TCDD modulation of gut microbiome correlated with liver and immune toxicity in streptozotocin (STZ)-induced hyperglycemic mice

Lefever, Daniel E.; Xu, Joella; Chen, Yingjia; Huang, Guannan; Nagy, Tamás; Guo, Tai L.

doi:10.1016/j.taap.2016.05.016

Cited by 58 publications

(47 citation statements)

References 60 publications

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“…Similar to our study, TCDD dramatically shifted taxonomic composition with increased relative abundance of Firmicutes at the expense of Bacteroidetes (Lefever et al 2016). On the contrary, a study with wild-type mice orally dosed with 2,3,7,8-tetrachlorodibenzofuran (TCDF), a less potent AhR activator, heightened host inflammation, and increased abundance of Bacteroides over Firmicutes (Zhang et al 2015).…”

Section: Higher Abundance Of Args In Tcdd-dosed Micesupporting

confidence: 82%

“…Our own previous studies showed that 30-nM TCDDdosed batch reactors did not influence gut commensals (including Enterobacteriaceae) in vitro (Stedtfeld et al 2016). No effects were observed with 1-1000 nM TCDD on bacteria grown on agar plates (Lefever et al 2016). In addition, TCDF did not influence gut commensals in AhR knockout mice (Zhang et al 2015).…”

Section: Higher Abundance Of Args In Tcdd-dosed Micementioning

confidence: 83%

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TCDD influences reservoir of antibiotic resistance genes in murine gut microbiome

Stedtfeld¹,

Stedtfeld²,

Fader

et al. 2017

FEMS Microbiology Ecology

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One sentence summary: An environmental toxicant that is not a metal, biocide or antimicrobial indirectly (via a non-inflammatory host response) influences the reservoir of antibiotic resistance genes in the murine gut. Editor: Kornelia Smalla ABSTRACTDysbiosis of the gut microbiome via antibiotics, changes in diet and infection can select for bacterial groups that more frequently harbor antimicrobial resistance genes (ARGs) and mobile genetic elements (MGEs). However, the impact of environmental toxicants on the reservoir of ARGs in the gut microbiome has received less attention. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent aryl hydrocarbon receptor (AhR) agonist with multiple toxic health effects including immune dysfunction. The selective pressure of TCDD on the abundance of ARG and MGE-harboring gut populations was examined using C57BL/6 mice exposed to 0-30 μg/kg TCDD for 28 and 92 days with the latter having a 30-day recovery period. DNA extracted from temporally collected fecal pellets was characterized using a qPCR array with 384 assays targeting ARGs and MGEs. Fourteen genes, typically observed in Enterobacteriaceae, increased significantly within 8 days of initial dosing, persisted throughout the treatment period, and remained induced 30 days post dosing. A qPCR primer set targeting Enterobacteriaceae also showed 10-to 100-fold higher abundance in TCDD-treated groups, which was further verified using metagenomics. Results show a bloom of ARG-harboring bacterial groups in the gut due to a xenobiotic compound that is not a metal, biocide or antimicrobial.

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Section: Higher Abundance Of Args In Tcdd-dosed Micesupporting

confidence: 82%

Section: Higher Abundance Of Args In Tcdd-dosed Micementioning

confidence: 83%

TCDD influences reservoir of antibiotic resistance genes in murine gut microbiome

Stedtfeld¹,

Stedtfeld²,

Fader

et al. 2017

FEMS Microbiology Ecology

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“…The bioinformatic analysis was performed as described (20). Briefly, the Read 1 and Read 2 sequence files from each sample were first merged, demultiplexed (a process that removes the internal tag and primers), and filtered with Phred Quality Score of 20, allowing for an error rate of 1 in 100.…”

Section: Methodsmentioning

confidence: 99%

Genistein prevention of hyperglycemia and improvement of glucose tolerance in adult non-obese diabetic mice are associated with alterations of gut microbiome and immune homeostasis

