Intestinal mucus barrier: a missing piece of the puzzle in food allergy

2020 ◽

Vol 26 (Supplement_1) ◽

pp. S42-S42

Author(s):

Kohei Sugihara ◽

Nobuhiko Kamada

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Gut Microbiota ◽

Control Diet ◽

Bacterial Strains ◽

Germ Free ◽

Intestinal Mucus ◽

Gnotobiotic Mice ◽

Mucus Barrier

Abstract Background Recent accumulating evidence suggests that amino acids have crucial roles in the maintenance of intestinal homeostasis. In inflammatory bowel disease (IBD), amino acid metabolism is changed in both host and the gut microbiota. Among amino acids, L-serine plays a central role in several metabolic processes that are essential for the growth and survival of both mammalian and bacterial cells. However, the role of L-serine in intestinal homeostasis and IBD remains incompletely understood. In this study, we investigated the effect of dietary L-serine on intestinal inflammation in a murine model of colitis. Methods Specific pathogen-free (SPF) mice were fed either a control diet (amino acid-based diet) or an L-serine-deficient diet (SDD). Colitis was induced by the treatment of dextran sodium sulfate (DSS). The gut microbiome was analyzed by 16S rRNA sequencing. We also evaluate the effect of dietary L-serine in germ-free mice and gnotobiotic mice that were colonized by a consortium of non-mucolytic bacterial strains or the consortium plus mucolytic bacterial strains. Results We found that the SDD exacerbated experimental colitis in SPF mice. However, the severity of colitis in SDD-fed mice was comparable to control diet-fed mice in germ-free condition, suggesting that the gut microbiota is required for exacerbation of colitis caused by the restriction of dietary L-serine. The gut microbiome analysis revealed that dietary L-serine restriction fosters the blooms of a mucus-degrading bacterium Akkermansia muciniphila and adherent-invasive Escherichia coli in the inflamed gut. Consistent with the expansion of mucolytic bacteria, SDD-fed mice showed a loss of the intestinal mucus layer. Dysfunction of the mucus barrier resulted in increased intestinal permeability, thereby leading to bacterial translocation to the intestinal mucosa, which subsequently increased the severity of colitis. The increased intestinal permeability and subsequent bacterial translocation were observed in SDD-fed gnotobiotic mice that colonized by mucolytic bacteria. In contrast, dietary L-serine restriction did not alter intestinal barrier integrity in gnotobiotic mice that colonized only by non-mucolytic bacteria. Conclusion Our results suggest that dietary L-serine regulates the integrity of the intestinal mucus barrier during inflammation by limiting the expansion of mucus degrading bacteria.

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Frontline defenders: goblet cell mediators dictate host-microbe interactions in the intestinal tract during health and disease

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00181.2017 ◽

2018 ◽

Vol 314 (3) ◽

pp. G360-G377 ◽

Cited By ~ 17

Author(s):

Joannie M. Allaire ◽

Vijay Morampudi ◽

Shauna M. Crowley ◽

Martin Stahl ◽

Hongbing Yu ◽

...

Keyword(s):

Host Defense ◽

Current Evidence ◽

Gi Tract ◽

Intestinal Mucus ◽

Mucin 2 ◽

Microbe Interactions ◽

Noxious Stimuli ◽

Sense And Respond ◽

Mucus Barrier ◽

Host Microbe Interactions

Goblet cells (GCs) are the predominant secretory epithelial cells lining the luminal surface of the mammalian gastrointestinal (GI) tract. Best known for their apical release of mucin 2 (Muc2), which is critical for the formation of the intestinal mucus barrier, GCs have often been overlooked for their active contributions to intestinal protection and host defense. In part, this oversight reflects the limited tools available to study their function but also because GCs have long been viewed as relatively passive players in promoting intestinal homeostasis and host defense. In light of recent studies, this perspective has shifted, as current evidence suggests that Muc2 as well as other GC mediators are actively released into the lumen to defend the host when the GI tract is challenged by noxious stimuli. The ability of GCs to sense and respond to danger signals, such as bacterial pathogens, has recently been linked to inflammasome signaling, potentially intrinsic to the GCs themselves. Moreover, further work suggests that GCs release Muc2, as well as other mediators, to modulate the composition of the gut microbiome, leading to both the expansion as well as the depletion of specific gut microbes. This review will focus on the mechanisms by which GCs actively defend the host from noxious stimuli, as well as describe advanced technologies and new approaches by which their responses can be addressed. Taken together, we will highlight current insights into this understudied, yet critical, aspect of intestinal mucosal protection and its role in promoting gut defense and homeostasis.

