Akkermansia muciniphila associated with improved child health produces the peptode larazotide that affects colonic epithelial cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE175488 | GEO | 2021/05/25
REPOSITORIES: GEO
Similar Datasets
Project description:Intestinal epithelia are protected by a layer of mucin secreted by goblet cells against mechanical and chemical injuries, potent causes of inflammation, and the most abundant secreted intestinal mucin is encoded by the Muc2 gene. Genetic deletion of Muc2 causes intestinal inflammation in early stage and tumors after 3 months. The underlying mechanisms are not clear, but epigenetic alterations, particularly, up- and down-regulated microRNAs are involved in the malignant transformation from colitis to cancer. We used miRNA array to profile the differential expression of the miRNAs in Muc2-/- mouse colonic epithelial lin comparison with those in wild-type mice. Total RNA were extracted from mouse colonic epithelial cells and Muc2-/- and +/+, and the RNA were hybridized on Affymetrix miRNA microarray to determine the alterations of miRNAs during colitis development and its malignant transformation from colitis to cancer. To the end, we found miRNA were differential expressed in the Muc2-/- mice, among them 20 miRNAs were significantly downregulated and 71 miRNAs were significantly upregulated in Muc2-/- mice, in comparison with Muc2+/+ mice (change fold >2 or <0.5; T<0.01, p value< 0.05, q value< 0.05).
2014-05-31 | E-GEOD-56577 | biostudies-arrayexpress
Project description:Intestinal epithelia are protected by a layer of mucin secreted by goblet cells against mechanical and chemical injuries, potent causes of inflammation, and the most abundant secreted intestinal mucin is encoded by the Muc2 gene. Genetic deletion of Muc2 causes intestinal inflammation in early stage and tumors after 3 months. The underlying mechanisms are not clear, but epigenetic alterations, particularly, up- and down-regulated microRNAs are involved in the malignant transformation from colitis to cancer. We used miRNA array to profile the differential expression of the miRNAs in Muc2-/- mouse colonic epithelial lin comparison with those in wild-type mice.
2014-05-31 | GSE56577 | GEO
Project description:Background; MUC2 mucin produced by intestinal goblet cells is the major component of the intestinal mucus barrier. MUC2 homo-oligomerizes intracellularly into large secreted polymers which give mucus its viscous properties. The inflammatory bowel disease (IBD) ulcerative colitis is characterized by depleted goblet cells and a reduced mucus layer, whereas goblet cells and the mucus layer are increased in the other major inflammatory bowel disease, Crohnâs disease. Methods and Findings; By murine N-ethyl-N-nitrosourea-mutagenesis we identified two distinct non-complementing missense mutations in Muc2 exons encoding N- and C-terminal homo-oligomerization domains causing an ulcerative colitis-like phenotype. Both strains developed mild spontaneous distal intestinal inflammation, chronic diarrhea, rectal bleeding and prolapse, increased susceptibility to acute and chronic colitis induced by a luminal toxin, aberrant Muc2 biosynthesis, smaller goblet cell thecae (less stored mucin) and a diminished mucus barrier. Enhanced local production of IL-1beta, TNF-alpha and IFN-gamma was seen in the distal colon. The number of leukocytes within mesenteric lymph nodes was increased five-fold and leukocytes cultured in vitro produced both Th1 and Th2 cytokines (IFN-gamma, TNF-alpha and IL-13). Intestinal permeability was increased and the luminal bacterial flora were more heavily coated with immunoglobulin as occurs in IBD. This pathology was accompanied by accumulation of the Muc2 precursor and ultrastructural and biochemical evidence of endoplasmic reticulum (ER) stress in goblet cells, activation of the unfolded protein response, and altered intestinal expression of genes involved in ER stress, inflammation, apoptosis and wound repair. Expression of mutated Muc2 oligomerization domains in vitro demonstrated that aberrant Muc2 oligomerization underlies the ER stress. These models show that mutations in Muc2 oligomerization domains can lead to aberrant assembly of the Muc2 complex leading to ER stress, a depleted mucus barrier and intestinal inflammation. In ulcerative colitis we demonstrate similar accumulation of non-glycosylated MUC2 precursor in goblet cells together with ultrastructural and biochemical evidence of ER stress even in non-inflamed intestinal tissue. Conclusions; The observations that mucin misfolding and ER stress lead directly to intestinal inflammation and that ER stress and goblet cell pathology occur in ulcerative colitis suggest that ER stress-related mucin depletion could be a fundamental component of the pathogenesis of colitis. Experiment Overall Design: 3 individual mice from the Eeyore, Winnie or Wild-type strains were compared as groups. An Affymetrix ID was compared between groups if the ID was Present within two of the three mice within each grouping. IDs were compared by calculating the log2 of Group One average signal divided by Group 2 average signal.
