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D'Addabbo P, Frezza D, Sulentic CE. Evolutive emergence and divergence of an Ig regulatory node: An environmental sensor getting cues from the aryl hydrocarbon receptor? Front Immunol 2023; 14:996119. [PMID: 36817426 PMCID: PMC9936319 DOI: 10.3389/fimmu.2023.996119] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 01/18/2023] [Indexed: 02/05/2023] Open
Abstract
One gene, the immunoglobulin heavy chain (IgH) gene, is responsible for the expression of all the different antibody isotypes. Transcriptional regulation of the IgH gene is complex and involves several regulatory elements including a large element at the 3' end of the IgH gene locus (3'RR). Animal models have demonstrated an essential role of the 3'RR in the ability of B cells to express high affinity antibodies and to express different antibody classes. Additionally, environmental chemicals such as aryl hydrocarbon receptor (AhR) ligands modulate mouse 3'RR activity that mirrors the effects of these chemicals on antibody production and immunocompetence in mouse models. Although first discovered as a mediator of the toxicity induced by the high affinity ligand 2,3,7,8-tetracholordibenzo-p-dioxin (dioxin), understanding of the AhR has expanded to a physiological role in preserving homeostasis and maintaining immunocompetence. We posit that the AhR also plays a role in human antibody production and that the 3'RR is not only an IgH regulatory node but also an environmental sensor receiving signals through intrinsic and extrinsic pathways, including the AhR. This review will 1) highlight the emerging role of the AhR as a key transducer between environmental signals and altered immune function; 2) examine the current state of knowledge regarding IgH gene regulation and the role of the AhR in modulation of Ig production; 3) describe the evolution of the IgH gene that resulted in species and population differences; and 4) explore the evidence supporting the environmental sensing capacity of the 3'RR and the AhR as a transducer of these cues. This review will also underscore the need for studies focused on human models due to the premise that understanding genetic differences in the human population and the signaling pathways that converge at the 3'RR will provide valuable insight into individual sensitivities to environmental factors and antibody-mediated disease conditions, including emerging infections such as SARS-CoV-2.
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Affiliation(s)
- Pietro D'Addabbo
- Department of Biology, University of Bari “Aldo Moro”, Bari, Italy
| | - Domenico Frezza
- Department of Biology E. Calef, University of Rome Tor Vergata, Rome, Italy
| | - Courtney E.W. Sulentic
- Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH, United States
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Li J, Li Y, Sha R, Zheng L, Xu L, Xie HQ, Zhao B. Effects of perinatal TCDD exposure on colonic microbiota and metabolism in offspring and mother mice. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 832:154762. [PMID: 35364153 DOI: 10.1016/j.scitotenv.2022.154762] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 03/17/2022] [Accepted: 03/18/2022] [Indexed: 06/14/2023]
Abstract
Emerging evidence supports that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) impacts the gut microbiota and metabolic pathways. TCDD can be transmitted from mother to child; thus, we hypothesize that maternal exposure to TCDD may affect the gut microbiota in mothers and offspring. To acquire in vivo evidence supporting this hypothesis, female C57BL/6 mice were administered with TCDD (0.1 and 10 μg/kg body weight (bw)) during pregnancy and lactation periods, and then changes of colonic microbiota in offspring and mothers were evaluated. High-throughput sequencing of the V4 regions of the 16S rRNA gene was performed. The composition and structure of the colonic microbiota in offspring and mothers were significantly influenced by 10 μg/kg bw TCDD as demonstrated by upregulation of harmful bacteria and downregulation of beneficial bacteria. Paradoxically, pathogenic bacteria and opportunistic pathogens were conversely decreased in the offspring of the low-dose TCDD treatment group. Tryptophan (Trp) metabolism exhibited a noticeable change caused by the alteration of colonic microbiota in offspring after maternal exposure to 10 μg/kg bw TCDD, which showed a linear dependence, demonstrating that pathogens or opportunistic pathogens may accelerate the dysbiosis of Trp metabolism. Trp metabolism dysregulation caused by the changed colonic microbiota may subsequently impact other intestinal segments or even living organisms. Our study provides new evidence indicating a potential influence of early TCDD exposure on the colonic microbiota and metabolism.