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Oral Immunogenicity in Mice and Sows of Enterotoxigenic Escherichia Coli Outer-Membrane Vesicles Incorporated into Zein-Based Nanoparticles

Vaccines ◽

10.3390/vaccines8010011 ◽

2019 ◽

Vol 8 (1) ◽

pp. 11 ◽

Cited By ~ 1

Author(s):

Jose Matías ◽

Ana Brotons ◽

Santiago Cenoz ◽

Isidoro Pérez ◽

Muthanna Abdulkarim ◽

...

Keyword(s):

Escherichia Coli ◽

Outer Membrane ◽

Membrane Vesicles ◽

Outer Membrane Vesicles ◽

Enterotoxigenic Escherichia Coli ◽

Protective Capacity ◽

Intestinal Mucus ◽

Suckling Piglets ◽

Specific Igg ◽

Mucus Barrier

Enterotoxigenic Escherichia coli (ETEC) strains are a major cause of illness and death in neonatal and recently weaned pigs. The immune protection of the piglets derives from maternal colostrum, since this species does not receive maternal antibodies through the placenta. In the present study, outer membrane vesicles (OMVs) obtained from main ETEC strains involved in piglet infection (F4 and F18 serotypes), encapsulated into zein nanoparticles coated with Gantrez®® AN-mannosamine conjugate, were used to orally immunize mice and pregnant sows. Loaded nanoparticles were homogeneous and spherical in a shape, with a size of 220–280 nm. The diffusion of nanoparticles through porcine intestinal mucus barrier was assessed by a Multiple Particle Tracking technique, showing that these particles were able to diffuse efficiently (1.3% diffusion coefficient), validating their oral use. BALB/c mice were either orally immunized with free OMVs or encapsulated into nanoparticles (100 µg OMVs/mouse). Results indicated that a single dose of loaded nanoparticles was able to elicit higher levels of serum specific IgG1, IgG2a and IgA, as well as intestinal IgA, with respect to the free antigens. In addition, nanoparticles induced an increase in levels of IL-2, IL-4 and IFN-γ with respect to the administration of free OMVs. Orally immunized pregnant sows with the same formulation elicited colostrum-, serum- (IgG, IgA or IgM) and fecal- (IgA) specific antibodies and, what is most relevant, offspring suckling piglets presented specific IgG in serum. Further studies are needed to determine the infection protective capacity of this new oral subunit vaccine

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The glycoconjugate-degrading enzymes of Clostridium perfringens: Tailored catalysts for breaching the intestinal mucus barrier

Glycobiology ◽

10.1093/glycob/cwaa050 ◽

2020 ◽

Cited By ~ 3

Author(s):

Kristin E Low ◽

Steven P Smith ◽

D Wade Abbott ◽

Alisdair B Boraston

Keyword(s):

Clostridium Perfringens ◽

Bacterial Species ◽

Opportunistic Pathogen ◽

Glycoside Hydrolases ◽

Necrotic Enteritis ◽

Carbohydrate Active Enzymes ◽

Intestinal Mucus ◽

Mucosal Layer ◽

Potential Component ◽

Mucus Barrier

Abstract The gastrointestinal (GI) tract of humans and animals is lined with mucus that serves as a barrier between the gut microbiota and the epithelial layer of the intestine. As the proteins present in mucus are typically heavily glycosylated, such as the mucins, several enteric commensal and pathogenic bacterial species are well-adapted to this rich carbon source and their genomes are replete with carbohydrate-active enzymes targeted toward dismantling the glycans and proteins present in mucus. One such species is Clostridium perfringens, a Gram-positive opportunistic pathogen indigenous to the gut of humans and animals. The genome of C. perfringens encodes numerous carbohydrate-active enzymes that are predicted or known to target glycosidic linkages within or on the termini of mucus glycans. Through this enzymatic activity, the degradation of the mucosal layer by C. perfringens has been implicated in a number of GI diseases, the most severe of which is necrotic enteritis. In this review, we describe the wide array of extracellular glycoside hydrolases, and their accessory modules, that is possessed by C. perfringens, and examine the unique multimodularity of these proteins in the context of degrading the glycoconjugates in mucus as a potential component of disease.

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Effects of dietary clays on performance and intestinal mucus barrier of broiler chicks challenged with Salmonella enterica serovar Typhimurium and on goblet cell function in vitro

Poultry Science ◽

10.3382/ps.2013-03587 ◽

2014 ◽

Vol 93 (4) ◽

pp. 839-847 ◽

Cited By ~ 13

Author(s):

J.A.S. Almeida ◽

N.P. Ponnuraj ◽

J.J. Lee ◽

P. Utterback ◽

H.R. Gaskins ◽

...