2008-04-06 | E-GEOD-9913 | biostudies-arrayexpress
Project description:Akkermansia muciniphila, a mucin-degrading microbe found in the human gut, is often associated with positive health outcomes. The abundance of Akkermansia muciniphila is modulated by the presence and accessibility of nutrients, which can be derived from diet or host glycoproteins. In particular, the ability to degrade host mucins, a class of proteins carrying densely O-glycosylated domains, provides a competitive advantage in the sustained colonization of niche mucosal environments. Although Akkermansia muciniphila is known to rely on mucins as a carbon and nitrogen source, the enzymatic machinery used by this microbe to process mucins in the gut is not yet fully characterized. Here, we focus on the mucin-selective metalloprotease, Amuc_0627 (AM0627), which is known to cleave between adjacent residues carrying truncated core 1 O-glycans. We showed that this enzyme is capable of degrading purified mucin 2 (MUC2), the major protein component of mucus in the gut. An X-ray crystal structure of AM0627 (1.9 Å resolution) revealed O-glycan binding residues that are conserved between structurally characterized enzymes from the same family. We further rationalized the substrate cleavage motif using molecular modeling to identify nonconserved glycan-interacting residues. Mutagenesis of these residues resulted in altered substrate preferences down to the glycan level, providing insight into the structural determinants of O-glycan recognition.
2022-06-09 | PXD032164 | Pride
Project description:The intestinal anaerobic bacterium Akkermansia muciniphila is specialized in the degradation of mucins, which are heavily O-glycosylated proteins that constitute the major components of the mucus lining the intestine. Despite that adhesion to mucins is considered critical for the persistence of A. muciniphila in the human intestinal tract, our knowledge of how this intestinal symbiont recognizes and binds to mucins is still limited. Here, we first show that the mucin-binding properties of A. muciniphila are independent of environmental oxygen concentrations and not abolished by pasteurization. We then dissected the mucin-binding properties of pasteurized A. muciniphila by use of a recently developed cell-based mucin array that enables display of the tandem repeats of human mucins with distinct O-glycan patterns and structures. We found that A. muciniphila recognizes the unsialylated LacNAc (Galβ1-4GlcNAc1-R) disaccharide selectively on core2 and core3 O-glycans. This disaccharide epitope is abundantly found on human colonic mucins capped by sialic acids, and we demonstrated that endogenous A. muciniphila neuraminidase activity can uncover the epitope and promote binding. In summary, our study provides insights into the mucin-binding properties important for colonization of a key mucin-foraging bacterium.
2024-05-30 | PXD051738 | Pride
Project description:Akkermansia muciniphila, a mucin-degrading microbe found in the human gut, is often associated with positive health outcomes. The abundance of Akkermansia muciniphila is modulated by the presence and accessibility of nutrients, which can be derived from diet or host glycoproteins. In particular, the ability to degrade host mucins, a class of proteins carrying densely O-glycosylated domains, provides a competitive advantage in the sustained colonization of niche mucosal environments. Although Akkermansia muciniphila is known to rely on mucins as a carbon and nitrogen source, the enzymatic machinery used by this microbe to process mucins in the gut is not yet fully characterized. Here, we focus on the mucin-selective metalloprotease, Amuc_0627 (AM0627), which is known to cleave between adjacent residues carrying truncated core 1 O-glycans. We showed that this enzyme is capable of degrading purified mucin 2 (MUC2), the major protein component of mucus in the gut. An X-ray crystal structure of AM0627 at 1.9 Å resolution revealed O-glycan binding residues that are conserved between structurally characterized enzymes from the same family. We further rationalized the substrate cleavage motif using molecular modeling to identify nonconserved glycan-interacting residues. Mutagenesis of these residues resulted in altered substrate preferences down to the glycan level, providing insight into the structural determinants of O-glycan recognition.