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Affiliation(s)
- Jiao Li
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yunping Li
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Environment, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
| | - Rui Sha
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Liping Zheng
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China; Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment of the People's Republic of China, Nanjing 210042, China
| | - Li Xu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Heidi Qunhui Xie
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Bin Zhao
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Environment, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
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Current Therapeutic Landscape and Safety Roadmap for Targeting the Aryl Hydrocarbon Receptor in Inflammatory Gastrointestinal Indications. Cells 2022; 11:cells11101708. [PMID: 35626744 PMCID: PMC9139855 DOI: 10.3390/cells11101708] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/30/2022] [Accepted: 05/16/2022] [Indexed: 02/07/2023] Open
Abstract
Target modulation of the AhR for inflammatory gastrointestinal (GI) conditions holds great promise but also the potential for safety liabilities both within and beyond the GI tract. The ubiquitous expression of the AhR across mammalian tissues coupled with its role in diverse signaling pathways makes development of a “clean” AhR therapeutically challenging. Ligand promiscuity and diversity in context-specific AhR activation further complicates targeting the AhR for drug development due to limitations surrounding clinical translatability. Despite these concerns, several approaches to target the AhR have been explored such as small molecules, microbials, PROTACs, and oligonucleotide-based approaches. These various chemical modalities are not without safety liabilities and require unique de-risking strategies to parse out toxicities. Collectively, these programs can benefit from in silico and in vitro methodologies that investigate specific AhR pathway activation and have the potential to implement thresholding parameters to categorize AhR ligands as “high” or “low” risk for sustained AhR activation. Exploration into transcriptomic signatures for AhR safety assessment, incorporation of physiologically-relevant in vitro model systems, and investigation into chronic activation of the AhR by structurally diverse ligands will help address gaps in our understanding regarding AhR-dependent toxicities. Here, we review the role of the AhR within the GI tract, novel therapeutic modality approaches to target the AhR, key AhR-dependent safety liabilities, and relevant strategies that can be implemented to address drug safety concerns. Together, this review discusses the emerging therapeutic landscape of modalities targeting the AhR for inflammatory GI indications and offers a safety roadmap for AhR drug development.
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Foxx CL, Nagy MR, King AE, Albin D, DeKrey GK. TCDD exposure alters fecal IgA concentrations in male and female mice. BMC Pharmacol Toxicol 2022; 23:25. [PMID: 35449084 PMCID: PMC9026712 DOI: 10.1186/s40360-022-00563-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 03/30/2022] [Indexed: 11/16/2022] Open
Abstract
Background Activation of the aryl hydrocarbon receptor (AhR) can alter diurnal rhythms including those for innate lymphoid cell numbers, cytokine and hormone levels, and feeding behaviors. Because immune responses and antibody levels are modulated by exposure to AhR agonists, we hypothesized that some of the variation previously reported for the effects of AhR activation on fecal secretory immunoglobulin A (sIgA) levels could be explained by dysregulation of the diurnal sIgA rhythm. Methods C57Bl/6 J mice were exposed to peanut oil or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 10 or 40 μg/Kg) and fecal sIgA levels were determined in samples collected every 4 h over 4 days. Results Fecal sIgA concentrations were not significantly different between light and dark phases of the photoperiod in either male or female mice, and there were no significant circadian rhythms observed, but TCDD exposure significantly altered both fecal mesor sIgA and serum IgA concentrations, in parallel, in male (increased) and female (biphasic) mice. Conclusions AhR activation can contribute to the regulation of steady state IgA/sIgA concentrations. Supplementary Information The online version contains supplementary material available at 10.1186/s40360-022-00563-9.
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Affiliation(s)
- Christine L Foxx
- School of Biological Sciences, College of Natural and Health Sciences, University of Northern Colorado, Greeley, CO, 80639, USA
| | - Madeline R Nagy
- School of Biological Sciences, College of Natural and Health Sciences, University of Northern Colorado, Greeley, CO, 80639, USA
| | - Aspen E King
- School of Biological Sciences, College of Natural and Health Sciences, University of Northern Colorado, Greeley, CO, 80639, USA
| | - Dreycey Albin
- Department of Computer Science, College of Engineering and Applied Science, University of Colorado, Boulder, 80309, CO, USA
| | - Gregory K DeKrey
- School of Biological Sciences, College of Natural and Health Sciences, University of Northern Colorado, Greeley, CO, 80639, USA.
