Gut Microbiota-Derived Riboflavin Mediates Protective Effects of MUC2 in Acute Pancreatitis via CD40-Macrophage Pathway
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ABSTRACT: Gut barrier dysfunction is critical in the pathogenesis of acute pancreatitis (AP), yet the underlying mechanisms remain unclear. Mucin 2 (MUC2), the primary component of the intestinal mucus layer, is essential for gut homeostasis and microbial eubiosis. This study aimed to elucidate the protective mechanism of intestinal MUC2 in AP.
INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase
PROVIDER: MTBLS12943 | MetaboLights | 2025-09-05
REPOSITORIES: MetaboLights
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Project description:<p> Gut barrier dysfunction is critical in the pathogenesis of acute pancreatitis (AP), yet the underlying mechanisms remain unclear. Mucin 2 (MUC2), the primary component of the intestinal mucus layer, is essential for gut homeostasis and microbial eubiosis. This study aimed to elucidate the protective mechanism of intestinal MUC2 in AP.</p>
2025-09-11 | MTBLS12981 | MetaboLights
Project description:The intestinal mucus layer produced by goblet cells is a critical component of innate immunity. The key host factors and regulatory mechanisms controlling goblet cell function in mucus layer formation remain poorly understood. This study identifies a function for the microprotein FXYD domain-containing transport regulator 3 (FXYD3) in goblet cells in regulating mucus layer formation to maintain intestinal homeostasis. Deficiency of FXYD3 in mouse intestinal epithelial cellsresults in a damaged mucus barrier, leading to microbiota dysbiosis and increased susceptibility to colitis. Mechanistically, FXYD3 interacts with endoplasmic reticulum Ca2+-ATPase SERCA2 to enhances its pump activity. FXYD3 deficiency causes defects in ER Ca2+ homeostasis and mucin glycosylation, impairing mucus layer integrity. Furthermore, metabolites of gut microbiota, propionate and butyrate promoteFXYD3 expression. In ulcerative colitis (UC) patients, FXYD3 expression is significantly downregulated and correlats with disease severity. These findings indicat FXYD3 is a key mediator of host-microbiota interactions for intestinal health.
2025-09-25 | GSE309210 | GEO
Project description:The human gut microbiota plays a central role in intestinal health and disease. However, many of its bacterial constituents are functionally still largely unexplored. A crucial prerequisite for bacterial survival and proliferation is the creation and/or exploitation of an own niche. For many bacterial species that are linked to human disease, the inner mucus layer was found to be an important niche. Allobaculum mucolyticum, is a novel, IBD-associated species that is thought be closely associated with the host epithelium. To explore how this bacterium is able to effectively colonize this niche, we screened its genome for factors that may contribute to mucosal colonization. We identified multiple secreted Carbohydrate Active Enzymes (CAZymes). These CAZymes are able to degrade mucin O-glycans after which some of the liberated monosaccharides can be utilized for bacterial growth. The enzymatic degradation of the mucin glycans may sensitize the mucus layer for further degradation and bacterial entry. Therefore, these enzymes may play a key role in bacterial colonization of the inner mucus layer, and thus may pose an interesting target for future therapeutic intervention.
2021-09-22 | PXD024919 | Pride
Project description:The intestinal mucosal barrier is a dynamic system that allows nutrient uptake, stimulates healthy microbe-host interactions, and prevents invasion by pathogens. The mucosa consists of epithelial cells connected by cellular junctions that regulate the passage of nutrients covered by a mucus layer that plays an important role in host-microbiome interactions. Mimicking the intestinal mucosa for in vitro assays, in particular the generation of a viscous mucus layer, has proven to be challenging. Here, we present a novel in vitro intestinal culture model that produces a robust mucus layer and is based on the widely used intestinal Caco-2 cell line. We investigated the effects of air-liquid interface (ALI) culturing compared to liquid-liquid interface (LLI) on Caco-2 cells grown under low-glucose conditions in Transwell plates. In addition, we determined the impact of vasointestinal peptide (VIP) on mucus secretion, epithelial barrier properties and microbe-mucus interactions. A combination of ALI culturing with VIP addition led to formation of a robust mucus layer on the apical surface of the Caco-2 confluent layer in which the intestinal secreted mucin MUC2 was a major component. RNAseq analysis demonstrated upregulation of unique gene clusters in response to ALI and VIP conditions, but the ALI-VIP combination treatment resulted in a significant upregulation of multiple mucin genes and proteins including MUC2, MUC13 and MUC17. Expression of tight junction proteins was significantly altered in the ALI-VIP condition leading to increased permeability to small molecules, more closely reflecting an intestinal epithelium permissive for nutrient uptake. In infection experiments with commensal Lactobacillus plantarum, pathogenic Salmonella enterica serovar Enteritidis, or enterotoxigenic Escherichia coli (ETEC), the ALI-VIP mucus layer separated the bacteria from the underlying epithelium. In conclusion, ALI-VIP culture of Caco-2 cells provides an attractive in vitro model to study the function of the intestinal mucosal barrier and pathogenic and commensal microbe-host interactions.
2024-12-04 | GSE283451 | 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:<p>Maintaining the integrity of the mucus layer is essential for host health. Studies have implicated that reduced or abnormal mucus production may lead to intestinal inflammation. When dietary nutrients are abundant in the gut, mucin degradation by microbes decreases. However, when nutrient availability declines, microbes increasingly turn to mucin as an energy source. This shift in resource utilization can profoundly alter interaction networks within the gut microbiota. In this study, we aimed to comprehensively investigate the interactions between the community members in different condition. Use non-targeted metabolomics to analyze the relationship between microbial interactions and metabolites.</p>
2025-07-18 | MTBLS11724 | MetaboLights
Project description:The intestinal epithelium is protected by a mucus layer infused with antimicrobial proteins, forming a physical and chemical barrier that limits microbial access to host tissue. Mucus barrier assembly is energetically costly, yet how production of its constituent proteins is matched to demand remains unclear. Here, we show that the microbiota regulates gut barrier immunity by enhancing translation of select defense proteins, including mucin 2 and lysozyme. This occurs via induction of histone deacetylase 5 (HDAC5) in secretory epithelial cells. HDAC5 deacetylates 14-3-3, enabling it to sequester Raptor, a component of mTORC1. This releases mTOR and activates downstream signaling that promotes translation of barrier defense proteins. Our findings reveal a mechanism by which the microbiota shapes barrier immunity through translational control.
2025-08-05 | GSE304136 | GEO
Project description:While growing in the human intestine, C. jejuni grows within the mucus layer. The largest constituents of this layer are the large mucin glycoproteins. A transcriptomic profile of C. jejuni NCTC11168 growing in a mucin-containing minimal medium seeks to describe the effect of the presence of mucin proteins on the transcriptome of C. jejuni. Microarray data was collected from three independent biological replicates and 9 technical replicates for each biological replicate.
2011-04-01 | E-GEOD-28295 | biostudies-arrayexpress
Project description:While growing in the human intestine, C. jejuni grows within the mucus layer. The largest constituents of this layer are the large mucin glycoproteins. A transcriptomic profile of C. jejuni NCTC11168 growing in a mucin-containing minimal medium seeks to describe the effect of the presence of mucin proteins on the transcriptome of C. jejuni.
2011-04-01 | GSE28295 | 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