Infant milk formula, produced by membrane filtration, promotes mucus production in the upper small intestine of young pigs.

Human breast milk promotes maturation of the infant gastrointestinal barrier, including the promotion of mucus production. In the quest to produce next generation infant milk formula (IMF), we have produced IMF by membrane filtration (MEM-IMF). With a higher quantity of native whey protein, MEM-IMF more closely mimics human breast milk than IMF produced using conventional heat treatment (HT-IMF). After a 4-week dietary intervention in young pigs, animals fed a MEM-IMF diet had a higher number of goblet cells, acidic mucus and mucin-2 in the jejunum compared to pigs fed HT-IMF (P < 0.05). In the duodenum, MEM-IMF fed pigs had increased trypsin activity in the gut lumen, increased mRNA transcript levels of claudin 1 in the mucosal scrapings and increased lactase activity in brush border membrane vesicles than those pigs fed HT-IMF (P < 0.05). In conclusion, MEM-IMF is superior to HT-IMF in the promotion of mucus production in the young gut.

Restoration of Lactobacillus johnsonii and Enterococcus faecalis Caused the Elimination of Tritrichomonas sp. in a Model of Antibiotic-Induced Dysbiosis.

Inflammatory bowel disease (IBD) is a multifactorial disease involving the interaction of the gut microbiota, genes, host immunity, and environmental factors. Dysbiosis in IBD is associated with pathobiont proliferation, so targeted antibiotic therapy is a rational strategy. When restoring the microbiota with probiotics, it is necessary to take into account the mutual influence of co-cultivated microorganisms, as the microbiota is a dynamic community of species that mediates homeostasis and physiological processes in the intestine. The aim of our study was to investigate the recovery efficacy of two potential probiotic bacteria, L. johnsonii and E. faecalis, in Muc2-/- mice with impaired mucosal layer. Two approaches were used to determine the efficacy of probiotic supplementation in mice with dysbiosis caused by mucin-2 deficiency: bacterial seeding on selective media and real-time PCR analysis. The recovery time and the type of probiotic bacteria relocated affected only the number of E. faecalis. A significant positive correlation was found between colony-forming unit (CFU) and the amount of E. faecalis DNA in the group that was replanted with probiotic E. faecalis. As for L. johnsonii, it could be restored to its original level even without any additional bacteria supplementation after two weeks. Interestingly, the treatment of mice with L. johnsonii caused a decrease in the amount of E. faecalis. Furthermore, either L. johnsonii or E. faecalis treatment eliminated protozoan overgrowth caused by antibiotic administration.

Study on the Protective Effect and Mechanism of Umbilicaria esculenta Polysaccharide in DSS-Induced Mice Colitis and Secondary Liver Injury.

This study aimed to explore the ameliorative effects and potential mechanisms of Huangshan Umbilicaria esculenta polysaccharide (UEP) in dextran sulfate sodium-induced acute ulcerative colitis (UC) and UC secondary liver injury (SLI). Results showed that UEP could ameliorate both colon and liver pathologic injuries, upregulate mouse intestinal tight junction proteins (TJs) and MUC2 expression, and reduce LPS exposure, thereby attenuating the effects of the gut-liver axis. Importantly, UEP significantly downregulated the secretion levels of TNF-α, IL-1ß, and IL-6 through inhibition of the NF-κB pathway and activated the Nrf2 signaling pathway to increase the expression levels of SOD and GSH-Px. In vitro, UEP inhibited the LPS-induced phosphorylation of NF-κB P65 and promoted nuclear translocation of Nrf2 in RAW264.7 cells. These results revealed that UEP ameliorated UC and SLI through NF-κB and Nrf2-mediated inflammation and oxidative stress. The study first investigated the anticolitis effect of UEP, suggesting its potential for the treatment of colitis and colitis-associated liver disease.

Insights into the effects of chronic combined chromium-nickel exposure on colon damage in mice through transcriptomic analysis and in vitro gastrointestinal digestion assay.

