Cargando…

A40 GUT MICROBIOTA PROMOTES NUTRIENT AVAILABLITY AND PATHOGENESIS OF AN ATTACHING/ EFFACING BACTERIAL PATHOGEN

BACKGROUND: Our gut microbiota plays an important role in protecting the gastrointestinal (GI) tract from invading enteric pathogens. Much of this colonization resistance is mediated by limiting nutrient availability, however, enteric pathogens have evolved strategies to subvert this competition, ut...

Descripción completa

Detalles Bibliográficos
Autores principales: Liang, Q, Allaire, J, Celiberto, L, Yu, H, Vallance, B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9991097/
http://dx.doi.org/10.1093/jcag/gwac036.040
_version_ 1784902071042965504
author Liang, Q
Allaire, J
Celiberto, L
Yu, H
Vallance, B
author_facet Liang, Q
Allaire, J
Celiberto, L
Yu, H
Vallance, B
author_sort Liang, Q
collection PubMed
description BACKGROUND: Our gut microbiota plays an important role in protecting the gastrointestinal (GI) tract from invading enteric pathogens. Much of this colonization resistance is mediated by limiting nutrient availability, however, enteric pathogens have evolved strategies to subvert this competition, utilizing commensal metabolites to facilitate their infection. Access to nutrients is not only crucial for a pathogen’s metabolic fitness, but can also drive the expression of virulence factors, a process high in energy demands. In addition, enteric pathogens, such as the attaching and effacing (A/E) bacterium Citrobacter rodentium, must cross the colonic mucus layer that normally prevents their direct access to the underlying epithelium. Intestinal mucus is comprised of highly glycosylated mucins, with the sugar sialic acid frequently occupying the terminal position of their O-glycan side chains. We hypothesize that C. rodentium utilizes commensal-liberated mucin sugars, such as sialic acid, as nutrients and signals to promote its virulence. PURPOSE: This study investigates the mechanisms by which A/E pathogens reach the colonic mucosal surface, and the role played by commensal microbes in facilitating the infection. METHOD: Expression of virulence factors secreted by C. rodentium in the presence or absence of sialic acid was analyzed by SDS-PAGE and mass spectrometry. Next, we infected specific-pathogen free (SPF), germfree (GF), and previously GF C57Bl/6 mice mono-colonized with Bacteroides thetaotaomicron, a mucus-degrading commensal, to examine their susceptibility to C. rodentium and to measure the levels of free sialic acid in their feces. RESULT(S): Sensing of sialic acid by C. rodentium, was found to induce the secretion of several key virulence proteins, enhancing the pathogen’s migration across the colonic mucus layer and adhesion to the underlying epithelium. Access to sialic acid within the gut environment was enhanced in the presence of microbiota, as the levels of free sialic acid were low in GF mice. Interestingly, despite GF mice carrying very high C. rodentium burdens, passage across the mucus layer and infection of their colonic epithelium was impaired as compared to SPF mice. Notably, B. thetaotaomicron was found to degrade whole mucus in vitro, facilitating its consumption by C. rodentium for growth, while B. thetaotaomicron mono-colonized GF mice showed increased susceptibility to colonic infection by C. rodentium. CONCLUSION(S): We demonstrate that although commensal microbes promote colonization resistance, as an A/E pathogen infection establishes, specific commensal bacteria accelerate infection in the GI tract by releasing an important nutrient, ie. sialic acid, from mucus. Access to sialic acid promotes C. rodentium virulence by inducing the key virulence factors that facilitate its translocation across the mucus layer as well as adhesion to the epithelium, thereby expediting disease progression. PLEASE ACKNOWLEDGE ALL FUNDING AGENCIES BY CHECKING THE APPLICABLE BOXES BELOW: CCC, CIHR, Other PLEASE INDICATE YOUR SOURCE OF FUNDING; CH.I.L.D. Foundation DISCLOSURE OF INTEREST: None Declared
format Online
Article
Text
id pubmed-9991097
