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Glycans form a highly variable constituent of our mucosal surfaces and profoundly affect our susceptibility to infection and disease. The diversity and importance of these surface glycans can be seen in individuals who lack a functional copy of the fucosyltransferase gene, FUT2 . Representing around one-fifth of the population, these individuals have an altered susceptibility to many bacterial and viral infections and diseases. The mediation of host–pathogen interactions by mucosal glycans, such as those added by FUT2, is poorly understood. We highlight, with specific examples, important mechanisms by which host glycans influence infection dynamics, including by: acting as pathogen receptors (or receptor-decoys), promoting microbial stability, altering the physical characteristics of mucus, and acting as immunological markers. We argue that the effect glycans have on infection dynamics has profound implications for many aspects of healthcare and policy, including clinical management, outbreak control, and vaccination policy. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests that microbiome-host crosstalk regulates intestinal immune activity and predisposition to inflammatory bowel disease (IBD). NF-κB is a master regulator of immune function and a validated target for the treatment of IBD. Here, we identify five Clostridium strains that suppress immune-mediated NF-κB activation in epithelial cell lines, PBMCs, and gut epithelial organoids from healthy human subjects and patients with IBD. Cell-free culture supernatant from Clostridium bolteae AHG0001 strain, but not the reference C. bolteae BAA-613 strain, suppresses inflammatory responses and endoplasmic reticulum stress in gut epithelial organoids derived from Winnie mice. The in vivo responses to Clostridium bolteae AHG0001 and BAA-613 mirror the in vitro activity. Thus, using our in vitro screening of bacteria capable of suppressing NF-κB in the context of IBD and using an ex vivo organoid-based approach, we identify a strain capable of alleviating colitis in a relevant pre-clinical animal model of IBD. [Display omitted] • Select strains of Clostridium from human stool samples can suppress NF-κB activation • The immunomodulatory effect of bacteria can be strain- and media-specific • Inter-patient variation suggests possible development of personalized medicine • In vitro immunosuppression assays using organoids predict in vivo activity The ability of gut bacteria to modulate inflammation remains cryptic. Using anaerobic cultures, Giri et al. identify multiple Firmicutes-affiliated bacteria capable of reducing NF-κB-mediated inflammatory signaling in a strain-dependent manner. Cell-free culture supernatants reduce inflammation in patient-derived organoids and in a pre-clinical model of colitis. [ABSTRACT FROM AUTHOR]

Background & Aims: The MUC1 mucin is expressed on the cell surface of epithelial cells lining the gastric mucosa. Epidemiologic studies suggest that functional allelic variations in the MUC1 gene may play a role in human susceptibility to Helicobacter pylori-associated pathologies, including gastric adenocarcinoma. We have evaluated the impact of Muc1 expression on the colonization and pathogenesis of gastric Helicobacter infections. Methods: Wild-type and Muc1-deficient mice were infected with H pylori and colonization and gastritis levels determined. Primary gastric cells were used to examine the impact of Muc1 expression on bacterial adherence. Results: Mice lacking Muc1 were colonized by 5-fold more H pylori within 1 day of infection, and this difference was maintained for at least 2 months postinfection. Mice heterozygous for the null Muc1 allele developed intermediate bacterial colonization. Although wild-type mice developed only a mild gastritis when infected for 2 months with H pylori, Muc1−/− mice developed an atrophic gastritis marked by loss of parietal cells. We demonstrate H pylori adhesion to purified MUC1 and significantly increased adhesion to cultured murine Muc1 null gastric epithelial cells, suggesting that Muc1 acts as a decoy limiting binding to the cell surface. Conclusions: Muc1 provides a protective barrier, which limits both acute and chronic colonization by H pylori, as well as playing a major role in limiting the inflammation induced by Helicobacter infection. We propose that Muc1 restricts access of H pylori to the epithelial surface, hence reducing exposure of the host to proinflammatory bacterial products. [Copyright &y& Elsevier]

Summary: Mucins are complex mucosal glycoproteins that can be highly expressed by adenocarcinomas, having diagnostic, therapeutic, and biological significance. MUC13 encodes a cell surface membrane-anchored mucin expressed in the normal gastrointestinal tract, trachea, and kidney as well as colorectal, esophageal, gastric, pancreatic, and lung cancers. MUC13 protein expression was determined immunohistochemically in 99 sporadic colorectal cancers, assessing proportion of tumor cells stained, stain intensity, and localization. In normal colon, intense apical membrane and variable cytoplasmic MUC13 staining was present in both goblet and columnar cells, with strongest reactivity in the upper crypts and surface epithelium. All cancers showed staining of most tumor cells, being most conspicuous in the apical membranes of gland spaces. Left-sided tumors had a higher overall proportion of MUC13-positive tumor cells than right-sided tumors (P < .05), and high staining intensity was more frequent in adenocarcinomas (81%) than mucinous tumors (50%) (P < .05). Poorly differentiated and late-stage tumors were more likely to have high-intensity cytoplasmic staining (P ≤ .025). Basolateral cell membranes were stained in 24% of cases, being more common in poorly differentiated tumors (55%) than well or moderately differentiated tumors (16%) (P ≤ .001). Partial or full circumferential MUC13 staining was frequently observed in areas of tumor budding. Although MUC13 immunoreactivity was not predictive of patient outcome, there was a trend toward poorer outcome in patients with tumors showing basolateral MUC13. In summary, MUC13 was expressed abundantly by all colorectal cancers, with the highest expression in more poorly differentiated tumors. [Copyright &y& Elsevier]

