Modulatory Influence of Segmented Filamentous Bacteria on Transcriptomic Response of Gnotobiotic Mice Exposed to TCDD

Abstract

Environmental toxicants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor (AhR), are known to induce host toxicity and structural shifts in the gut microbiota. Key bacterial populations with similar or opposing functional responses to AhR ligand exposure may potentially help regulate expression of genes associated with immune dysfunction. To examine this question and the mechanisms for AhR ligand-induced bacterial shifts, C57BL/6 gnotobiotic mice were colonized with and without segmented filamentous bacteria (SFB) – an immune activator. Mice were also colonized with polysaccharide A producing Bacteroides fragilis – an immune suppressor to serve as a commensal background. Following colonization, mice were administered TCDD (30 μg/kg) every 4 days for 28 days by oral gavage. Quantified with the nCounter® mouse immunology panel, opposing responses in ileal gene expression (e.g., genes associated with T-cell differentiation via the class II major histocompatibility complex) as a result of TCDD dosing and SFB colonization were observed. Genes that responded to TCDD in the presence of SFB did not show a significant response in the absence of SFB, and vice versa. Regulatory T-cells examined in the mesenteric lymph-nodes, spleen, and blood were also less impacted by TCDD in mice colonized with SFB. TCDD-induced shifts in abundance of SFB and B. fragilis compared with previous studies in mice with a traditional gut microbiome. With regard to the mouse model colonized with individual populations, results indicate that TCDD-induced host response was significantly modulated by the presence of SFB in the gut microbiome, providing insight into therapeutic potential between AhR ligands and key commensals.

The Dynamic Interplay between the Gut Microbiota and Autoimmune Diseases

“…In addition, Stedtfeld et al reported that compared with levels under a traditional gut microbiome, 2,3,7,8-tetrachloro dibenzo- p -dioxin (TCDD, an AhR ligand) induced shifts in the abundances of SFB and Bacteroides fragilis (an immune suppressor) in mice. Moreover, the TCDD-induced host response was significantly regulated by the presence of SFB in the gut microbiome, demonstrating therapeutic potential between AhR ligands and key commensals [42]. Dysbiosis of the gut microbiota has been identified as a potential factor that causes autoimmune diseases, which in humans are attributed to multiple factors, even though the relative contribution of the gut microbiota remains elusive.…”

The Human Gut Microbiome – A Potential Controller of Wellness and Disease

“…For this, the application of ‘humanized’ gnotobiotic animal model that harbors defined collection of sequenced microbial communities, has gained momentum in recent years in microbiome research ( Faith et al, 2010 ). This allows proof-of-mechanism study to examine the potential impacts of diet ( Turnbaugh et al, 2009b ), antibiotic, environmental toxicants ( Stedtfeld et al, 2017 ) and host genotypic variation ( Ley et al, 2005 ) on the microbiota and disease manifestation, due to changes in microbiota composition, transcriptomes, proteomes or metabolomes post-induced variations can be extracted and characterized to understand the operation of the microbiota. Besides, ‘humanized’ gnotobiotic mice can be used in preliminary testing of the therapeutic efficacy in treating dysbiosis-associated diseases, as they allow monitoring of the pharmacokinetic–pharmacodynamic changes in microbial communities, thus facilitating optimization of treatment and dosage regime ( Mahe et al, 1987 ; Silva et al, 1999 ).…”

Environmental toxicants in breast milk of Norwegian mothers and gut bacteria composition and metabolites in their infants at 1 month

“…In mice, dioxin-elicited changes in the host decreased B . fragilis [41], which, in our study was relatively lower in abundance in the higher breastmilk toxicants exposure group, as were some Lactobacillus . Due to financial constraints, we only had measured levels of the less toxic of the dioxin-like PCBs; however, we expect these to be moderately correlated with dioxins and other more toxic dioxin-like compounds [3].…”