Keyword(s):

Goblet Cell ◽

Salmonella Enterica ◽

Cell Function ◽

Salmonella Enterica Serovar Typhimurium ◽

Broiler Chicks ◽

Intestinal Mucus ◽

Serovar Typhimurium ◽

Mucus Barrier

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Comparative study of the intestinal mucus barrier in normal and inflamed colon

Gut ◽

10.1136/gut.2006.098160 ◽

2007 ◽

Vol 56 (3) ◽

pp. 343-350 ◽

Cited By ~ 204

Author(s):

A. Swidsinski ◽

V. Loening-Baucke ◽

F. Theissig ◽

H. Engelhardt ◽

S. Bengmark ◽

...

Keyword(s):

Comparative Study ◽

Intestinal Mucus ◽

Mucus Barrier

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Vibrio cholerae motility in aquatic and mucus-mimicking environments

10.1101/2021.07.06.451398 ◽

2021 ◽

Author(s):

Marianne Grognot ◽

Anisha Mittal ◽

Mattia Amyra Mah'moud ◽

Katja M Taute

Keyword(s):

Vibrio Cholerae ◽

Effective Diffusivity ◽

Statistical Characterization ◽

Host Environment ◽

Severe Diarrhea ◽

Intestinal Mucus ◽

Mucus Barrier ◽

Viscous Solutions ◽

Speed Fluctuations

Cholera disease is caused by Vibrio cholerae infecting the lining of the small intestine and results in severe diarrhea. V. cholerae's swimming motility is known to play a crucial role in pathogenicity and may aid the bacteria in crossing the intestinal mucus barrier to reach sites of infection, but the exact mechanisms are unknown. The cell can be either pushed or pulled by its single polar flagellum, but there is no consensus on the resulting repertoire of motility behaviors. We use high-throughput 3D bacterial tracking to observe V. cholerae swimming in buffer, in viscous solutions of the synthetic polymer PVP, and in mucin solutions that may mimic the host environment. We perform a statistical characterization of its motility behavior on the basis of large 3D trajectory datasets. We find that V. cholerae performs asymmetric run-reverse-flick motility, consisting of a sequence of a forward run, reversal, and a shorter backward run, followed by a turn by approximately 90°, called a flick, preceding the next forward run. Unlike many run-reverse-flick swimmers, V. cholerae's backward runs are much shorter than its forward runs, resulting in an increased effective diffusivity. We also find that the swimming speed is not constant, but subject to frequent decreases. The turning frequency in mucin matches that observed in buffer. Run-reverse-flick motility and speed fluctuations are present in all environments studied, suggesting that these behaviors may also occur in natural aquatic habitats as well as the host environment.

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Germline Variants of CYBA and TRPM4 Predispose to Familial Colorectal Cancer

10.20944/preprints202112.0354.v1 ◽

2021 ◽

Author(s):

Lizhen Zhu ◽

Beiping Miao ◽

Dagmara Dymerska ◽

Magdalena Kuświk ◽

Elena Bueno-Martínez ◽

...

Keyword(s):

Colorectal Cancer ◽

Stop Codon ◽

Bacterial Colonization ◽

Functional Characterization ◽

Premature Stop Codon ◽

Familial Colorectal Cancer ◽

Intestinal Mucus ◽

Healthy Elderly ◽

Predisposing Genes ◽

Mucus Barrier

Familial colorectal cancer (CRC) is only partially explained by known germline predisposing genes. We performed whole genome sequencing in 15 Polish families of many affected individuals, without mutations in known CRC predisposing genes. We focused on loss-of-function variants and functionally characterized them. We identified a frameshift variant in the CYBA gene (c.246delC) in one family and a splice site variant in the TRPM4 gene (c.25-1 G>T) in another family. While both variants were absent or extremely rare in gene variant databases, we identified four additional Polish familial CRC cases and two healthy elderly individuals with the CYBA variant (odds ratio 2.46, 95% confidence interval 0.48-12.69). Both variants led to a premature stop codon and to a truncated protein. Functional characterization of the variants showed that knockdown of CYBA or TRPM4 depressed generation of reactive oxygen species (ROS) in LS174T and HT-29 cell lines. Knockdown of TRPM4 resulted in decreased MUC2 protein production. CYBA encodes a component in the NADPH oxidase system which generates ROS and controls, e.g., bacterial colonization in the gut. Germline CYBA variants are associated with early onset inflammatory bowel disease, supported with experimental evidence on loss of intestinal mucus barrier function due to ROS deficiency. TRPM4 encodes a calcium-activated ion channel, which in a human colonic cancer cell line controls calcium-mediated secretion of MUC2, a major component of intestinal mucus barrier. We suggest that the gene defects in CYBA and TRPM4 mechanistically involve intestinal barrier integrity through ROS and mucus biology, which converges in chronic bowel inflammation.

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