Background & Aims: Protein misfolding and endoplasmic reticulum (ER) stress have been observed in intestinal secretory cells from patients with inflammatory bowel diseases and induce intestinal inflammation in mice. However, it is not clear how immune factors affect ER stress and therefore disease symptoms. Methods: We analyzed the effects of interleukin (IL)-10 on ER stress in intestinal tissues in wild-type C57BL/6, Winnie, IL-10 −/− , and Winnie × IL-10 +/− mice. In Winnie mice, misfolding of the intestinal mucin Muc2 initiates ER stress and inflammation. We also analyzed the effects of different inhibitors of IL-10 signaling and the N-glycosylation inhibitor tunicamycin in cultured human LS174T goblet cells. Results: Administration of neutralizing antibodies against IL-10 or its receptor (IL-10R1) to Winnie mice rapidly exacerbated ER stress and intestinal inflammation compared with mice given vehicle (controls). Antibodies against IL-10 also increased accumulation of misfolded Muc2 in the ER of goblet cells of Winnie mice and increased T-cell production of inflammatory cytokines. Winnie × IL-10 +/− mice and IL-10 −/− mice with a single Winnie allele each developed more severe inflammation than Winnie mice or IL-10 −/− mice. Administration of tunicamycin to wild-type mice caused intestinal ER stress, which increased when IL-10R1 was blocked. In LS174T cells, induction of ER stress with tunicamycin and misfolding of MUC2 were reduced by administration of IL-10; this reduction required STAT1 and STAT3. In LS174T cells incubated with tunicamycin, IL-10 up-regulated genes involved in MUC2 folding and in ER-associated degradation and maintained correct folding of MUC2, its transport from the ER, and its O-glycosylation and secretion. Conclusions: IL-10 prevents protein misfolding and ER stress by maintaining mucin production in goblet cells and helps the intestine preserve the mucus barrier. [Copyright &y& Elsevier]

Mucin 1 is a cell-membrane associated mucin, expressed on epithelial and immune cells that helps protect against pathogenic infections. In humans, MUC1 is highly polymorphic, predominantly due to the presence of a variable number tandem repeat (VNTR) region in the extracellular domain that results in MUC1 molecules of typically either short or long length. A genetic link is known between these MUC1 polymorphisms and inflammation-driven diseases, although the mechanism is not fully understood. We previously showed that MUC1 on murine macrophages specifically restricts activation of the NLRP3 inflammasome, thereby repressing inflammation. This study evaluated the effect of MUC1 VNTR polymorphisms on activity of the NLRP3 inflammasome in human macrophages, finding that long MUC1 alleles correlated with increased IL-1β production following NLRP3 inflammasome activation. This indicates that the length of MUC1 can influence IL-1β production, thus providing the first evidence of an immune-modulatory role of MUC1 VNTR polymorphisms in human macrophages. [ABSTRACT FROM AUTHOR]

Abstract: Selenoproteins are candidate mediators of selenium-dependent protection against tumorigenesis and inflammation in the gut. Expression and roles of only a limited number of intestinal selenoproteins have been described so far. Selenoprotein S (SelS) has been linked to various inflammatory diseases and is suggested to be involved in endoplasmic reticulum (ER) homeostasis regulation and antioxidative protection in a cell-type-dependent manner, but its protein expression, regulation, and function in the gut are not known. We here analyzed the expression and localization of SelS in the healthy and inflamed gut and studied its regulation and function in intestinal epithelial cell lines. SelS was expressed in the intestinal epithelium of the small and large intestine and colocalized with markers of Paneth cells and macrophages. It was upregulated in inflamed ileal tissue from Crohn's disease patients and in two models of experimental colitis in mice. We detected SelS in colorectal cell lines, where it colocalized with the ER marker calnexin. SelS protein expression was unaffected by enterocytic differentiation but increased in response to selenium supplementation and after treatment with the ER stress inducer tunicamycin. On the other hand, depletion of SelS in LS174T, HT29, and Caco-2 cells by RNA interference did not cause or modulate ER stress and had no effect on hydrogen peroxide-induced cell death. In summary, we introduce SelS as a novel marker of Paneth cells and intestinal ER stress. Although it is upregulated in Crohn's disease, its role in disease etiology remains to be established. [Copyright &y& Elsevier]

Abstract: Enteroendocrine cells of the gastric fundus are the predominant source of ghrelin production, although ghrelin gene transcripts and ghrelin-producing cells have been identified throughout the gastrointestinal tract. Various infectious, inflammatory and malignant disorders of the gastrointestinal system have been shown to alter ghrelin production and secretion and consequently to affect endocrine ghrelin levels and activity. Animal studies have demonstrated that ghrelin and synthetic ghrelin mimetics can reduce the severity of gastric and colonic inflammation and human clinical trials are underway to determine the efficacy of ghrelin in improving motility disorders. This review summarises the impact of gastrointestinal disease on ghrelin synthesis and secretion and the potential use of ghrelin and its mimetics for the treatment of these diseases. [Copyright &y& Elsevier]