Huang¹,

Xu²,

Lefever³

et al. 2017

Toxicology and Applied Pharmacology

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Although studies have linked soy phytoestrogen 4,7,4-trihydroxyisoflavone genistein (GEN) to reduced type 1 diabetes (T1D) risk, the mechanism of dietary GEN on T1D remains unknown. In our studies, adult non-obese diabetic (NOD) mouse model was employed to investigate the effects of GEN exposure on blood glucose level (BGL), glucose tolerance, gut microbiome, and immune responses. Adult male and female NOD mice were fed with either soy-based or casein-based diet, and received GEN at 20 mg/kg body weight by gavage daily. The BGL and immune responses (represented by serum antibodies, cytokines and chemokines, and histopathology) were monitored, while the fecal gut microbiome was sequenced for 16S ribosomal RNA to reveal any alterations in gut microbial communities. A significantly reduced BGL was found in NOD males fed with soy-based diet on day 98 after initial dosing and an improved glucose tolerance was observed on both diets. In addition, an anti-inflammatory response (suggested by reduced IgG2b and cytokine/chemokine levels, and alterations in the microbial taxonomy) was accompanied by an altered β-diversity in gut microbial species. Among the NOD females exposed to GEN, a later onset of T1D was observed. However, the profiles of gut microbiome, antibodies and cytokines/chemokines were all indicative of pro-inflammation This study demonstrated an association among GEN exposure, gut microbiome alteration, and immune homeostasis in NOD males. Although the mechanisms underlying the protective effects of GEN in NOD mice need to be explored further, the current study suggested a GEN-induced sex-specific effect in inflammatory status and gut microbiome.

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“…This is an important question as the gut microbiota plays a crucial role in host health and immune competence (Littman and Pamer 2011; Honda and Littman 2016). Previous studies have observed TCDD-induced dysbiosis of gut commensals including Candidatus Savagella also known as segmented filamentous bacteria (SFB), Firmicutes , and Enterobacteriaceae (Bhaduri 2015; Lefever et al 2016; Stedtfeld et al 2017, Modulatory influence of segmented filamentous bacteria on transcriptomic response of gnotobiotic mice exposed to TCDD, submitted). Experiments performed by our group and others suggest that gut commensal response is the result of TCDD-induced toxicity to the host, mediated in part, through the aryl hydrocarbon receptor (AhR), and not the direct influence of TCDD on bacteria (Lefever et al 2016; Stedtfeld et al 2017).…”

Section: Introductionmentioning

confidence: 99%

TCDD administered on activated carbon eliminates bioavailability and subsequent shifts to a key murine gut commensal

Stedtfeld¹,

Sallach

Crawford

et al. 2017

Appl Microbiol Biotechnol

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Activated carbon (AC) is an increasingly attractive remediation alternative for the sequestration of dioxins at contaminated sites globally. However, the potential for AC to reduce the bioavailability of dioxins in mammals and the residing gut microbiota has received less attention. This question was partially answered in a recent study examining 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced hallmark toxic responses in mice administered with TCDD sequestered by AC or freely available in corn oil by oral gavage. Results from that study support the use of AC to significantly reduce the bioavailability of TCDD to the host. Herein, we examined the bioavailability of TCDD sequestered to AC on a key murine gut commensal and the influence of AC on the community structure of the gut microbiota. The analysis included qPCR to quantify the expression of segmented filamentous bacteria (SFB) in the mouse ileum, which has responded to TCDD-induced host toxicity in previous studies and community structure via sequencing the 16S ribosomal RNA (rRNA) gene. The expression of SFB 16S rRNA gene and functional genes significantly increased with TCDD administered with corn oil vehicle. Such a response was absent when TCDD was sequestered by AC. In addition, AC appeared to have a minimal influence on murine gut community structure and diversity, affecting only the relative abundance of Lactobacillaceae and two other groups. Results of this study further support the remedial use of AC for eliminating bioavailability of TCDD to host and subsequent influence on the gut microbiome.

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TCDD modulation of gut microbiome correlated with liver and immune toxicity in streptozotocin (STZ)-induced hyperglycemic mice

Cited by 58 publications

References 60 publications

TCDD influences reservoir of antibiotic resistance genes in murine gut microbiome

TCDD influences reservoir of antibiotic resistance genes in murine gut microbiome

Genistein prevention of hyperglycemia and improvement of glucose tolerance in adult non-obese diabetic mice are associated with alterations of gut microbiome and immune homeostasis

TCDD administered on activated carbon eliminates bioavailability and subsequent shifts to a key murine gut commensal

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