Dietary and Microbial Oxazoles Induce Intestinal Inflammation by Modulating Aryl Hydrocarbon Receptor Responses

Iyer, Shankar S.; Gensollen, Thomas; Gandhi, Amit; Oh, Sungwhan F.; Neves, Joana F.; Collin, Frederic; Lavin, Richard; Serra, Carme; Glickman, Jonathan N.; Silva, Punyanganie S. de; Sartor, R. Balfour; Besra, Gurdyal S.; Hauser, Russell; Maxwell, Anthony; Llebaría, Amadeu; Blumberg, Richard S.

doi:10.1016/j.cell.2018.04.037

Cited by 89 publications

(72 citation statements)

References 46 publications

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“…In addition, it has been reported that transgenic mice expressing the constitutive active form of the AhR in keratinocytes showed an increased expression of various cytokines, including IL-1β [32]. Iyer et al [33] reported that AhR activation in intestinal epithelial cells by oxazole compounds induced inflammation. In line with a proinflammatory role of the AhR, the induction of IL-1β in leukocytes derived from bronchoalveolar lavage fluid of P. aeruginosa-infected mice was reduced in AhRdeficient cells [28].…”

Section: Discussionmentioning

confidence: 99%

Staphylococcus epidermidis Activates Aryl Hydrocarbon Receptor Signaling in Human Keratinocytes: Implications for Cutaneous Defense

Rademacher¹,

Simanski²,

Hesse³

et al. 2018

J Innate Immun

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Bacterial challenge of keratinocytes with the abundant skin commensal Staphylococcus epidermidis induces distinct innate immune responses, but the underlying molecular mechanisms are still emerging. We report that the aryl hydrocarbon receptor (AhR) was activated in human primary keratinocytes infected with S. epidermidis, leading to induction of the AhR-responsive gene cytochrome P450 1A1 (CYP1A1). In addition, functional AhR was required for S. epidermidis-mediated induction of IL-1β expression in keratinocytes. AhR-dependent gene induction of IL-1β and CYP1A1 was mediated by factor(s) < 2 kDa secreted by S. epidermidis. Blockade of the AhR in a 3D organotypic skin equivalent infected with S. epidermidis attenuated the S. epidermidis-induced CYP1A1 and IL-1β expression. Moreover, S. epidermidis also induced expression of IL-1α and of the antimicrobial peptide human β-defensin-3 in an AhR-dependent manner in a 3D skin equivalent. An increased outgrowth of S. epidermidis on the surface of skin explants treated with a specific AhR inhibitor further indicate a pivotal role of the AhR in mediating an epidermal defense response. Taken together, our data expand the role of the AhR in innate immunity and support a previously unappreciated contribution for the AhR in cutaneous defense.

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Section: Discussionmentioning

confidence: 99%

Staphylococcus epidermidis Activates Aryl Hydrocarbon Receptor Signaling in Human Keratinocytes: Implications for Cutaneous Defense

Rademacher¹,

Simanski²,

Hesse³

et al. 2018

J Innate Immun

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“…Consequently, the deletion of CD1d in the intestinal epithelium increases oxazolone‐induced inflammation, while nonepithelial cells contribute to pathogenic NKT cell activation . Interestingly, oxazolone compounds can be found in microbial and industrial sources and can activate iNKT cells and trigger CD1d‐dependent intestinal inflammatory responses . In a different experimental setting, overexpression of CD1d in a transgenic mouse model for type II iNKT cells is sufficient to induce the spontaneous development of intestinal inflammation, suggesting that interaction of NKT cells with CD1d‐expressing cells can lead to the dysregulation of type II NKT cell responses and subsequently contribute to the development of IBD .…”