Heavy metals interact with each other in a coexisting manner to produce complex combined toxicity to organisms. At present, the toxic effects of chronic co-exposure to heavy metals hexavalent chromium [Cr(VI)] and divalent nickel [Ni(II)] on organisms are seldom studied and the related mechanisms are poorly understood. In this study, we explored the mechanism of the colon injury in mice caused by chronic exposure to Cr or/and Ni. The results showed that, compared with the control group, Cr or/and Ni chronic exposure affected the body weight of mice, and led to infiltration of inflammatory cells in the colon, decreased the number of goblet cells, fusion of intracellular mucus particles and damaged cell structure of intestinal epithelial. In the Cr or/and Ni exposure group, the activity of nitric oxide synthase (iNOS) increased, the expression levels of MUC2 were significantly down-regulated, and those of ZO-1 and Occludin were significantly up-regulated. Interestingly, factorial analysis revealed an interaction between Cr and Ni, which was manifested as antagonistic effects on iNOS activity, ZO-1 and MUC2 mRNA expression levels. Transcriptome sequencing further revealed that the expression of genes-related to inflammation, intestinal mucus and tight junctions changed obviously. Moreover, the relative contents of Cr(VI) and Ni(II) in the Cr, Ni and Cr+Ni groups all changed with in-vitro gastrointestinal （IVG）digestion, especially in the Cr+Ni group. Our results indicated that the chronic exposure to Cr or/and Ni can lead to damage to the mice colon, and the relative content changes of Cr(VI) and Ni(II) might be the main reason for the antagonistic effect of Cr+Ni exposure on the colon damage.

Biochanin a ameliorates DSS-induced ulcerative colitis by improving colonic barrier function and protects against the development of spontaneous colitis in the Muc2 deficient mice.

There is an increasing appreciation that colonic barrier function is closely related to the development and progression of colitis. The mucus layer is a crucial component of the colonic barrier, responsible for preventing harmful bacteria from invading the intestinal epithelium and causing inflammation. Furthermore, a defective mucus barrier is also a significant characteristic of ulcerative colitis (UC). Biochanin A (BCA), an isoflavonoid, has garnered increasing interest due to its significant biological activities. However, the impact of BCA on UC has not been reported yet. In this study, we used a dextran sodium sulfate (DSS)-induced ulcerative colitis model and the Muc2 deficient (Muc2-/-) mice spontaneous colitis model to explore the mechanisms of BCA in the treatment of UC. Here, we verified that DSS-induced UC was observably attenuated and spontaneous colitis in Muc2-/- mice was relieved by BCA. Treatment with BCA improved colitis-related symptoms and reduced intestinal permeability by upregulating the levels of goblet cells and tight junction (TJ) proteins. In addition, we confirmed that BCA promotes autophagy through the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/Unc-51-like kinase 1 (ULK1) pathway, thereby alleviating DSS-induced UC. In addition, the administration of BCA was able to reduce apoptosis and promote proliferation by suppressing Cleaved Caspase-3 (Cleaved Cas-3) expression, and increasing PCNA and Ki67 levels. Further research revealed that BCA treatment ameliorated spontaneous colitis and alleviated epithelial damage in Muc2-/- mice by restoring the intestinal barrier and promoting autophagy. Our results demonstrated that BCA alleviated UC by enhancing intestinal barrier function and promoting autophagy. These findings indicate that BCA may be a novel treatment alternative for UC.

Mutational profile evaluates metastatic capacity of Chinese colorectal cancer patients, revealed by whole-exome sequencing.