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He Q, Huang J, Zheng T, Lin D, Zhang H, Li J, Sun Z. Treatment with mixed probiotics induced, enhanced and diversified modulation of the gut microbiome of healthy rats. FEMS Microbiol Ecol 2021; 97:6430860. [PMID: 34792102 DOI: 10.1093/femsec/fiab151] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 11/16/2021] [Indexed: 12/18/2022] Open
Abstract
Previous studies demonstrated that multi-strain probitics could more strongly regulate intestinal cytokines and the mucosal barrier than the individual ingredient strains. Nevertheless, the potentially different gut microbiome modulation effects between multi-strain and single-strain probiotics treatments remain unexplored. Here, we administered three different Lactiplantibacillus plantarum strains or their mixture to healthy Wistar rats and compared the shift of gut microbiome among the treatment groups. A 4-week intervention with mixed probiotics induced more drastic and diversified gut microbiome modulation than single-strain probiotics administration (alpha diversity increased 8% and beta diversity increased 18.7%). The three single-strain probiotics treatments all converged the gut microbiota, decreasing between-individual beta diversity by 12.7% on average after the treatment, while multi-strain probiotics treatment diversified the gut microbiome and increased between-individual beta diversity by 37.2% on average. Covariation analysis of the gut microbes suggests that multi-strain probiotics could exert synergistic, modified and enhanced modulation effects on the gut microbiome based on strain-specific modulation effects of probiotics. The more heterogeneous responses to the multi-strain probiotics treatment suggest that future precision microbiome modulation should consider the potential interactions of the probiotic strains, and personalized response to probiotic formulas due to heterogenous gut microbial compositions.
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Affiliation(s)
- Qiuwen He
- Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Key Laboratory of Dairy Products Processing, Ministry of Agriculture, Inner Mongolia Agricultural University, Huhhot, China
- Inner Mongolia Key Laboratory of Dairy Biotechnology and Engineering, Inner Mongolia Agricultural University, Hohhot 010018, China
| | - Jiating Huang
- Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong, China
| | - Tingting Zheng
- Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong, China
| | - Dan Lin
- Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong, China
| | - Heping Zhang
- Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Key Laboratory of Dairy Products Processing, Ministry of Agriculture, Inner Mongolia Agricultural University, Huhhot, China
| | - Jun Li
- Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong, China
- School of Data Science, City University of Hong Kong, Hong Kong, China
| | - Zhihong Sun
- Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Key Laboratory of Dairy Products Processing, Ministry of Agriculture, Inner Mongolia Agricultural University, Huhhot, China
- Inner Mongolia Key Laboratory of Dairy Biotechnology and Engineering, Inner Mongolia Agricultural University, Hohhot 010018, China
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Neamah WH, Busbee PB, Alghetaa H, Abdulla OA, Nagarkatti M, Nagarkatti P. AhR Activation Leads to Alterations in the Gut Microbiome with Consequent Effect on Induction of Myeloid Derived Suppressor Cells in a CXCR2-Dependent Manner. Int J Mol Sci 2020; 21:ijms21249613. [PMID: 33348596 PMCID: PMC7767008 DOI: 10.3390/ijms21249613] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 11/27/2020] [Accepted: 12/12/2020] [Indexed: 02/06/2023] Open
Abstract
Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent ligand for AhR and a known carcinogen. While AhR activation by TCDD leads to significant immunosuppression, how this translates into carcinogenic signal is unclear. Recently, we demonstrated that activation of AhR by TCDD in naïve C57BL6 mice leads to massive induction of myeloid derived-suppressor cells (MDSCs). In the current study, we investigated the role of the gut microbiota in TCDD-mediated MDSC induction. TCDD caused significant alterations in the gut microbiome, such as increases in Prevotella and Lactobacillus, while decreasing Sutterella and Bacteroides. Fecal transplants from TCDD-treated donor mice into antibiotic-treated mice induced MDSCs and increased regulatory T-cells (Tregs). Injecting TCDD directly into antibiotic-treated mice also induced MDSCs, although to a lesser extent. These data suggested that TCDD-induced dysbiosis plays a critical role in MDSC induction. Interestingly, treatment with TCDD led to induction of MDSCs in the colon and undetectable levels of cysteine. MDSCs suppressed T cell proliferation while reconstitution with cysteine restored this response. Lastly, blocking CXC chemokine receptor 2 (CXCR2) impeded TCDD-mediated MDSC induction. Our data demonstrate that AhR activation by TCDD triggers dysbiosis which, in turn, regulates, at least in part, induction of MDSCs.