2022-08-28 | PXD031225 | Pride
Project description:The use of Akkermansia muciniphila as potential therapeutic intervention is receiving increasing attention. Health benefits attributed to this bacterium include an improvement of metabolic disorders and exerting anti-inflammatory effects. The abundance of A. muciniphila is associated with a healthy gut in early mid- and later life. However, the effects of A. muciniphila on a decline in intestinal health during the aging process are not investigated yet. We supplemented accelerated aging Ercc1-/Δ7 mice with A. muciniphila for 10 weeks and investigated histological, transcriptional and immunological aspects of intestinal health. The thickness of the colonic mucus layer increased about 3-fold after long-term A. muciniphila supplementation and was even significantly thicker compared to mice supplemented with Lactobacillus plantarum WCFS1. Colonic gene expression profiles pointed towards a decreased expression of genes and pathways related to inflammation and immune function, and suggested a decreased presence of B cells in colon. Total B cell frequencies in spleen and mesenteric lymph nodes were not altered after A. muciniphila supplementation. Mature and immature B cell frequencies in bone marrow were increased, whereas B cell precursors were unaffected. These findings implicate that B cell migration rather than production was affected by A. muciniphila supplementation. Gene expression profiles in ileum pointed toward a decrease in metabolic- and immune-related processes and antimicrobial peptide production after A. muciniphila supplementation. Besides, A. muciniphila decreased the frequency of activated CD80+CD273- B cells in Peyer’s patches. Additionally, the increased numbers of peritoneal resident macrophages and a decrease in Ly6Cint monocyte frequencies in spleen and mesenteric lymph nodes add evidence for the potentially anti-inflammatory properties of A. muciniphila. Altogether, we show that supplementation with A. muciniphila prevented the age-related decline in thickness of the colonic mucus layer and attenuated inflammation and immune-related processes at old age. This study implies that A. muciniphila supplementation can contribute to a promotion of healthy aging.
2019-02-20 | GSE126730 | GEO
Project description:Background MUC2 mucin produced by intestinal goblet cells is the major component of the intestinal mucus barrier. MUC2 homo-oligomerizes intracellularly into large secreted polymers which give mucus its viscous properties. The inflammatory bowel disease (IBD) ulcerative colitis is characterized by depleted goblet cells and a reduced mucus layer, whereas goblet cells and the mucus layer are increased in the other major inflammatory bowel disease, Crohn’s disease. Methods and Findings By murine N-ethyl-N-nitrosourea-mutagenesis we identified two distinct non-complementing missense mutations in Muc2 exons encoding N- and C-terminal homo-oligomerization domains causing an ulcerative colitis-like phenotype. Both strains developed mild spontaneous distal intestinal inflammation, chronic diarrhea, rectal bleeding and prolapse, increased susceptibility to acute and chronic colitis induced by a luminal toxin, aberrant Muc2 biosynthesis, smaller goblet cell thecae (less stored mucin) and a diminished mucus barrier. Enhanced local production of IL-1beta, TNF-alpha and IFN-gamma was seen in the distal colon. The number of leukocytes within mesenteric lymph nodes was increased five-fold and leukocytes cultured in vitro produced both Th1 and Th2 cytokines (IFN-gamma, TNF-alpha and IL-13). Intestinal permeability was increased and the luminal bacterial flora were more heavily coated with immunoglobulin as occurs in IBD. This pathology was accompanied by accumulation of the Muc2 precursor and ultrastructural and biochemical evidence of endoplasmic reticulum (ER) stress in goblet cells, activation of the unfolded protein response, and altered intestinal expression of genes involved in ER stress, inflammation, apoptosis and wound repair. Expression of mutated Muc2 oligomerization domains in vitro demonstrated that aberrant Muc2 oligomerization underlies the ER stress. These models show that mutations in Muc2 oligomerization domains can lead to aberrant assembly of the Muc2 complex leading to ER stress, a depleted mucus barrier and intestinal inflammation. In ulcerative colitis we demonstrate similar accumulation of non-glycosylated MUC2 precursor in goblet cells together with ultrastructural and biochemical evidence of ER stress even in non-inflamed intestinal tissue. Conclusions The observations that mucin misfolding and ER stress lead directly to intestinal inflammation and that ER stress and goblet cell pathology occur in ulcerative colitis suggest that ER stress-related mucin depletion could be a fundamental component of the pathogenesis of colitis. Keywords: Single gene, multiple mutant comparison