Colorectal cancer (CRC) is the third most common cancer and the prevalence rate of CRC is increasing in the China. In this study, whole-exome sequencing (WES) was performed on primary tissues of 47 CRC Chinese patients including 22 metastatic and 25 non-metastatic patients. By comparison with data from western colorectal cancer patients in the Cancer Genome Atlas (TCGA), we identified a number of genes that are more likely to be mutated in Chinese colorectal cancer patients, such as MUC12, MUC12, MUC2, MUC4, HYDIN and KMT2C. Interestingly, MUC family genes including MUC12, MUC2 and MUC4, have mutation rates of >20%, while the mutation frequency was extremely low in western colorectal cancer patients, which were <3% in TCGA and 0% in Memorial Sloan Kettering Cancer Center (MSKCC). We detected metastasis-specific mutated genes including TCF7L2, MST1L, HRNR and SMAD4, while MUC4, NEB, FLG and RFPL4A alteration is more prevalent in the non-metastasis group. Further analysis reveals mutation genes in metastasis group are more focus in the Wnt and Hippo signaling pathway. APC, SMAD4 and TCF7L2 accounted for the major genetic abnormalities in this pathway. In conclusion, this study identified the unique characteristics of gene mutations in Chinese patients with colorectal cancer, and is a valuable reference for personalized treatment in Chinese CRC patients.

POFUT1 and PLAGL2 are characteristic markers of mucinous colorectal cancer associated with MUC2 expression.

Colorectal mucinous adenocarcinoma (MAC) is one of the most lethal histological types of colorectal cancer, and its mechanism of development is not well understood. In this study, we aimed to clarify the molecular characteristics of MAC via in silico analysis using The Cancer Genome Atlas database. The expression of genes on chromosome 20q (Chr20q) was negatively associated with the expression of MUC2, which is a key molecule that can be used to distinguish between MAC and nonmucinous adenocarcinoma (NMAC). This was consistent with a significant difference in copy number alteration of Chr20q between the two histological types. We further identified 475 differentially expressed genes (DEGs) between MAC and NMAC, and some of the Chr20q genes among the DEGs are considered to be pivotal genes used to define MAC. Both in vitro and in vivo analysis showed that simultaneous knockdown of POFUT1 and PLAGL2, both of which are located on Chr20q, promoted MUC2 expression. Moreover, these genes were highly expressed in NMAC but not in MAC according to the results of immunohistological studies using human samples. In conclusion, POFUT1 and PLAGL2 are considered to be important for defining MAC, and these genes are associated with MUC2 expression.

Evaluation of Ki-67, goblet cell and MUC2 mucin RNA expression in dogs with lymphoplasmacytic and granulomatous colitis.

Intestinal mucus barrier disruption may occur with chronic inflammatory enteropathies. The lack of studies evaluating mucus health in dogs with chronic colitis arises from inherent challenges with assessment of the intestinal mucus layer. It is therefore unknown if reduced goblet cell (GBC) numbers and/or mucin 2 (MUC2) expression, which are responsible for mucus production and secretion, correlate with inflammation severity in dogs with granulomatous colitis (GC) or lymphocytic-plasmacytic colitis (LPC). It is undetermined if Ki-67 immunoreactivity, which has been evaluated in dogs with small intestinal inflammation, similarly correlates to histologic severity in GC and LPC. Study objectives included comparing Ki-67 immunoreactivity, GBC population and MUC2 expression in dogs with GC, LPC and non-inflamed colon; and exploring the use of ribonucleic acid (RNAscope®) in-situ hybridization (ISH) to evaluate MUC2 expression in canine colon. Formalin-fixed endoscopic colonic biopsies were obtained from 48 dogs over an eight-year period. A blinded pathologist reviewed all biopsies. Dogs were classified into the GC (n=19), LPC (n=19) or no colitis (NC) (n=10) group based on final histopathological diagnosis. Ki-67 immunohistochemistry, Alcian-Blue/PAS staining to highlight GBCs, and RNAscope® ISH using customized canine MUC2-targeted probes were performed. At least five microscopic fields per dog were selected to measure Ki-67 labelling index (KI67%), GBC staining percentage (GBC%) and MUC2 expression (MUC2%) using image analysis software. Spearman's correlation coefficients were used to determine associations between World Small Animal Veterinary Association histologic score (WHS) and measured variables. Linear regression models were used to compare relationships between WHS with KI67%, GBC%, and MUC2%; and between GBC% and MUC2%. Median WHS was highest in dogs with GC. Median KI67% normalised to WHS was highest in the NC group (6.69%; range, 1.70-23.60%). Median GBC% did not correlate with colonic inflammation overall. Median MUC2% normalised to WHS in the NC group (10.02%; range, 3.05-39.09%) was two- and three-fold higher than in the GC and LPC groups respectively. With increased colonic inflammation, despite minimal changes in GBC% overall, MUC2 expression markedly declined in the LPC group (-27.4%; 95%-CI, -49.8, 5.9%) and mildly declined in the GC and NC groups. Granulomatous colitis and LPC likely involve different pathways regulating MUC2 expression. Decreased MUC2 gene expression is observed in dogs with chronic colitis compared to dogs without colonic signs. Changes in MUC2 expression appear influenced by GBC activity rather than quantity in GC and LPC.