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Elmassry MM, Zayed A, Farag MA. Gut homeostasis and microbiota under attack: impact of the different types of food contaminants on gut health. Crit Rev Food Sci Nutr 2020; 62:738-763. [DOI: 10.1080/10408398.2020.1828263] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Moamen M. Elmassry
- Department of Biological Sciences, Texas Tech University, Lubbock, Texas, USA
| | - Ahmed Zayed
- Department of Pharmacognosy, College of Pharmacy, Tanta University, Tanta, Egypt
- Institute of Bioprocess Engineering, Technical University of Kaiserslautern, Kaiserslautern, Germany
| | - Mohamed A. Farag
- Department of Pharmacognosy, College of Pharmacy, Cairo University, Cairo, Egypt
- Department of Chemistry, School of Sciences & Engineering, The American University in Cairo, New Cairo, Egypt
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Mokshagundam S, Ding T, Rumph JT, Dallas M, Stephens VR, Osteen KG, Bruner-Tran KL. Developmental 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure of either parent enhances the risk of necrotizing enterocolitis in neonatal mice. Birth Defects Res 2020; 112:1209-1223. [PMID: 32519502 DOI: 10.1002/bdr2.1742] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 04/22/2020] [Accepted: 05/20/2020] [Indexed: 01/09/2023]
Abstract
BACKGROUND Necrotizing enterocolitis (NEC) is a rare, but potentially fatal intestinal inflammatory condition most often arising in premature infants. Infants provided formula are also at greater risk of developing this disease. Although the majority of formula-fed, preterm infants do not develop NEC, up to 30% of infants with the disease do not survive. Thus, identifying additional, currently unrecognized factors, which may predispose a specific infant to NEC development would be a significant clinical advancement. In this regard, we have previously reported that offspring of female or male mice with a history of developmental exposure to the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exhibit altered sensitivity to inflammatory challenges and are frequently born premature. Herein, we examined the possibility that, compared to unexposed mice (F1NONE ), developmental TCDD exposure of either parent (maternal, F1MTCDD , or paternal, F1PTCDD ) would enhance the risk of NEC in offspring (F2TCDD mice) in association with supplemental formula feeding. METHODS Beginning on postnatal day 7, all neonates were randomized to maternal milk only or maternal milk with up to 20 supplemental formula feedings. All pups remained with the Dams and were additionally allowed to nurse ad libitum. RESULTS Formula-fed F2NONE pups rarely developed NEC while this disease was common in formula-fed F2MTCDD and F2PTCDD mice. Unexpectedly, 50% of F2MTCDD pups that were not provided supplemental formula also developed NEC. CONCLUSIONS Our studies provide evidence that a history of parental TCDD exposure enhances the risk of NEC in offspring and suggest exposure to environmental immunotoxicants such as TCDD may also contribute to this inflammatory disease in humans.
