Mucus Enhances Gut Homeostasis and Oral Tolerance by Delivering Immunoregulatory Signals

Shan, Meimei; Gentile, Maurizio; Yeiser, John R.; Walland, A; Bornstein, Victor Ugarte; Chen, Kang; He, Bing; Cassis, Linda; Bigas, Anna; Cols, Montserrat; Comerma, Laura; Huang, Bihui; Blander, J. Magarian; Xiong, Huabao; Mayer, Lloyd; Berin, M. Cecilia; Augenlicht, Leonard H.; Velcich, Anna; Cerutti, Andrea

doi:10.1126/science.1237910

Cited by 513 publications

(447 citation statements)

References 37 publications

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“…The goblet cells and their main product, the MUC2 mucin, have recently been shown to be involved in antigen presentation to CD103 + dendritic cells and are likely involved in tolerogenic processes (26,27). The processing of the MUC2 mucin and its cleavage by meprin β into a nonattached form is likely to be important for these processes.…”

Section: Discussionmentioning

confidence: 99%

Microbial-induced meprin β cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus

Schutte¹,

Ermund²,

Becker‐Pauly

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

164

160

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The mucus that covers and protects the epithelium of the intestine is built around its major structural component, the gel-forming MUC2 mucin. The gel-forming mucins have traditionally been assumed to be secreted as nonattached. The colon has a twolayered mucus system where the inner mucus is attached to the epithelium, whereas the small intestine normally has a nonattached mucus. However, the mucus of the small intestine of meprin β-deficient mice was now found to be attached. Meprin β is an endogenous zinc-dependent metalloprotease now shown to cleave the N-terminal region of the MUC2 mucin at two specific sites. When recombinant meprin β was added to the attached mucus of meprin β-deficient mice, the mucus was detached from the epithelium. Similar to meprin β-deficient mice, germ-free mice have attached mucus as they did not shed the membraneanchored meprin β into the luminal mucus. The ileal mucus of cystic fibrosis (CF) mice with a nonfunctional cystic fibrosis transmembrane conductance regulator (CFTR) channel was recently shown to be attached to the epithelium. Addition of recombinant meprin β to CF mucus did not release the mucus, but further addition of bicarbonate rendered the CF mucus normal, suggesting that MUC2 unfolding exposed the meprin β cleavage sites. Mucus is thus secreted attached to the goblet cells and requires an enzyme, meprin β in the small intestine, to be detached and released into the intestinal lumen. This process regulates mucus properties, can be triggered by bacterial contact, and is nonfunctional in CF due to poor mucin unfolding.protease | von Willebrand factor | gastrointestinal tract

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Section: Discussionmentioning

confidence: 99%

Microbial-induced meprin β cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus

Schutte¹,

Ermund²,

Becker‐Pauly

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

164

160

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“…We investigated the possibility that intestinal bacteria play a key role in NAFLD development. Meta 16S rRNA gene sequencing analysis of the intestinal microbiota revealed that the percentage of Gram-positive bacterial strains indigenous to the human and rodent intestinal tract [28] was increased in P-80 fed mice compared to the control. Several pathogens have specific strategies for penetrating mucus in order to gain access to epithelial cell surface.…”

Section: Rrna and Serum Metabolitementioning

confidence: 99%

Food Additive P-80 Impacts Mouse Gut Microbiota Promoting Intestinal Inflammation, Obesity and Liver Dysfunction

Singh¹

2016

SOJMID

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Open Access Research Articlethe globalization of unhealthy lifestyle. Key metabolic and physiological changes, including obesity, metabolic syndrome and Nonalcoholic Fatty Liver Disease (NAFLD) are commonly associated with chronic, non-communicable disease that are responsible for approximately 70% of the world's death.There are compelling arguments to include the composition of gut microbiota as a key risk factor for the development of obesity and obesity related metabolic disorders, including insulin resistance, type 2 diabetes, dyslipidemia and non-alcoholic fatty liver disease [3]. The gut microbiota has been implicated in having both direct (i.e. through effect on nutrient uptake) and indirect effect on health [4,5]. In mice, food additives have been demonstrated to affect the host microbiota interaction, leading to low-grade inflammation, adiposity and adiposity associated metabolic effect [6].We set out to elucidate whether alteration in the gut microbial community after P-80 ingestion is a causative agent of liver dysfunction. To explore this possibility, we setup an experiment to examine the impact of P-80 on gut microbiota using wild-type C57BL/ 6 mice. The experimental mice were gavaged with the amount of P-80 equal to 1% of their body weight. This amount correlates to the acceptable daily human intake of 1% per kg of polysorbate-80 to body weight [7]. Methods Mice and dietThe C57BL/6 (000664) mice were purchased from The Jackson Laboratory. The mice were maintained under specific pathogenfree conditions, on a 12-h light-dark cycle, and fed normal diet (12 kcal% fat, 29 kcal% protein, 59% kcal carbohydrate) ad libitum. For this study there were two groups: one control group (ingesting saline via gavage) and one experimental P-80 fed group (ingesting P-80 dissolve in saline, 1% per kg via gavage). This dose corresponds to the FDA Acceptable Daily Intake (ADI) in humans (1% per kg (body weight), adjusted to the mouse AbstractThe increasing prevalence of obesity has emerged as one of the most important global public health issue. The change to the human microbiome as a result of changes in the quality and quantity of food intake over the past several decades has been implicated in the development of obesity and metabolic syndrome. We administered polysorbate-80 to mice via gavage. The researchers monitor liver noninvasively using a bioluminescence imaging. For the liver dysfunction we measure the liver enzymes and PAS stain on liver, electron microscopy liver mitochondria. For the assessment of intestinal inflammation we measured fecal LCN2, LPS, MPO and flagellin by ELISA and qPCR. We use confocal microscopy to detect closet bacteria near the epithelium. 16S sequence was used for the composition of microbiota. Compared with control mice, those receiving emulsifier, showed impaired glycemic tolerance, hyperinsulinemia, altered liver enzymes, larger mitochondria and increased gall bladder size. Additionally, mice in the experimental group showed higher levels of DCA, reduced Muc2 RNA expression, reduced m...