Polysaccharide from Boletus aereus ameliorates DSS-induced colitis in mice by regulating the MANF/MUC2 signaling and gut microbiota.

Inflammatory bowel diseases (IBD) are chronic inflammatory conditions characterized by disruptions in the colonic mucus barrier and gut microbiota. In this study, a novel soluble polysaccharide obtained from Boletus aereus (BAP) through water extraction was examined for its structure. The protective effects of BAP on colitis were investigated using a DSS-induced mice model. BAP was found to promote the expression of intestinal mucosal and tight junction proteins, restore the compromised mucus barrier, and suppress the activation of inflammatory signaling. Moreover, BAP reshape the gut microbiota and had a positive impact on the composition of the gut microbiota by reducing inflammation-related microbes. Additionally, BAP decreased cytokine levels through the MANF-BATF2 signaling pathway. Correlation analysis revealed that MANF was negatively correlated with the DAI and the level of cytokines. Furthermore, the depletion of gut microbiota using antibiotic partially inhabited the effect of BAP on the activation of MANF and Muc2, indicating the role of gut microbiota in its protective effect against colitis. In conclusion, BAP had an obvious activation on MANF under gut inflammation. This provides new insights into the prospective use of BAP as a functional food to enhance intestinal health.

Aryl Hydrocarbon Receptor Regulates Muc2 Production Independently of IL-22 during Colitis.

We previously reported that an aryl hydrocarbon receptor (AhR) ligand, indole-3-carbinol (I3C), was effective at reducing colitis severity through immune cell-mediated interleukin-22 (IL-22) production. Intestinal epithelial cells (IECs) are also involved in regulating colitis, so we investigated their AhR-mediated mechanisms in the current report. A transcriptome analysis of IECs in wildtype (WT) mice revealed that during colitis, I3C regulated select mucin proteins, which could be attributed to goblet cell development. To address this, experiments under in vivo colitis (mice) or in vitro colon organoid conditions were undertaken to determine how select mucin proteins were altered in the absence or presence of AhR in IECs during I3C treatment. Comparing WT to IEC-specific AhR knockout mice (AhRΔIEC), the results showed that AhR expression was essential in IECs for I3C-mediated protection during colitis. AhR-deficiency also impaired mucin protein expression, particularly mucin 2 (Muc2), independently of IL-22. Collectively, this report highlights the important role of AhR in direct regulation of Muc2. These results provide justification for future studies aimed at determining how AhR might regulate select mucins through mechanisms such as direct transcription binding to enhance production.

Mucin Expression Profiles in Ulcerative Colitis: New Insights on the Histological Mucosal Healing.

