Mann-Whitney test.

Mentions: Effects of dietary TCDF on liver enzymes and morphology. The effect of sustained AHR activation on the gut was assessed using a potent AHR ligand, TCDF. Ahr+/+ and Ahr–/– mice treated with dietary TCDF (24 μg/kg body weight) exhibited mild and no histopathological changes in the liver, respectively (Figure 1A,B). Mildly elevated serum ALT (19.3–37.5 U/L) and ALP (36.5–52.2 U/L) levels (Figure 1C), but no significant differences in body weight (Figure 1D), were observed in the Ahr+/+ mice after TCDF treatment, thus indicating minimal hepatic toxicity. Further, no evidence of steatosis, bile duct injury, or cellular degeneration was found, as is often observed with high-dose TCDD treatment (Ozeki et al. 2011). Ahr–/– mice exhibited no significant changes in the liver enzymes ALT and ALP (Figure 1C). TCDF exposure in the Ahr–/– mice was confirmed using dichloromethane extracts of liver and assessing the induction of AHR signaling in a Hepa 1.1 stable reporter cell line (see Supplemental Material, Figure S1). Transcriptional targets of AHR, including Cyp1a1, Cyp1a2, and Cyp2e1, were significantly induced in the liver and across the small intestine (Figure 1E) and were AHR dependent (Figure 1F). These observations suggest that the subsequent metabolic changes described below were specific to AHR activation and not due to overt liver toxicity.


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)

Xenobiotic responses in mice after dietary exposure to vehicle or TCDF (24 μg/kg). Light microscopic examination of H&E-stained liver sections from Ahr+/+ (A) and Ahr–/– (B) mice; arrows indicate inflammatory foci (bars = 200 μm). (C) Serum concentrations of ALT (left) and ALP (right) from Ahr+/+ and Ahr–/– mice. (D) Percent change in body weight of Ahr+/+ mice recorded every other day during the adaptation and treatment periods. (E) Cyp1a1, Cyp1a2, Cyp2e1, and Cyp2a1 expression in the liver (left) and Cyp1a1 mRNA expression in the intestine (right) of Ahr+/+ mice. (F) Cyp1a1 and Cyp1a2 mRNA expression in the liver of Ahr–/– mice. Data are presented as mean ± SD; n = 5 or 6/group. NS, not significant.*p < 0.05, and **p < 0.01 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

f1: Xenobiotic responses in mice after dietary exposure to vehicle or TCDF (24 μg/kg). Light microscopic examination of H&E-stained liver sections from Ahr+/+ (A) and Ahr–/– (B) mice; arrows indicate inflammatory foci (bars = 200 μm). (C) Serum concentrations of ALT (left) and ALP (right) from Ahr+/+ and Ahr–/– mice. (D) Percent change in body weight of Ahr+/+ mice recorded every other day during the adaptation and treatment periods. (E) Cyp1a1, Cyp1a2, Cyp2e1, and Cyp2a1 expression in the liver (left) and Cyp1a1 mRNA expression in the intestine (right) of Ahr+/+ mice. (F) Cyp1a1 and Cyp1a2 mRNA expression in the liver of Ahr–/– mice. Data are presented as mean ± SD; n = 5 or 6/group. NS, not significant.*p < 0.05, and **p < 0.01 by two-tailed Student’s t-test or Mann-Whitney test.
Mentions: Effects of dietary TCDF on liver enzymes and morphology. The effect of sustained AHR activation on the gut was assessed using a potent AHR ligand, TCDF. Ahr+/+ and Ahr–/– mice treated with dietary TCDF (24 μg/kg body weight) exhibited mild and no histopathological changes in the liver, respectively (Figure 1A,B). Mildly elevated serum ALT (19.3–37.5 U/L) and ALP (36.5–52.2 U/L) levels (Figure 1C), but no significant differences in body weight (Figure 1D), were observed in the Ahr+/+ mice after TCDF treatment, thus indicating minimal hepatic toxicity. Further, no evidence of steatosis, bile duct injury, or cellular degeneration was found, as is often observed with high-dose TCDD treatment (Ozeki et al. 2011). Ahr–/– mice exhibited no significant changes in the liver enzymes ALT and ALP (Figure 1C). TCDF exposure in the Ahr–/– mice was confirmed using dichloromethane extracts of liver and assessing the induction of AHR signaling in a Hepa 1.1 stable reporter cell line (see Supplemental Material, Figure S1). Transcriptional targets of AHR, including Cyp1a1, Cyp1a2, and Cyp2e1, were significantly induced in the liver and across the small intestine (Figure 1E) and were AHR dependent (Figure 1F). These observations suggest that the subsequent metabolic changes described below were specific to AHR activation and not due to overt liver toxicity.

Bottom Line: 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.

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