Section: Nkt Cells In the Intestinal Compartmentmentioning

confidence: 99%

NKT cells and the regulation of intestinal immunity: a two‐way street

2020

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The mammalian gastrointestinal compartment is colonised by millions of microorganisms that have a central influence on human health. Intestinal homeostasis requires a continuous dialogue between the commensal bacteria and intestinal immune cells. While interactions between host and commensal bacteria are normally beneficial, allowing training and functional tuning of immune cells, dysregulated immune system-microbiota crosstalk can favour the development of chronic inflammatory diseases, as it is the case for inflammatory bowel disease (IBD). Natural killer T (NKT) cells, which recognise CD1-restricted microbial and self-lipids, contribute to the regulation of mucosal immunity by controlling intestinal homeostasis and participating in the development of IBD. Here, we provide an overview of the recently identified pathways underlying the crosstalk between commensal bacteria and NKT cells and discuss the effect of these interactions in intestinal health and disease.

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“…Aryl hydrocarbon receptor activation promotes tolerogenic dendritic cells [76], Th17 and T regulatory cell differentiation [77] and impacts innate lymphoid cell (ILC) homeostasis in the gut by stimulating ILC3 cells to produce IL-22 and suppressing ILC2 function including expression of IL-33 receptor, IL-5, IL-13 and amphiregulin [78]. It also boosts gut epithelial barrier function, including response to IL-10 [79,80], though there is some conflicting evidence on this point [81]. Like IDO activity, aryl hydrocarbon receptor activation influences, and is influenced by, microbial composition [64].…”

Section: Tryptophanmentioning

confidence: 99%

Gut Microbial-Derived Metabolomics of Asthma

et al. 2020

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In this review, we discuss gut microbial-derived metabolites involved with the origins and pathophysiology of asthma, a chronic respiratory disease that is influenced by the microbiome. Although both gut and airway microbiomes may be important in asthma development, we focus here on the gut microbiome and metabolomic pathways involved in immune system ontogeny. Metabolite classes with existing evidence that microbial-derived products influence asthma risk include short chain fatty acids, polyunsaturated fatty acids and bile acids. While tryptophan metabolites and sphingolipids have known associations with asthma, additional research is needed to clarify the extent to which the microbiome contributes to the effects of these metabolites on asthma. These metabolite classes can influence immune function in one of two ways: (i) promoting growth or maturity of certain immune cell populations or (ii) influencing antigenic load by enhancing the number or species of specific bacteria. A more comprehensive understanding of how gut microbes and metabolites interact to modify asthma risk and morbidity will pave the way for targeted diagnostics and treatments. Introduction: Microbiome-Metabolome Associations in AsthmaAsthma and other allergic diseases have well known associations with early life environmental exposures that modify the gut microbiota, such as living on a farm, mode of delivery, breastfeeding status and having a dog in the home [1]. As mounting animal and human data point to a prominent role of the gut microbiome in asthma development [2], relevant metabolomic mechanisms behind this association are beginning to be elucidated [3]. Integration of metabolomic data with gut microbiome data has been particularly fruitful in understanding the gut-lung axis as it pertains to asthma. Here, we review a set of metabolites and metabolite groups that appear to link the gut microbiota with asthma development and pathophysiology and immune system ontology. Some of these classes, such as short chain fatty acids, are relatively well-studied and understood, while others, including the sphingolipids, include more numerous metabolites with less straightforward relationships to asthma and allergy. While we focus here on the metabolite classes most prominently discussed in today's literature, future unbiased studies of asthma metabolomics are likely to identify additional important pathways.

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Dietary and Microbial Oxazoles Induce Intestinal Inflammation by Modulating Aryl Hydrocarbon Receptor Responses

Cited by 89 publications

References 46 publications

<b><i>Staphylococcus epidermidis</i></b> Activates Aryl Hydrocarbon Receptor Signaling in Human Keratinocytes: Implications for Cutaneous Defense

<b><i>Staphylococcus epidermidis</i></b> Activates Aryl Hydrocarbon Receptor Signaling in Human Keratinocytes: Implications for Cutaneous Defense

NKT cells and the regulation of intestinal immunity: a two‐way street

Gut Microbial-Derived Metabolomics of Asthma

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