A structural weakness of the mucus barrier (MB) is thought to be a cause of ulcerative colitis (UC). This study aims to investigate the mucin (MUC) composition of MB in normal mucosa and UC. Ileocolonic biopsies were taken at disease onset and after treatment in 40 patients, including 20 with relapsing and 20 with remitting UC. Ileocolonic biopsies from 10 non-IBD patients were included as controls. Gut-specific MUC1, MUC2, MUC4, MUC5B, MUC12, MUC13, MUC15, and MUC17 were evaluated immunohistochemically. The promoters of mucin genes were also examined. Normal mucosa showed MUC2, MUC5B, and MUC13 in terminal ileum and colon, MUC17 in ileum, and MUC1, MUC4, MUC12, and MUC15 in colon. Membranous, cytoplasmic and vacuolar expressions were highlighted. Overall, the mucin expression was abnormal in UC. Derangements in MUC1, MUC4, and MUC5B were detected both at onset and after treatment. MUC2 and MUC13 were unaffected. Sequence analysis revealed glucocorticoid-responsive elements in the MUC1 promoter, retinoic-acid-responsive elements in the MUC4 promoter, and butyrate-responsive elements in the MUC5B promoter. In conclusion, MUCs exhibited distinct expression patterns in the gut. Their expression was disrupted in UC, regardless of the treatment protocols. Abnormal MUC1, MUC4, and MUC5B expression marked the barrier dysfunction in UC.

Fecal-adherent mucus is a non-invasive source of primary human MUC2 for structural and functional characterization in health and disease.

The O-glycoprotein Mucin-2 (MUC2) forms the protective colon mucus layer. While animal models have demonstrated the importance of Muc2, few studies have explored human MUC2 in similar depth. Recent studies have revealed that secreted MUC2 is bound to human feces. We hypothesized human fecal MUC2 (HF-MUC2) was accessible for purification and downstream structural and functional characterization. We tested this via histologic and quantitative imaging on human fecal sections; extraction from feces for proteomic and O-glycomic characterization; and functional studies via growth and metabolic assays in vitro. Quantitative imaging of solid fecal sections showed a continuous mucus layer of varying thickness along human fecal sections with barrier functions intact. Lectin profiling showed HF-MUC2 bound several lectins but was weak to absent for Ulex europaeus 1 (α1,2 fucose-binding) and Sambucus nigra agglutinin (α2,6 sialic acid-binding), and did not have obvious b1/b2 barrier layers. HF-MUC2 separated by electrophoresis showed high molecular weight glycoprotein bands (∼1-2 MDa). Proteomics and Western analysis confirmed the enrichment of MUC2 and potential MUC2-associated proteins in HF-MUC2 extracts. MUC2 O-glycomics revealed diverse fucosylation, moderate sialylation, and little sulfation versus porcine colonic MUC2 and murine fecal Muc2. O-glycans were functional and supported the growth of Bacteroides thetaiotaomicron (B. theta) and short-chain fatty acid (SCFA) production in vitro. MUC2 could be similarly analyzed from inflammatory bowel disease stools, which displayed an altered glycomic profile and differential growth and SCFA production by B. theta versus healthy samples. These studies describe a new non-invasive platform for human MUC2 characterization in health and disease.

Relationship Between Immunophenotypes, Genetic Profiles, and Clinicopathologic Characteristics in Small Bowel Adenocarcinoma.

Small bowel adenocarcinoma (SBA) is rare, and scant data exist regarding its molecular and clinicopathologic characteristics. This study aimed to clarify the correlation between immunophenotypes, DNA mismatch repair status, genomic profiling, and clinicopathologic characteristics in patients with SBA. We examined 68 surgical resections from patients with primary SBA for immunohistochemical analyses of CK7, CK20, CD10, CDX2, MUC1, MUC2, MUC4, MUC5AC, and MUC6 expression as well as mismatch repair status. Genomic profiling was performed on 30 cases using targeted next-generation sequencing. Tumor mucin phenotypes were classified as gastric, intestinal, gastrointestinal, or null based on MUC2, MUC5AC, MUC6, and CD10 immunostaining. The expression of these proteins was categorized into 3 classifications according to their relationship to: (1) tumor location: CK7/CK20, MUC4, and MUC6; (2) histologic type: mucinous adenocarcinoma was positive for MUC2 and negative for MUC6; and (3) TNM stage: CD10 was downregulated, whereas MUC1 was upregulated in advanced TNM stages. CDX2 was a specific marker for SBA generally expressed in the small intestine. MUC1 and MUC4 expression was significantly associated with worse prognosis. MUC2 expression correlated with better prognosis, except for mucinous adenocarcinoma. Although the difference was not statistically significant, gastric-type tumors were more frequently located in the duodenum and were absent in the ileum. APC and CTNNB1 mutations were not found in the gastric-type tumors. The SBA immunophenotype correlated with tumor location, biological behavior, and genomic alterations. Our results suggest that the molecular pathway involved in carcinogenesis of gastric-type SBA differs from that of intestinal-type SBA.

