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Indole has a barrier-protective effect independent of its induction of IL-22 (A) IL-22 production by ileum explants from neonatal Abx-treated C57BL/6 mice harvested on day 7 post-weaning and stimulated in vitro with IL-23 (10 ng/mL) or indole as indicated for 24 h. Data are pooled from 4 independent experiments (n = 13, 11, 8, 10, 8, 8, and 4). (B) Transcript levels of Il22 in ileum LP tissue from neonatal Abx-treated C57BL/6 mice harvested on day 7 post-weaning where half of each ileum was left untreated and the other half was stimulated with 10 ng/mL indole for 1 h. Data are pooled from 2 independent experiments (n = 10). (C) Transcript levels of Il22 in ileum LP tissue from neonatal Abx-treated Rorgt Cre Ahr fl/fl mice and their Ahr fl/fl littermates harvested on day 7 post-weaning where half of each ileum was left untreated and the other half was stimulated with 10 ng/mL indole in vitro for 1 h.
Source publication
The increasing prevalence of food allergies has been linked to reduced commensal microbial diversity. In this article, we describe two features of allergy-protective Clostridia that contribute to their beneficial effects. Some Clostridial taxa bear flagella (a ligand for TLR5) and produce indole (a ligand for the aryl hydrocarbon receptor [AhR]). L...
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... Since we had isolated and sequenced the genomes of Lach_1 and Lach_2, two representative flagella-producing taxa in the Clostridia consortium, we examined the amino acid sequences of their predicted flagellin proteins to determine if they differ substantially from Salmonella FliC. After examination of the predicted protein structure ( Figure S4A) and alignment of their amino acid sequences ( Figure S4B), the Clostridia flagellins were more like one another (particularly at the N and C termini) than Salmonella FliC. This included differences in several amino acids known to be key for TLR5 binding in the D1 domain (denoted by black asterisks in Figure S4B). ...
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... Since we had isolated and sequenced the genomes of Lach_1 and Lach_2, two representative flagella-producing taxa in the Clostridia consortium, we examined the amino acid sequences of their predicted flagellin proteins to determine if they differ substantially from Salmonella FliC. After examination of the predicted protein structure ( Figure S4A) and alignment of their amino acid sequences ( Figure S4B), the Clostridia flagellins were more like one another (particularly at the N and C termini) than Salmonella FliC. This included differences in several amino acids known to be key for TLR5 binding in the D1 domain (denoted by black asterisks in Figure S4B). ...
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... examination of the predicted protein structure ( Figure S4A) and alignment of their amino acid sequences ( Figure S4B), the Clostridia flagellins were more like one another (particularly at the N and C termini) than Salmonella FliC. This included differences in several amino acids known to be key for TLR5 binding in the D1 domain (denoted by black asterisks in Figure S4B). 35 The Salmonella FliC was also accompanied by a very distinct flagellar operon, while those from Lach_1 and Lach_2 were more similar ( Figure S4C). ...
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... included differences in several amino acids known to be key for TLR5 binding in the D1 domain (denoted by black asterisks in Figure S4B). 35 The Salmonella FliC was also accompanied by a very distinct flagellar operon, while those from Lach_1 and Lach_2 were more similar ( Figure S4C). These experiments show that flagella enriched from the Clostridia consortium induce IL-22 in a TLR5-dependent manner. ...
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... therefore tested whether indole induced IL-22 production in ileal explants from Abx-treated mice. IL-22 production was significantly induced in response to 10 ng/mL indole but to a much lower extent than stimulation with IL-23 ( Figure 4A). We also examined indole's ability to induce IL-22 at the transcript level in LP tissues, where half of each ileum was left untreated while the other half was stimulated with indole ( Figure 4B). ...
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... production was significantly induced in response to 10 ng/mL indole but to a much lower extent than stimulation with IL-23 ( Figure 4A). We also examined indole's ability to induce IL-22 at the transcript level in LP tissues, where half of each ileum was left untreated while the other half was stimulated with indole ( Figure 4B). Induction of IL-22 was dependent on AhR signaling in RORγt + cells ( Figure 4C), which include ILC3s and T cells. ...
