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Fusobacterium nucleatum drives a pro-inflammatory intestinal microenvironment through metabolite receptor-dependent modulation of IL-17 expression

The colorectal cancer (CRC)-associated microbiota creates a pro-tumorigenic intestinal milieu and shapes immune responses within the tumor microenvironment. However, how oncomicrobes – like Fusobacterium nucleatum, found in the oral cavity and associated with CRC tissues– affect these distinct aspec...

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Autores principales: Brennan, Caitlin A., Clay, Slater L., Lavoie, Sydney L., Bae, Sena, Lang, Jessica K., Fonseca-Pereira, Diogo, Rosinski, Kathryn G., Ou, Nora, Glickman, Jonathan N., Garrett, Wendy S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8604392/
https://www.ncbi.nlm.nih.gov/pubmed/34781821
http://dx.doi.org/10.1080/19490976.2021.1987780
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author Brennan, Caitlin A.
Clay, Slater L.
Lavoie, Sydney L.
Bae, Sena
Lang, Jessica K.
Fonseca-Pereira, Diogo
Rosinski, Kathryn G.
Ou, Nora
Glickman, Jonathan N.
Garrett, Wendy S.
author_facet Brennan, Caitlin A.
Clay, Slater L.
Lavoie, Sydney L.
Bae, Sena
Lang, Jessica K.
Fonseca-Pereira, Diogo
Rosinski, Kathryn G.
Ou, Nora
Glickman, Jonathan N.
Garrett, Wendy S.
author_sort Brennan, Caitlin A.
collection PubMed
description The colorectal cancer (CRC)-associated microbiota creates a pro-tumorigenic intestinal milieu and shapes immune responses within the tumor microenvironment. However, how oncomicrobes – like Fusobacterium nucleatum, found in the oral cavity and associated with CRC tissues– affect these distinct aspects of tumorigenesis is difficult to parse. Herein, we found that neonatal inoculation of Apc(Min/+) mice with F. nucleatum strain Fn7-1 circumvents technical barriers preventing its intestinal colonization, drives colonic Il17a expression prior to tumor formation, and potentiates intestinal tumorigenesis. Using gnotobiotic mice colonized with a minimal complexity microbiota (the altered Schaedler’s flora), we observed that intestinal Fn7-1 colonization increases colonic Th17 cell frequency and their IL-17A and IL-17F expression, along with a concurrent increase in colonic lamina propria Il23p19 expression. As Fn7-1 stably colonizes the intestinal tract in our models, we posited that microbial metabolites, specifically short-chain fatty acids (SCFA) that F. nucleatum abundantly produces in culture and, as we demonstrate, in the intestinal tract, might mediate part of its immunomodulatory effects in vivo. Supporting this hypothesis, we found that Fn7-1 did not alter RORγt(+) CD4(+)T cell frequency in the absence of the SCFA receptor FFAR2. Taken together, our work suggests that F. nucleatum influences intestinal immunity by shaping Th17 responses in an FFAR2-dependent manner, although further studies are necessary to clarify the precise and multifaceted roles of FFAR2. The potential to increase intestinal Th17 responses is shared by another oncomicrobe, enterotoxigenic Bacteroides fragilis, highlighting a conserved pathway that could potentially be targeted to slow oncomicrobe-mediated CRC.
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spelling pubmed-86043922021-11-20 Fusobacterium nucleatum drives a pro-inflammatory intestinal microenvironment through metabolite receptor-dependent modulation of IL-17 expression Brennan, Caitlin A. Clay, Slater L. Lavoie, Sydney L. Bae, Sena Lang, Jessica K. Fonseca-Pereira, Diogo Rosinski, Kathryn G. Ou, Nora Glickman, Jonathan N. Garrett, Wendy S. Gut Microbes Research Paper The colorectal cancer (CRC)-associated microbiota creates a pro-tumorigenic intestinal milieu and shapes immune responses within the tumor microenvironment. However, how oncomicrobes – like Fusobacterium nucleatum, found in the oral cavity and associated with CRC tissues– affect these distinct aspects of tumorigenesis is difficult to parse. Herein, we found that neonatal inoculation of Apc(Min/+) mice with F. nucleatum strain Fn7-1 circumvents technical barriers preventing its intestinal colonization, drives colonic Il17a expression prior to tumor formation, and potentiates intestinal tumorigenesis. Using gnotobiotic mice colonized with a minimal complexity microbiota (the altered Schaedler’s flora), we observed that intestinal Fn7-1 colonization increases colonic Th17 cell frequency and their IL-17A and IL-17F expression, along with a concurrent increase in colonic lamina propria Il23p19 expression. As Fn7-1 stably colonizes the intestinal tract in our models, we posited that microbial metabolites, specifically short-chain fatty acids (SCFA) that F. nucleatum abundantly produces in culture and, as we demonstrate, in the intestinal tract, might mediate part of its immunomodulatory effects in vivo. Supporting this hypothesis, we found that Fn7-1 did not alter RORγt(+) CD4(+)T cell frequency in the absence of the SCFA receptor FFAR2. Taken together, our work suggests that F. nucleatum influences intestinal immunity by shaping Th17 responses in an FFAR2-dependent manner, although further studies are necessary to clarify the precise and multifaceted roles of FFAR2. The potential to increase intestinal Th17 responses is shared by another oncomicrobe, enterotoxigenic Bacteroides fragilis, highlighting a conserved pathway that could potentially be targeted to slow oncomicrobe-mediated CRC. Taylor & Francis 2021-11-15 /pmc/articles/PMC8604392/ /pubmed/34781821 http://dx.doi.org/10.1080/19490976.2021.1987780 Text en © 2021 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Paper
Brennan, Caitlin A.
Clay, Slater L.
Lavoie, Sydney L.
Bae, Sena
Lang, Jessica K.
Fonseca-Pereira, Diogo
Rosinski, Kathryn G.
Ou, Nora
Glickman, Jonathan N.
Garrett, Wendy S.
Fusobacterium nucleatum drives a pro-inflammatory intestinal microenvironment through metabolite receptor-dependent modulation of IL-17 expression
title Fusobacterium nucleatum drives a pro-inflammatory intestinal microenvironment through metabolite receptor-dependent modulation of IL-17 expression
title_full Fusobacterium nucleatum drives a pro-inflammatory intestinal microenvironment through metabolite receptor-dependent modulation of IL-17 expression
title_fullStr Fusobacterium nucleatum drives a pro-inflammatory intestinal microenvironment through metabolite receptor-dependent modulation of IL-17 expression
title_full_unstemmed Fusobacterium nucleatum drives a pro-inflammatory intestinal microenvironment through metabolite receptor-dependent modulation of IL-17 expression
title_short Fusobacterium nucleatum drives a pro-inflammatory intestinal microenvironment through metabolite receptor-dependent modulation of IL-17 expression
title_sort fusobacterium nucleatum drives a pro-inflammatory intestinal microenvironment through metabolite receptor-dependent modulation of il-17 expression
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8604392/
https://www.ncbi.nlm.nih.gov/pubmed/34781821
http://dx.doi.org/10.1080/19490976.2021.1987780
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