Mucin-Phenotype and Expression of the Protein V-Set and Immunoglobulin Domain Containing 1 (VSIG1): New Insights into Gastric Carcinogenesis.

In gastric cancer (GC), intestinal metaplasia (IM) is a common precursor lesion, but its relationship to the MUC2/MUC5AC/CDX2 axis is not completely understood. Although V-set and immunoglobulin domain containing 1 (VSIG1) is supposed to be a specific marker for gastric mucosa and GC, respectively, no data about its relationship with IM or mucin phenotype have been published. The aim of our study was to explore the possible linkage between IM and these four molecules. The clinicopathological features of 60 randomly selected GCs were examined in association with VSIG1, MUC2, MUC5AC and CDX2. Two online database platforms were also used to establish the transcription factors (TFs) network involved in MUC2/MUC5AC/CDX2 cascade. IM was more frequently encountered in females (11/16 cases) and in patients below 60 years old (10/16 cases). Poorly differentiated (G3) carcinomas tended to show a loss of CDX2 (27/33 cases) but not of MUC2 and MUC5AC. MUC5AC and CDX2 were lost in parallel with the depth of invasion of the pT4 stage (28/35 and 29/35 cases), while an advanced Dukes-MAC-like stage was only correlated with CDX2 and VSIG1 loss (20/37 and 30/37 cases). VSIG1 was directly correlated with MUC5AC (p = 0.04) as an indicator of gastric phenotype. MUC2-negative cases showed a propensity towards lymphatic invasion (37/40 cases) and distant metastases, while CDX2-negative cases tended to associate with hematogenous dissemination (30/40 cases). Regarding the molecular network, only 3 of the 19 TFs involved in this carcinogenic cascade (SP1, RELA, NFKB1) interacted with all targeted genes. In GC, VSIG1 can be considered an indicator of gastric phenotype carcinomas, where carcinogenesis is mainly driven by MUC5AC. Although infrequently encountered in GC, CDX2 positivity might indicate a locally advanced stage and risk for vascular invasion, especially in tumors developed against the background of IM. The loss of VSIG1 indicates a risk for lymph node metastases.

Colonic mucin-2 attenuates acute necrotizing pancreatitis in rats by modulating intestinal homeostasis.

Mucin-2 (MUC2) secreted by goblet cells participates in the intestinal barrier, but its mechanism in acute necrotizing pancreatitis (ANP) remains unclear. In acute pancreatitis (AP) patients, the functions of goblet cells (MUC2, FCGBP, CLCA1, and TFF3) decreased, and MUC2 was negatively correlated with AP severity. ANP rats treated with pilocarpine (PILO) (PILO+ANP rats) to deplete MUC2 showed more serious pancreatic and colonic injuries, goblet cell dysfunction, gut dysbiosis, and bacterial translocation than those of ANP rats. GC-MS analysis of feces showed that PILO+ANP rats had lower levels of butyric acid, isobutyric acid, isovaleric acid, and hexanoic acid than those of ANP rats. The expression of MUC2 was associated with colonic injury and gut dysbiosis. All these phenomena could be relieved, and goblet cell functions were also partially reversed by MUC2 supplementation in ANP rats. TNF-α-treated colonoids had exacerbated goblet cell dysfunction. MUC2 expression was negatively correlated with the levels of pro-inflammatory cytokines (IL-1ß and IL-6) (p < .05) and positively related to the expression of tight junction proteins (Claudin 1, Occludin, and ZO1) (p < .05). Downregulating MUC2 by siRNA increased the levels of the pro-inflammatory cytokines in colonoids. MUC2 might maintain intestinal homeostasis to alleviate ANP.