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-99910972023-03-08 A40 GUT MICROBIOTA PROMOTES NUTRIENT AVAILABLITY AND PATHOGENESIS OF AN ATTACHING/ EFFACING BACTERIAL PATHOGEN Liang, Q Allaire, J Celiberto, L Yu, H Vallance, B J Can Assoc Gastroenterol Poster of Distinction BACKGROUND: Our gut microbiota plays an important role in protecting the gastrointestinal (GI) tract from invading enteric pathogens. Much of this colonization resistance is mediated by limiting nutrient availability, however, enteric pathogens have evolved strategies to subvert this competition, utilizing commensal metabolites to facilitate their infection. Access to nutrients is not only crucial for a pathogen’s metabolic fitness, but can also drive the expression of virulence factors, a process high in energy demands. In addition, enteric pathogens, such as the attaching and effacing (A/E) bacterium Citrobacter rodentium, must cross the colonic mucus layer that normally prevents their direct access to the underlying epithelium. Intestinal mucus is comprised of highly glycosylated mucins, with the sugar sialic acid frequently occupying the terminal position of their O-glycan side chains. We hypothesize that C. rodentium utilizes commensal-liberated mucin sugars, such as sialic acid, as nutrients and signals to promote its virulence. PURPOSE: This study investigates the mechanisms by which A/E pathogens reach the colonic mucosal surface, and the role played by commensal microbes in facilitating the infection. METHOD: Expression of virulence factors secreted by C. rodentium in the presence or absence of sialic acid was analyzed by SDS-PAGE and mass spectrometry. Next, we infected specific-pathogen free (SPF), germfree (GF), and previously GF C57Bl/6 mice mono-colonized with Bacteroides thetaotaomicron, a mucus-degrading commensal, to examine their susceptibility to C. rodentium and to measure the levels of free sialic acid in their feces. RESULT(S): Sensing of sialic acid by C. rodentium, was found to induce the secretion of several key virulence proteins, enhancing the pathogen’s migration across the colonic mucus layer and adhesion to the underlying epithelium. Access to sialic acid within the gut environment was enhanced in the presence of microbiota, as the levels of free sialic acid were low in GF mice. Interestingly, despite GF mice carrying very high C. rodentium burdens, passage across the mucus layer and infection of their colonic epithelium was impaired as compared to SPF mice. Notably, B. thetaotaomicron was found to degrade whole mucus in vitro, facilitating its consumption by C. rodentium for growth, while B. thetaotaomicron mono-colonized GF mice showed increased susceptibility to colonic infection by C. rodentium. CONCLUSION(S): We demonstrate that although commensal microbes promote colonization resistance, as an A/E pathogen infection establishes, specific commensal bacteria accelerate infection in the GI tract by releasing an important nutrient, ie. sialic acid, from mucus. Access to sialic acid promotes C. rodentium virulence by inducing the key virulence factors that facilitate its translocation across the mucus layer as well as adhesion to the epithelium, thereby expediting disease progression. PLEASE ACKNOWLEDGE ALL FUNDING AGENCIES BY CHECKING THE APPLICABLE BOXES BELOW: CCC, CIHR, Other PLEASE INDICATE YOUR SOURCE OF FUNDING; CH.I.L.D. Foundation DISCLOSURE OF INTEREST: None Declared Oxford University Press 2023-03-07 /pmc/articles/PMC9991097/ http://dx.doi.org/10.1093/jcag/gwac036.040 Text en ڣ The Author(s) 2023. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Poster of Distinction
Liang, Q
Allaire, J
Celiberto, L
Yu, H
Vallance, B
A40 GUT MICROBIOTA PROMOTES NUTRIENT AVAILABLITY AND PATHOGENESIS OF AN ATTACHING/ EFFACING BACTERIAL PATHOGEN
title A40 GUT MICROBIOTA PROMOTES NUTRIENT AVAILABLITY AND PATHOGENESIS OF AN ATTACHING/ EFFACING BACTERIAL PATHOGEN
title_full A40 GUT MICROBIOTA PROMOTES NUTRIENT AVAILABLITY AND PATHOGENESIS OF AN ATTACHING/ EFFACING BACTERIAL PATHOGEN
title_fullStr A40 GUT MICROBIOTA PROMOTES NUTRIENT AVAILABLITY AND PATHOGENESIS OF AN ATTACHING/ EFFACING BACTERIAL PATHOGEN
title_full_unstemmed A40 GUT MICROBIOTA PROMOTES NUTRIENT AVAILABLITY AND PATHOGENESIS OF AN ATTACHING/ EFFACING BACTERIAL PATHOGEN
title_short A40 GUT MICROBIOTA PROMOTES NUTRIENT AVAILABLITY AND PATHOGENESIS OF AN ATTACHING/ EFFACING BACTERIAL PATHOGEN
title_sort a40 gut microbiota promotes nutrient availablity and pathogenesis of an attaching/ effacing bacterial pathogen
topic Poster of Distinction
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9991097/
http://dx.doi.org/10.1093/jcag/gwac036.040
work_keys_str_mv AT liangq a40gutmicrobiotapromotesnutrientavailablityandpathogenesisofanattachingeffacingbacterialpathogen
AT allairej a40gutmicrobiotapromotesnutrientavailablityandpathogenesisofanattachingeffacingbacterialpathogen
AT celibertol a40gutmicrobiotapromotesnutrientavailablityandpathogenesisofanattachingeffacingbacterialpathogen
AT yuh a40gutmicrobiotapromotesnutrientavailablityandpathogenesisofanattachingeffacingbacterialpathogen
AT vallanceb a40gutmicrobiotapromotesnutrientavailablityandpathogenesisofanattachingeffacingbacterialpathogen