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Affiliation(s)
- Shilpa Mokshagundam
- Women's Reproductive Health Research Center, Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Tianbing Ding
- Women's Reproductive Health Research Center, Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Jelonia T Rumph
- Department of Immunology, Microbiology and Physiology, Meharry Medical College, Nashville, Tennessee, USA
| | | | - Victoria R Stephens
- Women's Reproductive Health Research Center, Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.,Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Kevin G Osteen
- Women's Reproductive Health Research Center, Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.,Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.,VA Tennessee Valley Healthcare System, Nashville, Tennessee, USA
| | - Kaylon L Bruner-Tran
- Women's Reproductive Health Research Center, Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
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Li Y, Xie HQ, Zhang W, Wei Y, Sha R, Xu L, Zhang J, Jiang Y, Guo TL, Zhao B. Type 3 innate lymphoid cells are altered in colons of C57BL/6 mice with dioxin exposure. THE SCIENCE OF THE TOTAL ENVIRONMENT 2019; 662:639-645. [PMID: 30703721 DOI: 10.1016/j.scitotenv.2019.01.139] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 01/10/2019] [Accepted: 01/12/2019] [Indexed: 06/09/2023]
Abstract
Type 3 innate lymphoid cells (ILC3s) are distributed in the gut and regulate inflammation by secreting cytokines, including interferon (IFN)-γ and interleukin (IL)-17. The maintenance and function of ILC3s involve the activity of aryl hydrocarbon receptor (AhR), a potent ligand of which is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), one of the most toxic dioxin congeners. Thus, TCDD exposure might affect ILC3s. To obtain in vivo evidence supporting this notion, we exposed female C57BL/6 mice orally to TCDD (low/high doses: 0.1/10 μg/kg body weight) during pregnancy and lactation periods, and after the exposure, evaluated the mothers and offspring for alterations in ILC3 differentiation and function in the colon. ILC3 frequency among colonic lamina propria lymphocytes was preferentially diminished in the offspring, and, in parallel, the median fluorescence intensity (MFI) of retinoic acid receptor-related orphan receptor (ROR)γt, which is associated with ILC3 differentiation, was also decreased in ILC3s. Conversely, the percentages of two subsets of the cells, one positive for natural cytotoxicity receptor NKp46 and the other for IL-17a, were increased in TCDD-exposed mothers and offspring. Moreover, the percentage of IFN-γ+ ILC3s was increased specifically in the mothers, but this was in conjunction with a significant decrease in the MFI of IFN-γ, which suggests that the IFN-γ+ ILC3 subset was functionally altered. In conclusion, maternal exposure to TCDD suppresses ILC3 differentiation in the offspring and influences ILC3 function in distinct manners in the mother and offspring. Our study provides new insights into the intergenerational interference of dioxins in colonic ILC3s.
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Affiliation(s)
- Yunping Li
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Heidi Qunhui Xie
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wanglong Zhang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yunbo Wei
- Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250014, China
| | - Rui Sha
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Li Xu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jianqing Zhang
- Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China
| | - Yousheng Jiang
- Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China
| | - Tai L Guo
- Department of Veterinary Biosciences and Diagnostic Imaging, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA
| | - Bin Zhao
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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Defois C, Ratel J, Garrait G, Denis S, Le Goff O, Talvas J, Mosoni P, Engel E, Peyret P. Food Chemicals Disrupt Human Gut Microbiota Activity And Impact Intestinal Homeostasis As Revealed By In Vitro Systems. Sci Rep 2018; 8:11006. [PMID: 30030472 PMCID: PMC6054606 DOI: 10.1038/s41598-018-29376-9] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Accepted: 07/04/2018] [Indexed: 12/22/2022] Open
Abstract
Growing evidence indicates that the human gut microbiota interacts with xenobiotics, including persistent organic pollutants and foodborne chemicals. The toxicological relevance of the gut microbiota-pollutant interplay is of great concern since chemicals may disrupt gut microbiota functions, with a potential impairment of host homeostasis. Herein we report within batch fermentation systems the impact of food contaminants (polycyclic aromatic hydrocarbons, polychlorobiphenyls, brominated flame retardants, dioxins, pesticides and heterocyclic amines) on the human gut microbiota by metatranscriptome and volatolome i.e. “volatile organic compounds” analyses. Inflammatory host cell response caused by microbial metabolites following the pollutants-gut microbiota interaction, was evaluated on intestinal epithelial TC7 cells. Changes in the volatolome pattern analyzed via solid-phase microextraction coupled to gas chromatography-mass spectrometry mainly resulted in an imbalance in sulfur, phenolic and ester compounds. An increase in microbial gene expression related to lipid metabolism processes as well as the plasma membrane, periplasmic space, protein kinase activity and receptor activity was observed following dioxin, brominated flame retardant and heterocyclic amine exposure. Conversely, all food contaminants tested induced a decreased in microbial transcript levels related to ribosome, translation and nucleic acid binding. Finally, we demonstrated that gut microbiota metabolites resulting from pollutant disturbances may promote the establishment of a pro-inflammatory state in the gut, as stated with the release of cytokine IL-8 by intestinal epithelial cells.
