<italic toggle="yes">Fusobacterium nucleatum</italic> Secretes Outer Membrane Vesicles and Promotes Intestinal Inflammation

ABSTRACT Multiple studies have implicated microbes in the development of inflammation, but the mechanisms remain unknown. Bacteria in the genus Fusobacterium have been identified in the intestinal mucosa of patients with digestive diseases; thus, we hypothesized that Fusobacterium nucleatum promotes...

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Autores principales:	Melinda A. Engevik, Heather A. Danhof, Wenly Ruan, Amy C. Engevik, Alexandra L. Chang-Graham, Kristen A. Engevik, Zhongcheng Shi, Yanling Zhao, Colleen K. Brand, Evan S. Krystofiak, Susan Venable, Xinli Liu, Kendal D. Hirschi, Joseph M. Hyser, Jennifer K. Spinler, Robert A. Britton, James Versalovic
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	Fusobacterium nucleatum enteroids organoids inflammation outer membrane vesicles TLR4 Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ebd421ea1ed24b248d975fb71e9bd169
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spelling	oai:doaj.org-article:ebd421ea1ed24b248d975fb71e9bd1692021-11-10T18:37:48Z<italic toggle="yes">Fusobacterium nucleatum</italic> Secretes Outer Membrane Vesicles and Promotes Intestinal Inflammation10.1128/mBio.02706-202150-7511https://doaj.org/article/ebd421ea1ed24b248d975fb71e9bd1692021-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02706-20https://doaj.org/toc/2150-7511ABSTRACT Multiple studies have implicated microbes in the development of inflammation, but the mechanisms remain unknown. Bacteria in the genus Fusobacterium have been identified in the intestinal mucosa of patients with digestive diseases; thus, we hypothesized that Fusobacterium nucleatum promotes intestinal inflammation. The addition of >50 kDa F. nucleatum conditioned media, which contain outer membrane vesicles (OMVs), to colonic epithelial cells stimulated secretion of the proinflammatory cytokines interleukin-8 (IL-8) and tumor necrosis factor (TNF). In addition, purified F. nucleatum OMVs, but not compounds <50 kDa, stimulated IL-8 and TNF production; which was decreased by pharmacological inhibition of Toll-like receptor 4 (TLR4). These effects were linked to downstream effectors p-ERK, p-CREB, and NF-κB. F. nucleatum >50-kDa compounds also stimulated TNF secretion, p-ERK, p-CREB, and NF-κB activation in human colonoid monolayers. In mice harboring a human microbiota, pretreatment with antibiotics and a single oral gavage of F. nucleatum resulted in inflammation. Compared to mice receiving vehicle control, mice treated with F. nucleatum showed disruption of the colonic architecture, with increased immune cell infiltration and depleted mucus layers. Analysis of mucosal gene expression revealed increased levels of proinflammatory cytokines (KC, TNF, IL-6, IFN-γ, and MCP-1) at day 3 and day 5 in F. nucleatum-treated mice compared to controls. These proinflammatory effects were absent in mice who received F. nucleatum without pretreatment with antibiotics, suggesting that an intact microbiome is protective against F. nucleatum-mediated immune responses. These data provide evidence that F. nucleatum promotes proinflammatory signaling cascades in the context of a depleted intestinal microbiome. IMPORTANCE Several studies have identified an increased abundance of Fusobacterium in the intestinal tracts of patients with colon cancer, liver cirrhosis, primary sclerosing cholangitis, gastroesophageal reflux disease, HIV infection, and alcoholism. However, the direct mechanism(s) of action of Fusobacterium on pathophysiological within the gastrointestinal tract is unclear. These studies have identified that F. nucleatum subsp. polymorphum releases outer membrane vesicles which activate TLR4 and NF-κB to stimulate proinflammatory signals in vitro. Using mice harboring a human microbiome, we demonstrate that F. nucleatum can promote inflammation, an effect which required antibiotic-mediated alterations in the gut microbiome. Collectively, these results suggest a mechanism by which F. nucleatum may contribute to intestinal inflammation.Melinda A. EngevikHeather A. DanhofWenly RuanAmy C. EngevikAlexandra L. Chang-GrahamKristen A. EngevikZhongcheng ShiYanling ZhaoColleen K. BrandEvan S. KrystofiakSusan VenableXinli LiuKendal D. HirschiJoseph M. HyserJennifer K. SpinlerRobert A. BrittonJames VersalovicAmerican Society for MicrobiologyarticleFusobacterium nucleatumenteroidsorganoidsinflammationouter membrane vesiclesTLR4MicrobiologyQR1-502ENmBio, Vol 12, Iss 2 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Fusobacterium nucleatum enteroids organoids inflammation outer membrane vesicles TLR4 Microbiology QR1-502
