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: 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

Bile acid metabolism in animals treated with vehicle or TCDF (24 μg/kg). Abbreviations: CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; G, glycine-conjugated; LCA, lithocholic acid; MCA, muricholic acid; NS, not significant; T, taurine-conjugated species; UDCA, ursodeoxycholic acid. Quantification of specific bile acids levels in intestinal tissue (A,B) and feces (C,D) throughout the enterohepatic circulation of Ahr+/+ mice. (E) Quantification of total bile acids in liver, intestine, cecum, and feces of Ahr+/+ mice; the bile acid profile in the small intestine shows the data from jejunum segment. qPCR analysis of Fgf15, Fxr, and Shp mRNAs in the ileum (F) and Fxr and Shp mRNA expression in the liver (G) of Ahr+/+ and Ahr–/– mice. (H) qPCR analysis of Cyp7a1, Cyp8b1, Cyp27a1, Akr1d1, and Cyp7b1 mRNAs in the liver of Ahr+/+ mice. (I–K) mRNA encoding bile acid transporters involved in taurine biosynthesis and bile acid conjugation in the ileum (I), and mRNA encoding bile acid transporters in the distal liver (J) and ileum (K) of vehicle- and TCDF-treated Ahr+/+ mice. Data are presented as mean ± SD; n = 6/group. See also Supplemental Material, Tables S1 and S2.*p < 0.05, and **p < 0.01, by two-tailed Student’s t-test.
© Copyright Policy - public-domain
Related In: Results  -  Collection

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

f4: Bile acid metabolism in animals treated with vehicle or TCDF (24 μg/kg). Abbreviations: CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; G, glycine-conjugated; LCA, lithocholic acid; MCA, muricholic acid; NS, not significant; T, taurine-conjugated species; UDCA, ursodeoxycholic acid. Quantification of specific bile acids levels in intestinal tissue (A,B) and feces (C,D) throughout the enterohepatic circulation of Ahr+/+ mice. (E) Quantification of total bile acids in liver, intestine, cecum, and feces of Ahr+/+ mice; the bile acid profile in the small intestine shows the data from jejunum segment. qPCR analysis of Fgf15, Fxr, and Shp mRNAs in the ileum (F) and Fxr and Shp mRNA expression in the liver (G) of Ahr+/+ and Ahr–/– mice. (H) qPCR analysis of Cyp7a1, Cyp8b1, Cyp27a1, Akr1d1, and Cyp7b1 mRNAs in the liver of Ahr+/+ mice. (I–K) mRNA encoding bile acid transporters involved in taurine biosynthesis and bile acid conjugation in the ileum (I), and mRNA encoding bile acid transporters in the distal liver (J) and ileum (K) of vehicle- and TCDF-treated Ahr+/+ mice. Data are presented as mean ± SD; n = 6/group. See also Supplemental Material, Tables S1 and S2.*p < 0.05, and **p < 0.01, by two-tailed Student’s t-test.

Mentions: Bile acid metabolism. It is well known that gut microbiota has profound effects on bile acid metabolism (Nicholson et al. 2012). To determine whether the composition of bile acids was affected by dietary TCDF exposure, we used UPLC-TQMS to examine bile acids and their levels in the liver, intestine, cecum, and feces, according to published methods (Jiang et al. 2015). Compared with vehicle-treated mice, TCDF-treated Ahr+/+ mice had significantly higher levels of DCA in the small intestine and feces (Figure 4A and 4C), and they also had significantly higher levels of three conjugated bile acids (GCA, TCDCA, and TβMCA) (Figure 4B,D) that were affected by gut microbial metabolism, as previously reported (Sayin et al. 2013). The size of the bile acid pool was significantly increased in TCDF-treated mice (Figure 4E). In addition, levels of LCA (intestine and cecum), CDCA (liver), and TLCA (liver and feces) in TCDF-treated mice were higher than those in vehicle-treated mice (see Supplemental Material, Figure S3A–E).


