Specific Gut Microbial Enzymes Drive Colitis Promotion by Triclosan

Zhang, Jianan; Walker, Morgan A.; Sanidad, Katherine Z.; Zhang, Hongna; Zhao, Ermin; Chacón-Vargas, Katherine; Yeliseyev, Vladimir; Parsonnet, Julie; Haggerty, Thomas D.; Wang, Guangqiang; Shimpson, Joshua; Jariwala, Parth B.; Beaty, Violet V.; Yang, Jing; Panigraphy, Anand; Minter, Lisa M.; Kim, Dae-Young; Gibbons, John; Liu, Lin; Li, Zhengze; Xiao, Hang; Borlandelli, Valentina; Overkleeft, Hermen S.; Cloer, Erica W.; Major, Michael B.; Goldfarb, Dennis; Cai, Zongwei; Redinbo, Matthew R.; Zhang, Guodong

doi:10.1021/scimeetings.1c01195

Cited by 3 publications

(7 citation statements)

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“…48 However, if subjected to enterohepatic circulation, gut microbial β-glucuronidases could lead to exposure of the colonic epithelium to the parent compound again. 49 This mechanism is known to participate in drug toxicity 50 and was reported for structurally similar xenobiotic small molecules, such as triclosan, 49 or endogenous estrogens. 51 Hence, even assuming a low-concentration dietary intake (see Cell Culture and Experimental Layout section), this does not exclude the possibility of recurrent intestinal exposure to Alternaria toxins.…”

Section: ■ Discussionmentioning

confidence: 83%

Alternaria alternata Mycotoxins Activate the Aryl Hydrocarbon Receptor and Nrf2-ARE Pathway to Alter the Structure and Immune Response of Colon Epithelial Cells

Groestlinger

Spindler

Pahlke

et al. 2022

Chem. Res. Toxicol.

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After ingestion of food commodities, the gastrointestinal tract (GIT) poses the first barrier against xenobiotics and pathogens. Therefore, it is regularly confronted with external stressors potentially affecting the inflammatory response and the epithelial barrier. Alternaria mycotoxins such as alternariol (AOH) and altertoxin II (ATX-II) are frequently occurring food and feed contaminants that are described for their immunomodulatory capacities. Hence, this study aimed at exploring the effect of AOH and ATX-II as single compounds or binary mixtures on the immune response and epithelial homeostasis in noncancerous colon epithelial cells HCEC-1CT. Both toxins suppressed mRNA levels of proinflammatory mediators interleukin-8 (IL-8), tumor necrosis factor α (TNF-α), and secretion of IL-8, as well as mRNA levels of the matrix metallopeptidase 2 (MMP-2). Binary combinations of AOH and ATX-II reduced the response of the single toxins. Additionally, AOH and ATX-II modified immunolocalization of transmembrane proteins such as integrin β1, zona occludens 1 (ZO-1), claudin 4 (Cldn 4), and occludin (Ocln), which support colonic tissue homeostasis and intestinal barrier function. Moreover, the cellular distribution of ZO-1 was affected by ATX-II. Mechanistically, these effects could be traced back to the involvement of several transcription factors. AOH activated the nuclear translocation of the aryl hydrocarbon receptor (AhR) and the nuclear factor erythroid 2-related factor 2 (Nrf2), governing cell metabolic competence and structural integrity. This was accompanied by altered distribution of the NF-κB p65 protein, an important regulator of inflammatory response. ATX-II also induced AhR and Nrf2 translocation, albeit failing to substantiate the effect of AOH on the colonic epithelium. Hence, both toxins coherently repress the intestinal immune response on the cytokine transcriptional and protein levels. Furthermore, both mycotoxins affected the colonic epithelial integrity by altering the cell architecture.

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Section: ■ Discussionmentioning

confidence: 83%

Alternaria alternata Mycotoxins Activate the Aryl Hydrocarbon Receptor and Nrf2-ARE Pathway to Alter the Structure and Immune Response of Colon Epithelial Cells

Groestlinger

Spindler

Pahlke

et al. 2022

Chem. Res. Toxicol.