spellingShingle	Fusobacterium nucleatum enteroids organoids inflammation outer membrane vesicles TLR4 Microbiology QR1-502 Melinda A. Engevik Heather A. Danhof Wenly Ruan Amy C. Engevik Alexandra L. Chang-Graham Kristen A. Engevik Zhongcheng Shi Yanling Zhao Colleen K. Brand Evan S. Krystofiak Susan Venable Xinli Liu Kendal D. Hirschi Joseph M. Hyser Jennifer K. Spinler Robert A. Britton James Versalovic <italic toggle="yes">Fusobacterium nucleatum</italic> Secretes Outer Membrane Vesicles and Promotes Intestinal Inflammation
description	ABSTRACT Multiple studies have implicated microbes in the development of inflammation, but the mechanisms remain unknown. Bacteria in the genus Fusobacterium have been identified in the intestinal mucosa of patients with digestive diseases; thus, we hypothesized that Fusobacterium nucleatum promotes intestinal inflammation. The addition of >50 kDa F. nucleatum conditioned media, which contain outer membrane vesicles (OMVs), to colonic epithelial cells stimulated secretion of the proinflammatory cytokines interleukin-8 (IL-8) and tumor necrosis factor (TNF). In addition, purified F. nucleatum OMVs, but not compounds <50 kDa, stimulated IL-8 and TNF production; which was decreased by pharmacological inhibition of Toll-like receptor 4 (TLR4). These effects were linked to downstream effectors p-ERK, p-CREB, and NF-κB. F. nucleatum >50-kDa compounds also stimulated TNF secretion, p-ERK, p-CREB, and NF-κB activation in human colonoid monolayers. In mice harboring a human microbiota, pretreatment with antibiotics and a single oral gavage of F. nucleatum resulted in inflammation. Compared to mice receiving vehicle control, mice treated with F. nucleatum showed disruption of the colonic architecture, with increased immune cell infiltration and depleted mucus layers. Analysis of mucosal gene expression revealed increased levels of proinflammatory cytokines (KC, TNF, IL-6, IFN-γ, and MCP-1) at day 3 and day 5 in F. nucleatum-treated mice compared to controls. These proinflammatory effects were absent in mice who received F. nucleatum without pretreatment with antibiotics, suggesting that an intact microbiome is protective against F. nucleatum-mediated immune responses. These data provide evidence that F. nucleatum promotes proinflammatory signaling cascades in the context of a depleted intestinal microbiome. IMPORTANCE Several studies have identified an increased abundance of Fusobacterium in the intestinal tracts of patients with colon cancer, liver cirrhosis, primary sclerosing cholangitis, gastroesophageal reflux disease, HIV infection, and alcoholism. However, the direct mechanism(s) of action of Fusobacterium on pathophysiological within the gastrointestinal tract is unclear. These studies have identified that F. nucleatum subsp. polymorphum releases outer membrane vesicles which activate TLR4 and NF-κB to stimulate proinflammatory signals in vitro. Using mice harboring a human microbiome, we demonstrate that F. nucleatum can promote inflammation, an effect which required antibiotic-mediated alterations in the gut microbiome. Collectively, these results suggest a mechanism by which F. nucleatum may contribute to intestinal inflammation.
format	article
author	Melinda A. Engevik Heather A. Danhof Wenly Ruan Amy C. Engevik Alexandra L. Chang-Graham Kristen A. Engevik Zhongcheng Shi Yanling Zhao Colleen K. Brand Evan S. Krystofiak Susan Venable Xinli Liu Kendal D. Hirschi Joseph M. Hyser Jennifer K. Spinler Robert A. Britton James Versalovic
author_facet	Melinda A. Engevik Heather A. Danhof Wenly Ruan Amy C. Engevik Alexandra L. Chang-Graham Kristen A. Engevik Zhongcheng Shi Yanling Zhao Colleen K. Brand Evan S. Krystofiak Susan Venable Xinli Liu Kendal D. Hirschi Joseph M. Hyser Jennifer K. Spinler Robert A. Britton James Versalovic
author_sort	Melinda A. Engevik
title	<italic toggle="yes">Fusobacterium nucleatum</italic> Secretes Outer Membrane Vesicles and Promotes Intestinal Inflammation
title_short	<italic toggle="yes">Fusobacterium nucleatum</italic> Secretes Outer Membrane Vesicles and Promotes Intestinal Inflammation
title_full	<italic toggle="yes">Fusobacterium nucleatum</italic> Secretes Outer Membrane Vesicles and Promotes Intestinal Inflammation
title_fullStr	<italic toggle="yes">Fusobacterium nucleatum</italic> Secretes Outer Membrane Vesicles and Promotes Intestinal Inflammation
title_full_unstemmed	<italic toggle="yes">Fusobacterium nucleatum</italic> Secretes Outer Membrane Vesicles and Promotes Intestinal Inflammation
title_sort	<italic toggle="yes">fusobacterium nucleatum</italic> secretes outer membrane vesicles and promotes intestinal inflammation
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/ebd421ea1ed24b248d975fb71e9bd169
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<italic toggle="yes">Fusobacterium nucleatum</italic> Secretes Outer Membrane Vesicles and Promotes Intestinal Inflammation

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