Total Lipopolysaccharide from the Human Gut Microbiome Silences Toll-Like Receptor Signaling

ABSTRACT Cohabitation of microbial communities with the host enables the formation of a symbiotic relationship that maintains homeostasis in the gut and beyond. One prevailing model suggests that this relationship relies on the capacity of host cells and tissues to remain tolerant to the strong immu...

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Autores principales:	Eva d’Hennezel, Sahar Abubucker, Leon O. Murphy, Thomas W. Cullen
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	microbiome lipopolysaccharide microbial communities symbiosis tolerance Toll-like receptors Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/31c2601de12a4e298c1a8fe332543565
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spelling	oai:doaj.org-article:31c2601de12a4e298c1a8fe3325435652021-12-02T18:15:43ZTotal Lipopolysaccharide from the Human Gut Microbiome Silences Toll-Like Receptor Signaling10.1128/mSystems.00046-172379-5077https://doaj.org/article/31c2601de12a4e298c1a8fe3325435652017-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00046-17https://doaj.org/toc/2379-5077ABSTRACT Cohabitation of microbial communities with the host enables the formation of a symbiotic relationship that maintains homeostasis in the gut and beyond. One prevailing model suggests that this relationship relies on the capacity of host cells and tissues to remain tolerant to the strong immune stimulation generated by the microbiota such as the activation of Toll-like receptor 4 (TLR4) pathways by lipopolysaccharide (LPS). Indeed, gut microbial LPS is thought to be one of the most potent activators of innate immune signaling and an important mediator of the microbiome’s influence on host physiology. In this study, we performed computational and experimental analyses of healthy human fecal samples to examine the TLR4 signaling capacity of the gut microbiota. These analyses revealed that an immunoinhibitory activity of LPS, conserved across the members of the order Bacteroidales and derived from an underacylated structural feature, silences TLR4 signaling for the entire consortium of organisms inhabiting the human gut. Comparative analysis of metagenomic data from the Human Microbiome Project and healthy-donor samples indicates that immune silencing via LPS is a microbe-intrinsic feature in all healthy adults. These findings challenge the current belief that robust TLR4 signaling is a feature of the microbiome and demonstrate that microbiome-derived LPS has the ability to facilitate host tolerance of gut microbes. These findings have broad implications for how we model host-microbe interactions and for our understanding of microbiome-linked disease. IMPORTANCE While the ability for humans to host a complex microbial ecosystem is an essential property of life, the mechanisms allowing for immune tolerance of such a large microbial load are not completely understood and are currently the focus of intense research. This study shows that an important proinflammatory pathway that is commonly triggered by pathogenic bacteria upon interaction with the host is, in fact, actively repressed by the bacteria of the gut microbiome, supporting the idea that beneficial microbes themselves contribute to the immune tolerance in support of homeostasis. These findings are important for two reasons. First, many currently assume that proinflammatory signaling by lipopolysaccharide is a fundamental feature of the gut flora. This assumption influences greatly how host-microbiome interactions are theoretically modeled but also how they are experimentally studied, by using robust TLR signaling conditions to simulate commensals. Second, elucidation of the mechanisms that support host-microbe tolerance is key to the development of therapeutics for both intestinal and systemic inflammatory disorders.Eva d’HennezelSahar AbubuckerLeon O. MurphyThomas W. CullenAmerican Society for Microbiologyarticlemicrobiomelipopolysaccharidemicrobial communitiessymbiosistoleranceToll-like receptorsMicrobiologyQR1-502ENmSystems, Vol 2, Iss 6 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	microbiome lipopolysaccharide microbial communities symbiosis tolerance Toll-like receptors Microbiology QR1-502
spellingShingle	microbiome lipopolysaccharide microbial communities symbiosis tolerance Toll-like receptors Microbiology QR1-502 Eva d’Hennezel Sahar Abubucker Leon O. Murphy Thomas W. Cullen Total Lipopolysaccharide from the Human Gut Microbiome Silences Toll-Like Receptor Signaling
description	ABSTRACT Cohabitation of microbial communities with the host enables the formation of a symbiotic relationship that maintains homeostasis in the gut and beyond. One prevailing model suggests that this relationship relies on the capacity of host cells and tissues to remain tolerant to the strong immune stimulation generated by the microbiota such as the activation of Toll-like receptor 4 (TLR4) pathways by lipopolysaccharide (LPS). Indeed, gut microbial LPS is thought to be one of the most potent activators of innate immune signaling and an important mediator of the microbiome’s influence on host physiology. In this study, we performed computational and experimental analyses of healthy human fecal samples to examine the TLR4 signaling capacity of the gut microbiota. These analyses revealed that an immunoinhibitory activity of LPS, conserved across the members of the order Bacteroidales and derived from an underacylated structural feature, silences TLR4 signaling for the entire consortium of organisms inhabiting the human gut. Comparative analysis of metagenomic data from the Human Microbiome Project and healthy-donor samples indicates that immune silencing via LPS is a microbe-intrinsic feature in all healthy adults. These findings challenge the current belief that robust TLR4 signaling is a feature of the microbiome and demonstrate that microbiome-derived LPS has the ability to facilitate host tolerance of gut microbes. These findings have broad implications for how we model host-microbe interactions and for our understanding of microbiome-linked disease. IMPORTANCE While the ability for humans to host a complex microbial ecosystem is an essential property of life, the mechanisms allowing for immune tolerance of such a large microbial load are not completely understood and are currently the focus of intense research. This study shows that an important proinflammatory pathway that is commonly triggered by pathogenic bacteria upon interaction with the host is, in fact, actively repressed by the bacteria of the gut microbiome, supporting the idea that beneficial microbes themselves contribute to the immune tolerance in support of homeostasis. These findings are important for two reasons. First, many currently assume that proinflammatory signaling by lipopolysaccharide is a fundamental feature of the gut flora. This assumption influences greatly how host-microbiome interactions are theoretically modeled but also how they are experimentally studied, by using robust TLR signaling conditions to simulate commensals. Second, elucidation of the mechanisms that support host-microbe tolerance is key to the development of therapeutics for both intestinal and systemic inflammatory disorders.
format	article
author	Eva d’Hennezel Sahar Abubucker Leon O. Murphy Thomas W. Cullen
author_facet	Eva d’Hennezel Sahar Abubucker Leon O. Murphy Thomas W. Cullen
author_sort	Eva d’Hennezel
title	Total Lipopolysaccharide from the Human Gut Microbiome Silences Toll-Like Receptor Signaling
title_short	Total Lipopolysaccharide from the Human Gut Microbiome Silences Toll-Like Receptor Signaling
title_full	Total Lipopolysaccharide from the Human Gut Microbiome Silences Toll-Like Receptor Signaling
title_fullStr	Total Lipopolysaccharide from the Human Gut Microbiome Silences Toll-Like Receptor Signaling
title_full_unstemmed	Total Lipopolysaccharide from the Human Gut Microbiome Silences Toll-Like Receptor Signaling
title_sort	total lipopolysaccharide from the human gut microbiome silences toll-like receptor signaling
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/31c2601de12a4e298c1a8fe332543565
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Total Lipopolysaccharide from the Human Gut Microbiome Silences Toll-Like Receptor Signaling

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