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“…[155] Human fecal isolates reactivated triclosan ex vivo, which correlated with the abundance of active β-glucuronidases identified using GUS-Biotin-ABP. [155] Furthermore, triclosan administration in mice exacerbated dextran sodium sulfate (DSS)-induced colitis, which was reversed upon bacterial β-glucuronidase inhibition. [155] ABPP has also been extended to the isolation of specific gut microbes with active β-glucuronidase enzymes.…”

Section: Microbial Metabolism In the Gut Microbiomementioning

confidence: 93%

“…[156] Although triclosan is inactivated and secreted as its glucuronide (Figure 14b), [156] further studies show that subclasses of bacterial β-glucuronidases reactivate triclosan in mice. [155] Human fecal isolates reactivated triclosan ex vivo, which correlated with the abundance of active β-glucuronidases identified using GUS-Biotin-ABP. [155] Furthermore, triclosan administration in mice exacerbated dextran sodium sulfate (DSS)-induced colitis, which was reversed upon bacterial β-glucuronidase inhibition.…”

Section: Microbial Metabolism In the Gut Microbiomementioning

confidence: 93%

“…[155] Furthermore, triclosan administration in mice exacerbated dextran sodium sulfate (DSS)-induced colitis, which was reversed upon bacterial β-glucuronidase inhibition. [155] ABPP has also been extended to the isolation of specific gut microbes with active β-glucuronidase enzymes. [154] GlcA-ABP (Figure 14a) fluorescently labeled cells with active βglucuronidases, which enabled fluorescence-activated cell sorting for bacterial enrichment.…”

Section: Microbial Metabolism In the Gut Microbiomementioning

confidence: 99%

“…(b) Triclosan reactivation and reabsorption by gut microbial βglucuronidases. [155] host proteins. [161] A second-generation inhibitor (AAA-10, Figure 15d) [165] protected against intestinal barrier erosion and liver inflammation in rats fed a high-fat diet.…”

Section: Microbial Metabolism In the Gut Microbiomementioning

confidence: 99%

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Chemoproteomic Approaches for Unraveling Prokaryotic Biology

Malarney

Chang

2023

Israel Journal of Chemistry

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Bacteria are ubiquitous lifeforms with important roles in the environment, biotechnology, and human health. Many of the functions that bacteria perform are mediated by proteins and enzymes, which catalyze metabolic transformations of small molecules and modifications of proteins. To better understand these biological processes, chemical proteomic approaches, including activity-based protein profiling, have been developed to interrogate protein function and enzymatic activity in physiologically relevant contexts. Here, chemoproteomic strategies and technological advances for studying bacterial physiology, pathogenesis, and metabolism are discussed. The development of chemoproteomic approaches for characterizing protein function and enzymatic activity within bacteria remains an active area of research, and continued innovations are expected to provide breakthroughs in understanding bacterial biology.

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Human Airway Organoids and Multimodal Imaging-Based Toxicity Evaluation of 1-Nitropyrene

Zhou,

Li,

Chen

et al. 2024

Environ. Sci. Technol.

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Despite significant advances in understanding the general health impacts of air pollution, the toxic effects of air pollution on cells in the human respiratory tract are still elusive. A robust, biologically relevant in vitro model for recapitulating the physiological response of the human airway is needed to obtain a thorough understanding of the molecular mechanisms of air pollutants. In this study, by using 1-nitropyrene (1-NP) as a proofof-concept, we demonstrate the effectiveness and reliability of evaluating environmental pollutants in physiologically active human airway organoids. Multimodal imaging tools, including live cell imaging, fluorescence microscopy, and MALDI-mass spectrometry imaging (MSI), were implemented to evaluate the cytotoxicity of 1-NP for airway organoids. In addition, lipidomic alterations upon 1-NP treatment were quantitatively analyzed by nontargeted lipidomics. 1-NP exposure was found to be associated with the overproduction of reactive oxygen species (ROS), and dysregulation of lipid pathways, including the SM-Cer conversion, as well as cardiolipin in our organoids. Compared with that of cell lines, a higher tolerance of 1-NP toxicity was observed in the human airway organoids, which might reflect a more physiologically relevant response in the native airway epithelium. Collectively, we have established a novel system for evaluating and investigating molecular mechanisms of environmental pollutants in the human airways via the combinatory use of human airway organoids, multimodal imaging analysis, and MS-based analyses.

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Specific Gut Microbial Enzymes Drive Colitis Promotion by Triclosan

Cited by 3 publications

References 0 publications

Alternaria alternata Mycotoxins Activate the Aryl Hydrocarbon Receptor and Nrf2-ARE Pathway to Alter the Structure and Immune Response of Colon Epithelial Cells

Alternaria alternata Mycotoxins Activate the Aryl Hydrocarbon Receptor and Nrf2-ARE Pathway to Alter the Structure and Immune Response of Colon Epithelial Cells

Chemoproteomic Approaches for Unraveling Prokaryotic Biology

Human Airway Organoids and Multimodal Imaging-Based Toxicity Evaluation of 1-Nitropyrene

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