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Megna BW, Carney PR, Kennedy GD. Intestinal inflammation and the diet: Is food friend or foe? World J Gastrointest Surg 2016; 8:115-123. [PMID: 26981185 PMCID: PMC4770165 DOI: 10.4240/wjgs.v8.i2.115] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 11/15/2015] [Accepted: 12/11/2015] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic intestinal illness of autoimmune origin affecting millions across the globe. The most common subtypes include ulcerative colitis (UC) and Crohn’s disease. While many medical treatments for IBD exist, none come without the risk of significant immunosuppression and in general do not have benign side effect profiles. Surgical intervention exists only as radical resection for medically refractory UC. There exists a dire need for novel treatments that target the inherent pathophysiologic disturbances of IBD, rather than global immune suppression. One avenue of investigation that could provide such an agent is the interaction between certain dietary elements and the aryl hydrocarbon receptor (AHR). The AHR is a cytosolic transcription factor with a rich history in environmental toxicant handling, however, recently a role has emerged for the AHR as a modulator of the gastrointestinal immune system. Studies have come to elucidate these effects to include the enhancement of Th cell subset differentiation, interactions between enteric flora and the luminal wall, and modulation of inflammatory interleukin and cytokine signaling. This review highlights advancements in our understanding of AHR activity in the digestive tract and how this stimulation may be wrought by certain dietary “micronutriceuticals”, namely indole-3-carbinol (I3C) and its derivatives. Greater clarity surrounding these dynamics could lead to a novel diet-derived agonist of the AHR which is not only non-toxic, but also efficacious in the amelioration of clinical IBD.
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Park JH, Choi AJ, Kim SJ, Jeong SY. 3,3'-Diindolylmethane Inhibits Flt3L/GM-CSF-induced-bone Marrow-derived CD103(+) Dendritic Cell Differentiation Regulating Phosphorylation of STAT3 and STAT5. Immune Netw 2015; 15:278-90. [PMID: 26770182 PMCID: PMC4700404 DOI: 10.4110/in.2015.15.6.278] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 11/05/2015] [Accepted: 11/07/2015] [Indexed: 01/05/2023] Open
Abstract
The intestinal immune system maintains oral tolerance to harmless antigens or nutrients. One mechanism of oral tolerance is mediated by regulatory T cell (Treg)s, of which differentiation is regulated by a subset of dendritic cell (DC)s, primarily CD103+ DCs. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, plays an important role in regulating immunity. The intestines are exposed to various AhR ligands, including endogenous metabolites and phytochemicals. It was previously reported that AhR activation induced tolerogenic DCs in mice or in cultures of bone marrow-derived DCs. However, given the variety of tolerogenic DCs, which type of tolerogenic DCs is regulated by AhR remains unknown. In this study, we found that AhR ligand 3,3'-diindolylmethane (DIM) inhibited the development of CD103+ DCs from mouse bone marrow cells stimulated with Flt3L and GM-CSF. DIM interfered with phosphorylation of STAT3 and STAT5 inhibiting the expression of genes, including Id2, E2-2, IDO-1, and Aldh1a2, which are associated with DC differentiation and functions. Finally, DIM suppressed the ability of CD103+ DCs to induce Foxp3+ Tregs.
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Affiliation(s)
- Joo-Hung Park
- Department of Biology, Changwon National University, Changwon 51140, Korea
| | - Ah-Jeong Choi
- Department of Biology, Changwon National University, Changwon 51140, Korea
| | - Soo-Ji Kim
- Department of Biology, Changwon National University, Changwon 51140, Korea
| | - So-Yeon Jeong
- Department of Biology, Changwon National University, Changwon 51140, Korea
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Muenyi CS, Carrion SL, Jones LA, Kennedy LH, Slominski AT, Sutter CH, Sutter TR. Effects of in utero exposure of C57BL/6J mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin on epidermal permeability barrier development and function. ENVIRONMENTAL HEALTH PERSPECTIVES 2014; 122:1052-1058. [PMID: 24904982 PMCID: PMC4181931 DOI: 10.1289/ehp.1308045] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 06/04/2014] [Indexed: 05/29/2023]
Abstract
BACKGROUND Development of the epidermal permeability barrier (EPB) is essential for neonatal life. Defects in this barrier are found in many skin diseases such as atopic dermatitis. OBJECTIVE We investigated the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the development and function of the EPB. METHODS Timed-pregnant C57BL/6J mice were gavaged with corn oil or TCDD (10 μg/kg body weight) on gestation day 12. Embryos were harvested on embryonic day (E) 15, E16, E17, and postnatal day (PND) 1. RESULTS A skin permeability assay showed that TCDD accelerated the development of the EPB, beginning at E15. This was accompanied by a significant decrease in transepidermal water loss (TEWL), enhanced stratification, and formation of the stratum corneum (SC). The levels of several ceramides were significantly increased at E15 and E16. PND1 histology revealed TCDD-induced acanthosis and epidermal hyperkeratosis. This was accompanied by disrupted epidermal tight junction (TJ) function, with increased dye leakage at the terminal claudin-1-staining TJs of the stratum granulosum. Because the animals did not have enhanced rates of TEWL, a commonly observed phenotype in animals with TJ defects, we performed tape-stripping. Removal of most of the SC resulted in a significant increase in TEWL in TCDD-exposed PND1 pups compared with their control group. CONCLUSIONS These findings demonstrate that in utero exposure to TCDD accelerates the formation of an abnormal EPB with leaky TJs, warranting further study of environmental exposures, epithelial TJ integrity, and atopic disease.