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... also examined indole's ability to induce IL-22 at the transcript level in LP tissues, where half of each ileum was left untreated while the other half was stimulated with indole ( Figure 4B). Induction of IL-22 was dependent on AhR signaling in RORγt + cells ( Figure 4C), which include ILC3s and T cells. 37,38 Neonatal Abx-treated mice that received daily intragastric (i.g.) gavage of indole also had reduced concentrations of FITCdextran measurable in their serum compared with their water-gavaged littermates ( Figure 4D). ...
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... of IL-22 was dependent on AhR signaling in RORγt + cells ( Figure 4C), which include ILC3s and T cells. 37,38 Neonatal Abx-treated mice that received daily intragastric (i.g.) gavage of indole also had reduced concentrations of FITCdextran measurable in their serum compared with their water-gavaged littermates ( Figure 4D). However, daily treatment with indole did not result in elevated expression of the IL-22 target gene Reg3b ( Figure 4E). ...
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... Neonatal Abx-treated mice that received daily intragastric (i.g.) gavage of indole also had reduced concentrations of FITCdextran measurable in their serum compared with their water-gavaged littermates ( Figure 4D). However, daily treatment with indole did not result in elevated expression of the IL-22 target gene Reg3b ( Figure 4E). Co-administration of a neutralizing antibody to IL-22 reduced Reg3b expression but did not impair the indole-induced reduction in intestinal barrier permeability ( Figure 4F). ...
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... daily treatment with indole did not result in elevated expression of the IL-22 target gene Reg3b ( Figure 4E). Co-administration of a neutralizing antibody to IL-22 reduced Reg3b expression but did not impair the indole-induced reduction in intestinal barrier permeability ( Figure 4F). These results suggest that while indole acts as an AhR ligand to induce IL-22 production, it may also have an IL-22-in-dependent barrier-protective effect. ...
Citations
... Similarly, activation of AhR signaling by indoles improved barrier function and prevented adverse reactions to food in mice. 118 Microbial factors can also affect intestinal barrier function and have been proposed as cofactors in CeD pathogenesis. Using an ex vivo approach, early studies found that E coli and Shigella led to tight junction alterations and increased translocation of gliadin peptides to the lamina propria. ...
Increasing evidence suggests that alterations in the gut microbiome (GM) play a pivotal role in the pathogenesis of pediatric food allergy (FA). This scoping review analyzes the current evidence on GM features associated with pediatric FAs and highlights the importance of the GM as a potential target of intervention for preventing and treating this common condition in the pediatric age. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, we searched PubMed and Embase using the keywords (gut microbiome OR dysbiosis OR gut microbiota OR microbiome signatures) AND (food allergy OR IgE-mediated food allergy OR food protein-induced allergic proctocolitis OR food protein-induced enterocolitis OR non-IgE food allergy OR cow milk allergy OR hen egg allergy OR peanut allergy OR fish allergy OR shellfish allergy OR tree nut allergy OR soy allergy OR wheat allergy OR rice allergy OR food sensitization). We included 34 studies reporting alterations in the GM in children affected by FA compared with healthy controls. The GM in pediatric FAs is characterized by a higher abundance of harmful microorganisms (e.g., Enterobacteriaceae, Clostridium sensu stricto , Ruminococcus gnavus , and Blautia spp.) and lower abundance of beneficial bacteria (e.g., Bifidobacteriaceae, Lactobacillaceae , some Bacteroides species). Moreover, we provide an overview of the mechanisms of action elicited by these bacterial species in regulating immune tolerance and of the main environmental factors that can modulate the composition and function of the GM in early life. Altogether, these data improve our knowledge of the pathogenesis of FA and can open the way to innovative diagnostic, preventive, and therapeutic strategies for managing these conditions.
The increasing prevalence of immune‐mediated non‐communicable chronic diseases, such as food allergies, has prompted a deeper investigation into the role of the gut microbiome in modulating immune responses. Here, we explore the complex interactions between commensal microbes and the host immune system, highlighting the critical role of gut bacteria in maintaining immune homeostasis. We examine how modern lifestyle practices and environmental factors have disrupted co‐evolved host–microbe interactions and discuss how changes in microbiome composition impact epithelial barrier function, responses to food allergens, and susceptibility to allergic diseases. Finally, we examine the potential of bioengineered microbiome‐based therapies, and live biotherapeutic products, for reestablishing immune homeostasis to prevent or treat food allergies.