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. 2015 Jul;123(7):679-88.
doi: 10.1289/ehp.1409055. Epub 2015 Mar 13.

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

Limin Zhang  1 , Robert G Nichols, Jared Correll, Iain A Murray, Naoki Tanaka, Philip B Smith, Troy D Hubbard, Aswathy Sebastian, Istvan Albert, Emmanuel Hatzakis, Frank J Gonzalez, Gary H Perdew, Andrew D Patterson
Affiliations

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

Limin Zhang et al. Environ Health Perspect. 2015 Jul.

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.

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Conflict of interest statement

The authors declare they have no actual or potential competing financial interests.

Figures

Figure 1
Figure 1
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.
Figure 2
Figure 2
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.
Figure 3
Figure 3
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.
Figure 4
Figure 4
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.
Figure 5
Figure 5
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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