Age-Related Mucus Barrier Dysfunction in Mice Is Related to the Changes in Muc2 Mucin in the Colon.

During aging, the protective function of mucus barrier is significantly reduced among which changes in colonic mucus barrier function received the most attention. Additionally, the incidence of colon-related diseases increases significantly in adulthood, posing a threat to the health of the elderly. However, the specific changes in colonic mucus barrier with aging and the underlying mechanisms have not been fully elucidated. To understand the effects of aging on the colonic mucus barrier, changes in the colonic mucus layer were evaluated in mice aged 2, 12, 18, and 24 months. Microbial invasion, thickness, and structure of colonic mucus in mice at different months of age were analyzed by in situ hybridization fluorescence staining, AB/PAS staining, and cryo-scanning electron microscopy. Results showed that the aged colon exhibited intestinal mucus barrier dys-function and altered mucus properties. During aging, microorganisms invaded the mucus layer to reach epithelial cells. Compared with young mice, the thickness of mucus layer in aged mice in-creased by 11.66 µm. And the contents of the main components and glycosylation structure of colon changed. Among them, the proportion of goblet cells decreased significantly in older mice, and the expression of spdef genes that regulate goblet cell differentiation decreased. Further, the expression of key enzymes involved in mucin core structure formation and glycan modification also changed with aging. The expression of core 1 ß1,3-galactosyltransferase (C1GalT1) which is the key enzyme forming the main core structure increased by one time, while core 2 ß1,6 N-acetylglucosaminyltransferase (C2GnT) and core 3 ß1,3 N-acetylglucosaminyltransferase (C3GnT) decreased 2 to 6- and 2-fold, respectively. Also, the expression of sialyltransferase, one of the mucin-glycan modifying enzymes, was decreased by 1-fold. Overall, our results indicate that the goblet cells/glycosyltransferase/O-glycan axis plays an important role in maintaining the physicochemical properties of colonic mucus and the stability of intestinal environment.

Mucin-microbiome signatures shape the tumor microenvironment in gastric cancer.

BACKGROUND AND AIMS: We aimed to identify mucin-microbiome signatures shaping the tumor microenvironment in gastric adenocarcinomas and clinical outcomes. METHODS: We performed high-throughput profiling of the mucin phenotypes present in 108 gastric adenocarcinomas and 20 functional dyspepsia cases using validated mucin-based RT-qPCRs with subsequent immunohistochemistry validation and correlated the data with clinical outcome parameters. The gastric microbiota was assessed by 16S rRNA gene sequencing, taxonomy, and community composition determined, microbial networks analyzed, and the metagenome inferred in association with mucin phenotypes and expression. RESULTS: Gastric adenocarcinomas with an intestinal mucin environment or high-level MUC13 expression are associated with poor survival. On the contrary, gastric MUC5AC or MUC6 abundance was associated with a more favorable outcome. The oral taxa Neisseria, Prevotella, and Veillonella had centralities in tumors with intestinal and mixed phenotypes and were associated with MUC13 overexpression, highlighting their role as potential drivers in MUC13 signaling in GC. Furthermore, dense bacterial networks were observed in intestinal and mixed mucin phenotype tumors whereas the lowest community complexity was shown in null mucin phenotype tumors due to higher Helicobacter abundance resulting in a more decreased diversity. Enrichment of oral or intestinal microbes was mucin phenotype dependent. More specifically, intestinal mucin phenotype tumors favored the establishment of pro-inflammatory oral taxa forming strong co-occurrence networks. CONCLUSIONS: Our results emphasize key roles for mucins in gastric cancer prognosis and shaping microbial networks in the tumor microenvironment. Specifically, the enriched oral taxa associated with aberrant MUC13 expression can be potential biomarkers in predicting disease outcomes. Video Abstract.

Orchestration of MUC2 - The key regulatory target of gut barrier and homeostasis: A review.