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“…Polarized secretion is also required in many differentiated tissues, such as the digestive tract, where secreted components along the apical surface form the mucous membrane that confers protection from mechanical and microbial insults (1) and provides immunoregulatory signals (2). Indeed, disruptions in the secreted mucous membrane are associated with diseases of the digestive tract, such as colitis and colon cancer (3)(4)(5)(6).…”

mentioning

confidence: 99%

O-Glycosylation regulates polarized secretion by modulating Tango1 stability

Zhang

Syed

Härd

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Polarized secretion is crucial in many tissues. The conserved protein modification, O-glycosylation, plays a role in regulating secretion. However, the mechanisms by which this occurs are unknown. Here, we demonstrate that an O-glycosyltransferase functions as a novel regulator of secretion and secretory vesicle formation in vivo by glycosylating the essential Golgi/endoplasmic reticulum protein, Tango1 (Transport and Golgi organization 1), and conferring protection from furin-mediated proteolysis. Loss of the O-glycosyltransferase PGANT4 resulted in Tango1 cleavage, loss of secretory granules, and disrupted apical secretion. The secretory defects seen upon loss of pgant4 could be rescued either by overexpression of Tango1 or by knockdown of a specific furin (Dfur2) in vivo. Our studies elucidate a novel regulatory mechanism whereby secretion is influenced by the yin/yang of O-glycosylation and proteolytic cleavage. Moreover, our data have broader implications for the potential treatment of diseases resulting from the loss of O-glycosylation by modulating the activity of specific proteases.R egulation of secretory vesicle formation and polarized secretion in vivo is crucial to ensure the proper deposition of signaling molecules, morphogens, and matrix components that mediate growth and differentiation. Polarized secretion is also required in many differentiated tissues, such as the digestive tract, where secreted components along the apical surface form the mucous membrane that confers protection from mechanical and microbial insults (1) and provides immunoregulatory signals (2). Indeed, disruptions in the secreted mucous membrane are associated with diseases of the digestive tract, such as colitis and colon cancer (3-6).Recent studies aimed at identifying the factors that influence secretion have elucidated novel proteins that function in unique aspects of secretion, including the enzymes responsible for the addition of sugars to mucins and other proteins (mucin-type O-glycosylation) (7). O-glycosylation is an essential, evolutionarily conserved protein modification (8, 9) that has direct medical relevance, as aberrations are responsible for the human diseases familial tumoral calcinosis (10, 11) and Tn syndrome (12). Loss of this protein modification affected constitutive secretion and Golgi apparatus structure in Drosophila cell culture (7, 13) and secretion in the developing respiratory system in vivo (14). Additionally, loss of O-glycosylation also disrupted secretion of an extracellular matrix protein (Tiggrin) in the developing wing, resulting in aberrant basement membrane formation and disrupted integrin-mediated cell adhesion (15). Mammalian studies have confirmed the effects of O-glycosylation on secretion, as loss of a glycosyltransferase (ppGalNAcT-1) disrupted secretion of laminin and collagen during mammalian organogenesis, altering the composition of the basement membrane and disrupting proper FGF signaling and organ growth (16). Although these studies all point to a role for O-glycosylation in se...

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Mucus Enhances Gut Homeostasis and Oral Tolerance by Delivering Immunoregulatory Signals

Cited by 513 publications

References 37 publications

Microbial-induced meprin β cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus

Microbial-induced meprin β cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus

Food Additive P-80 Impacts Mouse Gut Microbiota Promoting Intestinal Inflammation, Obesity and Liver Dysfunction

O-Glycosylation regulates polarized secretion by modulating Tango1 stability

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