2008-03-01 | GSE9913 | GEO
Project description:Colonic goblet cells respond to invading enteropathogens by secreting Muc2 mucin and other specific goblet cell proteins that physically entrap and expel microbes away from the epithelium. At present, it is unclear how innate effectors in the gut, including small cationic cathelicidin peptides secreted by the intestinal epithelium and leukocytes, contribute to mucus barrier defense during infections. In this study, we used cathelicidin-deficient (Camp-/-) mice, colonoids, and human colonic LS174T goblet cells to elucidate the mechanisms by which cathelicidin regulates goblet cell secretions in innate host defense against attaching/effacing Citrobacter rodentium. We showed that even though Camp-/- littermates infected with C. rodentium displayed increased fecal shedding and epithelial colonization, Muc2 mucin granules were retained in bloated colonic goblet cells that impaired mucus secretion and expressed less mucus-associated proteins, as quantified by proteomic analysis. C. rodentium infected Camp-/- littermates showed impaired reactive oxygen species (ROS) production and transcriptomic profiling associated with decreased ROS biosynthesis and an increase in ROS negative regulators. Camp-/- bone marrow derived macrophages produced less ROS than their wild-type counterparts. In LS174T goblet cells, human cathelicidin LL-37 promptly induced the secretion of goblet cell-associated TFF3 and RELMβ, which was dependent on ROS production. These findings demonstrate that cathelicidin signaling in colonic goblet cells regulates mucus and mucin-associated protein secretion via an ROS-dependent mechanism to clear bacterial infections and restore gut homeostasis.
2023-05-04 | PXD041957 | Pride
Project description:Kees2018 - Genome-scale constraint-based
model of the mucin-degrader Akkermansia
muciniphila
This model is described in the article:
Model-driven design of a
minimal medium for Akkermansia muciniphila confirms mucus
adaptation.
van der Ark KCH, Aalvink S,
Suarez-Diez M, Schaap PJ, de Vos WM, Belzer C.
Microb Biotechnol 2018 Jan; :
Abstract:
The abundance of the human intestinal symbiont Akkermansia
muciniphila has found to be inversely correlated with several
diseases, including metabolic syndrome and obesity.
A. muciniphila is known to use mucin as sole carbon and
nitrogen source. To study the physiology and the potential for
therapeutic applications of this bacterium, we designed a
defined minimal medium. The composition of the medium was based
on the genome-scale metabolic model of A. muciniphila and
the composition of mucin. Our results indicate that
A. muciniphila does not code for GlmS, the enzyme that
mediates the conversion of fructose-6-phosphate (Fru6P) to
glucosamine-6-phosphate (GlcN6P), which is essential in
peptidoglycan formation. The only annotated enzyme that could
mediate this conversion is Amuc-NagB on locus Amuc_1822. We
found that Amuc-NagB was unable to form GlcN6P from Fru6P at
physiological conditions, while it efficiently catalyzed the
reverse reaction. To overcome this inability,
N-acetylglucosamine needs to be present in the medium for
A. muciniphila growth. With these findings, the
genome-scale metabolic model was updated and used to accurately
predict growth of A. muciniphila on synthetic media. The
finding that A. muciniphila has a necessity for GlcNAc,
which is present in mucin further prompts the adaptation to its
mucosal niche.
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To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
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2021-02-15 | MODEL1710040000 | BioModels