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Wang T, Wyrick KL, Pecka MR, Wills TB, Vorderstrasse BA. Mechanistic exploration of AhR-mediated host protection against Streptococcus pneumoniae infection. Int Immunopharmacol 2012; 13:490-8. [PMID: 22634480 DOI: 10.1016/j.intimp.2012.05.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Revised: 04/28/2012] [Accepted: 05/10/2012] [Indexed: 12/14/2022]
Abstract
Streptococcus pneumoniae is a primary cause of invasive bacterial infection and pneumonia and is one of the leading causes of death worldwide. In prior studies we showed that pre-treating mice with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent agonist of the aryl hydrocarbon receptor (AhR), protects against S. pneumoniae-induced mortality and reduces pulmonary bacterial burden. The current studies were conducted to help elucidate the mechanism for this protective effect, and to characterize the response in the lung during the first 10h following infection. C57Bl/6 mice were treated with TCDD one day prior to intranasal infection with serotype 3 S. pneumoniae. Monitoring of bacteria in the lung airways revealed that bacterial growth was inhibited in the TCDD-treated animals within 10h of infection. To address the mechanism of this rapid protective response, macrophages, neutrophils, and invariant Natural Killer T (iNKT) cells were quantified, and levels of natural antibodies produced by B-1 B cells were evaluated. Functional assays addressed whether AhR activation reduced the capacity of lung epithelial cells to bind bacteria, and whether TCDD treatment enhanced production of antimicrobial agents in the lung or blood. None of the hypothesized mechanisms was able to explain the protective effect. Finally, the exposure paradigm was manipulated to test whether administration of TCDD after instillation of the bacteria was also protective. Results showed that TCDD must be administered in advance of exposure to bacteria, suggesting that the lung environment is rendered inhospitable to the pathogens.
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Affiliation(s)
- Tao Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, WA 99164, USA
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15
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Abstract
The gut-associated lymphoid tissue is the largest immune organ in the body and is the primary route by which we are exposed to antigens. Tolerance induction is the default immune pathway in the gut, and the type of tolerance induced relates to the dose of antigen fed: anergy/deletion (high dose) or regulatory T-cell (Treg) induction (low dose). Conditioning of gut dendritic cells (DCs) by gut epithelial cells and the gut flora, which itself has a major influence on gut immunity, induces CD103(+) retinoic acid-dependent DC that induces Tregs. A number of Tregs are induced at mucosal surfaces. Th3 type Tregs are transforming growth factor-β dependent and express latency-associated peptide (LAP) on their surface and were discovered in the context of oral tolerance. Tr1 type Tregs (interleukin-10 dependent) are induced by nasal antigen and forkhead box protein 3(+) iTregs are induced by oral antigen and by oral administration of aryl hydrocarbon receptor ligands. Oral or nasal antigen ameliorates autoimmune and inflammatory diseases in animal models by inducing Tregs. Furthermore, anti-CD3 monoclonal antibody is active at mucosal surfaces and oral or nasal anti-CD3 monoclonal antibody induces LAP(+) Tregs that suppresses animal models (experimental autoimmune encephalitis, type 1 and type 2 diabetes, lupus, arthritis, atherosclerosis) and is being tested in humans. Although there is a large literature on treatment of animal models by mucosal tolerance and some positive results in humans, this approach has yet to be translated to the clinic. The successful translation will require defining responsive patient populations, validating biomarkers to measure immunologic effects, and using combination therapy and immune adjuvants to enhance Treg induction. A major avenue being investigated for the treatment of autoimmunity is the induction of Tregs and mucosal tolerance represents a non-toxic, physiologic approach to reach this goal.
