<named-content content-type="genus-species">Bifidobacterium dentium</named-content> Fortifies the Intestinal Mucus Layer via Autophagy and Calcium Signaling Pathways

ABSTRACT Much remains unknown about how the intestinal microbiome interfaces with the protective intestinal mucus layer. Bifidobacterium species colonize the intestinal mucus layer and can modulate mucus production by goblet cells. However, select Bifidobacterium strains can also degrade protective...

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Autores principales:	Melinda A. Engevik, Berkley Luk, Alexandra L. Chang-Graham, Anne Hall, Beatrice Herrmann, Wenly Ruan, Bradley T. Endres, Zhongcheng Shi, Kevin W. Garey, Joseph M. Hyser, James Versalovic
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	acetate bifidobacteria epithelium GABA glycans goblet cells Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9df25faecc214510a661581000847ab5
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spelling	oai:doaj.org-article:9df25faecc214510a661581000847ab52021-11-15T15:55:24Z<named-content content-type="genus-species">Bifidobacterium dentium</named-content> Fortifies the Intestinal Mucus Layer via Autophagy and Calcium Signaling Pathways10.1128/mBio.01087-192150-7511https://doaj.org/article/9df25faecc214510a661581000847ab52019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01087-19https://doaj.org/toc/2150-7511ABSTRACT Much remains unknown about how the intestinal microbiome interfaces with the protective intestinal mucus layer. Bifidobacterium species colonize the intestinal mucus layer and can modulate mucus production by goblet cells. However, select Bifidobacterium strains can also degrade protective glycans on mucin proteins. We hypothesized that the human-derived species Bifidobacterium dentium would increase intestinal mucus synthesis and expulsion, without extensive degradation of mucin glycans. In silico data revealed that B. dentium lacked the enzymes necessary to extensively degrade mucin glycans. This finding was confirmed by demonstrating that B. dentium could not use naive mucin glycans as primary carbon sources in vitro. To examine B. dentium mucus modulation in vivo, Swiss Webster germfree mice were monoassociated with live or heat-killed B. dentium. Live B. dentium-monoassociated mice exhibited increased colonic expression of goblet cell markers Krüppel-like factor 4 (Klf4), Trefoil factor 3 (Tff3), Relm-β, Muc2, and several glycosyltransferases compared to both heat-killed B. dentium and germfree counterparts. Likewise, live B. dentium-monoassociated colon had increased acidic mucin-filled goblet cells, as denoted by Periodic Acid-Schiff-Alcian Blue (PAS-AB) staining and MUC2 immunostaining. In vitro, B. dentium-secreted products, including acetate, were able to increase MUC2 levels in T84 cells. We also identified that B. dentium-secreted products, such as γ-aminobutyric acid (GABA), stimulated autophagy-mediated calcium signaling and MUC2 release. This work illustrates that B. dentium is capable of enhancing the intestinal mucus layer and goblet cell function via upregulation of gene expression and autophagy signaling pathways, with a net increase in mucin production. IMPORTANCE Microbe-host interactions in the intestine occur along the mucus-covered epithelium. In the gastrointestinal tract, mucus is composed of glycan-covered proteins, or mucins, which are secreted by goblet cells to form a protective gel-like structure above the epithelium. Low levels of mucin or alterations in mucin glycans are associated with inflammation and colitis in mice and humans. Although current literature links microbes to the modulation of goblet cells and mucins, the molecular pathways involved are not yet fully understood. Using a combination of gnotobiotic mice and mucus-secreting cell lines, we have identified a human-derived microbe, Bifidobacterium dentium, which adheres to intestinal mucus and secretes metabolites that upregulate the major mucin MUC2 and modulate goblet cell function. Unlike other Bifidobacterium species, B. dentium does not extensively degrade mucin glycans and cannot grow on mucin alone. This work points to the potential of using B. dentium and similar mucin-friendly microbes as therapeutic agents for intestinal disorders with disruptions in the mucus barrier.Melinda A. EngevikBerkley LukAlexandra L. Chang-GrahamAnne HallBeatrice HerrmannWenly RuanBradley T. EndresZhongcheng ShiKevin W. GareyJoseph M. HyserJames VersalovicAmerican Society for MicrobiologyarticleacetatebifidobacteriaepitheliumGABAglycansgoblet cellsMicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	acetate bifidobacteria epithelium GABA glycans goblet cells Microbiology QR1-502
spellingShingle	acetate bifidobacteria epithelium GABA glycans goblet cells Microbiology QR1-502 Melinda A. Engevik Berkley Luk Alexandra L. Chang-Graham Anne Hall Beatrice Herrmann Wenly Ruan Bradley T. Endres Zhongcheng Shi Kevin W. Garey Joseph M. Hyser James Versalovic <named-content content-type="genus-species">Bifidobacterium dentium</named-content> Fortifies the Intestinal Mucus Layer via Autophagy and Calcium Signaling Pathways