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)

Bile acid metabolism in animals treated with vehicle or TCDF (24 μg/kg). Abbreviations: CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; G, glycine-conjugated; LCA, lithocholic acid; MCA, muricholic acid; NS, not significant; T, taurine-conjugated species; UDCA, ursodeoxycholic acid. Quantification of specific bile acids levels in intestinal tissue (A,B) and feces (C,D) throughout the enterohepatic circulation of Ahr+/+ mice. (E) Quantification of total bile acids in liver, intestine, cecum, and feces of Ahr+/+ mice; the bile acid profile in the small intestine shows the data from jejunum segment. qPCR analysis of Fgf15, Fxr, and Shp mRNAs in the ileum (F) and Fxr and Shp mRNA expression in the liver (G) of Ahr+/+ and Ahr–/– mice. (H) qPCR analysis of Cyp7a1, Cyp8b1, Cyp27a1, Akr1d1, and Cyp7b1 mRNAs in the liver of Ahr+/+ mice. (I–K) mRNA encoding bile acid transporters involved in taurine biosynthesis and bile acid conjugation in the ileum (I), and mRNA encoding bile acid transporters in the distal liver (J) and ileum (K) of vehicle- and TCDF-treated Ahr+/+ mice. Data are presented as mean ± SD; n = 6/group. See also Supplemental Material, Tables S1 and S2.*p < 0.05, and **p < 0.01, 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

f4: Bile acid metabolism in animals treated with vehicle or TCDF (24 μg/kg). Abbreviations: CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; G, glycine-conjugated; LCA, lithocholic acid; MCA, muricholic acid; NS, not significant; T, taurine-conjugated species; UDCA, ursodeoxycholic acid. Quantification of specific bile acids levels in intestinal tissue (A,B) and feces (C,D) throughout the enterohepatic circulation of Ahr+/+ mice. (E) Quantification of total bile acids in liver, intestine, cecum, and feces of Ahr+/+ mice; the bile acid profile in the small intestine shows the data from jejunum segment. qPCR analysis of Fgf15, Fxr, and Shp mRNAs in the ileum (F) and Fxr and Shp mRNA expression in the liver (G) of Ahr+/+ and Ahr–/– mice. (H) qPCR analysis of Cyp7a1, Cyp8b1, Cyp27a1, Akr1d1, and Cyp7b1 mRNAs in the liver of Ahr+/+ mice. (I–K) mRNA encoding bile acid transporters involved in taurine biosynthesis and bile acid conjugation in the ileum (I), and mRNA encoding bile acid transporters in the distal liver (J) and ileum (K) of vehicle- and TCDF-treated Ahr+/+ mice. Data are presented as mean ± SD; n = 6/group. See also Supplemental Material, Tables S1 and S2.*p < 0.05, and **p < 0.01, by two-tailed Student’s t-test.
Mentions: Bile acid metabolism. It is well known that gut microbiota has profound effects on bile acid metabolism (Nicholson et al. 2012). To determine whether the composition of bile acids was affected by dietary TCDF exposure, we used UPLC-TQMS to examine bile acids and their levels in the liver, intestine, cecum, and feces, according to published methods (Jiang et al. 2015). Compared with vehicle-treated mice, TCDF-treated Ahr+/+ mice had significantly higher levels of DCA in the small intestine and feces (Figure 4A and 4C), and they also had significantly higher levels of three conjugated bile acids (GCA, TCDCA, and TβMCA) (Figure 4B,D) that were affected by gut microbial metabolism, as previously reported (Sayin et al. 2013). The size of the bile acid pool was significantly increased in TCDF-treated mice (Figure 4E). In addition, levels of LCA (intestine and cecum), CDCA (liver), and TLCA (liver and feces) in TCDF-treated mice were higher than those in vehicle-treated mice (see Supplemental Material, Figure S3A–E).

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