The gut mucosa of human is covered by mucus, functioning as a crucial defense line for the intestine against external stimuli and pathogens. Mucin2 (MUC2) is a subtype of secretory mucins generated by goblet cells and is the major macromolecular component of mucus. Currently, there is an increasing interest on the investigations of MUC2, noting that its function is far beyond a maintainer of the mucus barrier. Moreover, numerous gut diseases are associated with dysregulated MUC2 production. Appropriate production level of MUC2 and mucus contributes to gut barrier function and homeostasis. The production of MUC2 is regulated by a series of physiological processes, which are orchestrated by various bioactive molecules, signaling pathways and gut microbiota, etc., forming a complex regulatory network. Incorporating the latest findings, this review provided a comprehensive summary of MUC2, including its structure, significance and secretory process. Furthermore, we also summarized the molecular mechanisms of the regulation of MUC2 production aiming to provide developmental directions for future researches on MUC2, which can act as a potential prognostic indicator and targeted therapeutic manipulation for diseases. Collectively, we elucidated the micro-level mechanisms underlying MUC2-related phenotypes, hoping to offer some constructive guidance for intestinal and overall health of mankind.

[Mucins expression in gastric cancer: connection of MUC status with clinical, morphological and prognostic characteristics of the tumor]. / Ekspressiya mutsinov v rake zheludka: svyaz' MUC-statusa s kliniko-morfologicheskimi i prognosticheskimi kharakteristikami opukholi.

OBJECTIVE: Clarification of the prognostic value and relationship of MUC-phenotypes of gastric cancer with clinical and morphological parameters. MATERIAL AND METHODS: Surgical material from 310 patients with a verified diagnosis of gastric cancer was studied. Samples were immunohistochemically stained with antibodies to MUC2, CD10, MUC5AC. The results were compared with clinical and morphological characteristics of gastric cancer and patient survival data. RESULTS: The MUC-null and MUC-mix groups significantly differ in the prevalence of subtotal/total tumors from the MUC-I group (p=0.022 and p=0.007, respectively), where there are significantly fewer such tumors. Tubular tumors were more common in the MUC-null group compared to the MUC-G (p=0.026) and MUC-mix (p=0.006) groups, and there were fewer cases with the presence of "signet-ring" cells in the MUC-null group (p=0.000). When studying the discohesive histological type, the literature data on smaller tumor sizes and a lower frequency of lymph node metastasis for MUC-G status were not confirmed, but a more frequent proximal localization of MUC-I tumors was found (p=0.003). No statistically significant differences in survival were found in the analysis of the total sample. Differences in survival were found only in discohesive cancers, where the best survival was recorded for the MUC-null group, and the worst for the MUC-mix group (p=0.022). MUC status is not an independent predictor of gastric cancer (HR=1.662, p=0.093). CONCLUSION: Between tumors with different MUC statuses, there were differences in localization and belonging to individual histological types. Significant differences in survival were found only for discohesive cancers with MUC-null and MUC-mix statuses. Separation of gastric cancers according to MUC status may have only limited predictive value in selected histological forms of cancer.

Muc2-dependent microbial colonization of the jejunal mucus layer is diet sensitive and confers local resistance to enteric pathogen infection.

Intestinal mucus barriers normally prevent microbial infections but are sensitive to diet-dependent changes in the luminal environment. Here we demonstrate that mice fed a Western-style diet (WSD) suffer regiospecific failure of the mucus barrier in the small intestinal jejunum caused by diet-induced mucus aggregation. Mucus barrier disruption due to either WSD exposure or chromosomal Muc2 deletion results in collapse of the commensal jejunal microbiota, which in turn sensitizes mice to atypical jejunal colonization by the enteric pathogen Citrobacter rodentium. We illustrate the jejunal mucus layer as a microbial habitat, and link the regiospecific mucus dependency of the microbiota to distinctive properties of the jejunal niche. Together, our data demonstrate a symbiotic mucus-microbiota relationship that normally prevents jejunal pathogen colonization, but is highly sensitive to disruption by exposure to a WSD.