description	ABSTRACT Much remains unknown about how the intestinal microbiome interfaces with the protective intestinal mucus layer. Bifidobacterium species colonize the intestinal mucus layer and can modulate mucus production by goblet cells. However, select Bifidobacterium strains can also degrade protective glycans on mucin proteins. We hypothesized that the human-derived species Bifidobacterium dentium would increase intestinal mucus synthesis and expulsion, without extensive degradation of mucin glycans. In silico data revealed that B. dentium lacked the enzymes necessary to extensively degrade mucin glycans. This finding was confirmed by demonstrating that B. dentium could not use naive mucin glycans as primary carbon sources in vitro. To examine B. dentium mucus modulation in vivo, Swiss Webster germfree mice were monoassociated with live or heat-killed B. dentium. Live B. dentium-monoassociated mice exhibited increased colonic expression of goblet cell markers Krüppel-like factor 4 (Klf4), Trefoil factor 3 (Tff3), Relm-β, Muc2, and several glycosyltransferases compared to both heat-killed B. dentium and germfree counterparts. Likewise, live B. dentium-monoassociated colon had increased acidic mucin-filled goblet cells, as denoted by Periodic Acid-Schiff-Alcian Blue (PAS-AB) staining and MUC2 immunostaining. In vitro, B. dentium-secreted products, including acetate, were able to increase MUC2 levels in T84 cells. We also identified that B. dentium-secreted products, such as γ-aminobutyric acid (GABA), stimulated autophagy-mediated calcium signaling and MUC2 release. This work illustrates that B. dentium is capable of enhancing the intestinal mucus layer and goblet cell function via upregulation of gene expression and autophagy signaling pathways, with a net increase in mucin production. IMPORTANCE Microbe-host interactions in the intestine occur along the mucus-covered epithelium. In the gastrointestinal tract, mucus is composed of glycan-covered proteins, or mucins, which are secreted by goblet cells to form a protective gel-like structure above the epithelium. Low levels of mucin or alterations in mucin glycans are associated with inflammation and colitis in mice and humans. Although current literature links microbes to the modulation of goblet cells and mucins, the molecular pathways involved are not yet fully understood. Using a combination of gnotobiotic mice and mucus-secreting cell lines, we have identified a human-derived microbe, Bifidobacterium dentium, which adheres to intestinal mucus and secretes metabolites that upregulate the major mucin MUC2 and modulate goblet cell function. Unlike other Bifidobacterium species, B. dentium does not extensively degrade mucin glycans and cannot grow on mucin alone. This work points to the potential of using B. dentium and similar mucin-friendly microbes as therapeutic agents for intestinal disorders with disruptions in the mucus barrier.
format	article
author	Melinda A. Engevik Berkley Luk Alexandra L. Chang-Graham Anne Hall Beatrice Herrmann Wenly Ruan Bradley T. Endres Zhongcheng Shi Kevin W. Garey Joseph M. Hyser James Versalovic
author_facet	Melinda A. Engevik Berkley Luk Alexandra L. Chang-Graham Anne Hall Beatrice Herrmann Wenly Ruan Bradley T. Endres Zhongcheng Shi Kevin W. Garey Joseph M. Hyser James Versalovic
author_sort	Melinda A. Engevik
title	<named-content content-type="genus-species">Bifidobacterium dentium</named-content> Fortifies the Intestinal Mucus Layer via Autophagy and Calcium Signaling Pathways
title_short	<named-content content-type="genus-species">Bifidobacterium dentium</named-content> Fortifies the Intestinal Mucus Layer via Autophagy and Calcium Signaling Pathways
title_full	<named-content content-type="genus-species">Bifidobacterium dentium</named-content> Fortifies the Intestinal Mucus Layer via Autophagy and Calcium Signaling Pathways
title_fullStr	<named-content content-type="genus-species">Bifidobacterium dentium</named-content> Fortifies the Intestinal Mucus Layer via Autophagy and Calcium Signaling Pathways
title_full_unstemmed	<named-content content-type="genus-species">Bifidobacterium dentium</named-content> Fortifies the Intestinal Mucus Layer via Autophagy and Calcium Signaling Pathways
title_sort	<named-content content-type="genus-species">bifidobacterium dentium</named-content> fortifies the intestinal mucus layer via autophagy and calcium signaling pathways
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/9df25faecc214510a661581000847ab5
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<named-content content-type="genus-species">Bifidobacterium dentium</named-content> Fortifies the Intestinal Mucus Layer via Autophagy and Calcium Signaling Pathways

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