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Affiliation(s)
- Howard L Weiner
- Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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Chmill S, Kadow S, Winter M, Weighardt H, Esser C. 2,3,7,8-Tetrachlorodibenzo-p-dioxin impairs stable establishment of oral tolerance in mice. Toxicol Sci 2010; 118:98-107. [PMID: 20729464 DOI: 10.1093/toxsci/kfq232] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The toxic environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent immunomodulatory chemical. TCDD activates the aryl hydrocarbon receptor (AhR) and suppresses peripheral humoral and cellular adaptive immune responses. Though the major route of uptake is via food, little is known until now on the immunotoxic effects of TCDD on the gut-associated lymphoid tissue. We show here that AhR is strongly expressed along the small intestine, especially in intestinal epithelial cells (IEC). The AhR marker gene cyp1a1 is induced in IEC by oral TCDD exposure. We asked how TCDD affects oral tolerance, a unique function of mucosal immunity. C57BL/6 mice were injected with 10 μg/kg body weight TCDD and fed with ovalbumin (OVA) in a high-dose tolerization protocol. Mice were immunized and boosted with OVA on days 12, 23, and 55 after tolerization. Five of 14, 6 of 15, and 13 of 14 TCDD-treated mice generated OVA-specific immunoglobulin (Ig)G1 antibodies after the first, second, and third immunization with OVA, respectively. Only one mouse harbored anti-OVA IgG1 antibodies in the control group even after the third immunization with OVA. OVA-specific IgA in fecal samples of tolerized and TCDD-exposed mice could be detected at the levels of nontolerized mice, whereas completely absent in tolerant control mice. Correlated to this, we found in TCDD-treated mice an increase in interleukin-6 producing CD103+ dendritic cells (DC) present in the gut-draining mesenteric lymph nodes (MLN) and a small increase in the frequency of Th17 cells. Neither the frequencies nor the absolute numbers of immune cells in the lamina propria (LP) or in intraepithelial lymphocytes were changed by TCDD treatment. Our data not only have implications for food allergies in settings of environmental exposure but also raise concerns regarding the harmlessness of overdosing potential AhR agonist in food, which needs to be studied further.
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Affiliation(s)
- Stefanie Chmill
- Institute for Environmental Medical Research, Molecular Immunology Unit, 40225 Düsseldorf, Germany
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17
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Abstract
Multiple mechanisms of tolerance are induced by oral antigen. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral antigen induces T-helper 2 [interleukin (IL)-4/IL-10] and Th3 [transforming growth factor (TGF)-beta] T cells plus CD4+CD25+ regulatory cells and latency-associated peptide+ T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-beta, cholera toxin B subunit, Flt-3 ligand, and anti-CD40 ligand. Oral (and nasal) antigen administration suppresses animal models of autoimmune diseases including experimental autoimmune encephalitis, uveitis, thyroiditis, myasthenia, arthritis, and diabetes in the non-obese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, graft rejection, allergy, colitis, stroke, and models of Alzheimer's disease. Oral tolerance has been tested in human autoimmune diseases including multiple sclerosis (MS), arthritis, uveitis, and diabetes and in allergy, contact sensitivity to dinitrochlorobenzene (DNCB), and nickel allergy. Although positive results have been observed in phase II trials, no effect was observed in phase III trials of CII in rheumatoid arthritis or oral myelin and glatiramer acetate (GA) in MS. Large placebo effects were observed, and new trials of oral GA are underway. Oral insulin has recently been shown to delay onset of diabetes in at-risk populations, and confirmatory trials of oral insulin are being planned. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time, and antigen-specific mechanisms of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy, and early therapy.
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Affiliation(s)
- Howard L. Weiner
- Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Andre Pires da Cunha
- Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Francisco Quintana
- Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Henry Wu
- Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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