Intestinal Muc2 mucin O-glycosylation is affected by microbiota and regulated by differential expression of glycosyltranferases

Arike, Liisa; Holmén-Larsson, Jessica; Hansson, Gunnar C.

doi:10.1093/glycob/cww134

Cited by 107 publications

(159 citation statements)

References 43 publications

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“…Glycosylation of the intestinal mucus and epithelium is quite complex and can change in response to microbial colonization. 60 This is interesting because host glycans can serve as nutrient sources or adhesion receptors for microbes, including pathogens. One glycosylation modification, α(1,2)fucosylation, is especially intriguing.…”

Section: Mucus and Glycosylationmentioning

confidence: 99%

Gut microbiota: Role in pathogen colonization, immune responses, and inflammatory disease

Pickard

Zeng

Caruso

et al. 2017

Immunological Reviews

1,177

823

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Summary The intestinal tract of mammals is colonized by a large number of microorganisms including trillions of bacteria that are referred to collectively as the gut microbiota. These indigenous microorganisms have co-evolved with the host in a symbiotic relationship. In addition to metabolic benefits, symbiotic bacteria provide the host with several functions that promote immune homeostasis, immune responses and protection against pathogen colonization. The ability of symbiotic bacteria to inhibit pathogen colonization is mediated via several mechanisms including direct killing, competition for limited nutrients and enhancement of immune responses. Pathogens have evolved strategies to promote their replication in the presence of the gut microbiota. Perturbation of the gut microbiota structure by environmental and genetic factors increases the risk of pathogen infection, promotes the overgrowth of harmful pathobionts, and the development of inflammatory disease. Understanding the interaction of the microbiota with pathogens and the immune system will provide critical insight into the pathogenesis of disease and the development of strategies to prevent and treat inflammatory disease.

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Section: Mucus and Glycosylationmentioning

confidence: 99%

Gut microbiota: Role in pathogen colonization, immune responses, and inflammatory disease

Pickard

Zeng

Caruso

et al. 2017

Immunological Reviews

1,177

823

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“…The number of mucus-producing goblet cells does not decline in specialized follicle-associated epithelium in aged mice [20]. The mucus protein composition is relatively homogeneous along the intestine; however, the main mucin component synthesized and secreted by intestinal goblet cells, MUC2, shows region specific O-glycan patterns [21,22].…”

Section: Clostridium Perfringens Coliforms Enterococci [1] Streptomentioning

confidence: 99%

The pleiotropic effects of prebiotic galacto-oligosaccharides on the aging gut

Arnold

Roach

Fabela

et al. 2020

Preprint

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Background: Prebiotic galacto-oligosaccharides (GOS) have an extensively demonstrated beneficial impact on intestinal health. In this study, we determined the mechanistic impact of GOS diets on hallmarks of gut aging: microbiome dysbiosis, inflammation, and intestinal barrier defects (“leaky gut”). We also evaluated if short-term GOS feeding influenced how the aging gut responded to antibiotic challenges, since these interventions are common and relevant in older adults. Finally, we assessed the ability of colonic organoids to reproduce in vivo responses to GOS.Results: Old animals had a distinct microbiome characterized by lower diversity, increased ratios of non-saccharolytic versus saccharolytic bacteria and lower abundance of O-Glycosyl hydrolases . GOS treatment increased abundance of non-saccharolytic ( Akkermansia muciniphila ) and saccharolytic bacteria (species of Bacteroides and Lactobacillus ), and increased the abundance of β-galactosidases and β-glucosidases in young and old animals . Clyndamicin treatment reduced the abundance of beneficial bacteria including Bifidobacterium and Lactobacillus , while increasing Akkermansia, Clostridium, Coprococcus, Enterococcus, Bacillus, Bacteroides, and Paenibacillus . Prebiotics impacted the effects of the antibiotics decreasing the abundance of Akkermansia in the GOS-antibiotic groups compared to the control-antibiotics groups. GOS reduced the age-associated increased intestinal permeability via increased MUC2 expression and mucus biosynthesis. T ranscriptomics analysis of colon from old animals fed GOS diets showed increased expression of genes involved in small molecule metabolic processes and specifically the respirasome, which could indicate an increased oxidative metabolism and energetic efficiency. In young mice, GOS induced expression of binding-related genes and the galectin gene Lgals1 , a β-galactosyl-binding lectin that bridges molecules by their sugar moieties, forming a signaling and adhesion network. Further analysis showed higher expression levels of genes in focal adhesion, PI3K-Akt and ECM-receptor interaction pathways. GOS reduced the expression of TNF  in old animals, and altered serum levels of inflammatory biomarkers IL-6, IL-17, IP-10 and Eotaxin. Stools from young mice exhibiting variable bifidogenic response to GOS, injected into colon organoids in the presence of prebiotics, reproduced the response and non-response phenotypes.Conclusions: GOS modulation of intestinal homeostasis likely occurs through direct GOS-host interactions via modulation of host gene expression and mucus production, as well as through interactions mediated by the gut microbiota that result in increased or restored saccharolytic potential.

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“…72 For example, the Asn-420-Gln mutant EGFR did not bind to the EGF ligand, but spontaneously induced oligomerization, resulting F I G U R E 7 The cross-restoration of ST3GAL3, ST3GAL4, or ST3GAL6 in ST3GAL6 KO cells differed in the alteration of sialylation in target proteins. 23,34,[74][75][76] Most sialytransferases modify proteins in the Golgi apparatus. Equal amounts of cell lysates as indicated were immunoprecipitated with MAM-agarose or SSA-agarose for 1 hour at 4°C with rotation, and then the immunoprecipitates were washed twice with lysis buffer and subjected to SDS-PAGE.…”

Section: Qi Et Almentioning

confidence: 99%

ST3GAL3, ST3GAL4, and ST3GAL6 differ in their regulation of biological functions via the specificities for the α2,3‐sialylation of target proteins

Isaji

Duan

et al. 2019

FASEB j.

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The α2,3‐sialylation of N‐glycans is considered important but complicated because the functions of the three β‐galactoside α2,3‐sialyltransferases, ST3GAL3, ST3GAL4, and ST3GAL6, could be compensating for one another. To distinguish their specific functions, we established each individual knockout (KO) cell line. Loss of either the ST3GAL3 or ST3GAL6 genes decreased cell proliferation and colony formation, as opposed to the effect in the ST3GAL4 KO cells. The phosphorylation levels of ERK and AKT were significantly suppressed in the ST3GAL6 KO and ST3GAL3 KO cells, respectively. The cell aggregations were clearly observed in the KO cells, particularly the ST3GAL3 KO and ST3GAL6 KO cells, and the expression levels of E‐cadherin and claudin‐1 were enhanced in both those cell lines, but were suppressed in the ST3GAL4 KO cells. Those alterations were reversed with an overexpression of each corresponding gene in rescued cells. Of particular interest, the α2,3‐sialylation levels of β1 integrin were clearly suppressed in the ST3GAL4 KO cells, but these were increased in the ST3GAL3 KO and ST3GAL6 KO cells, whereas the α2,3‐sialylation levels of EGFR were significantly decreased in the ST3GAL6 KO cells. The decrease in α2,3‐sialylation increased the α2,6‐sialylation on β1, but not EGFR. Furthermore, a cross‐restoration of each of the three genes in ST3GAL6 KO cells showed that overexpression of ST3GAL6 sufficiently rescued the total α2,3‐sialylation levels, cell morphology, and α2,3‐sialylation of EGFR, whereas the α2,3‐sialylation levels of β1 were greatly enhanced by an overexpression of ST3GAL4. These results clearly demonstrate that the three α2,3‐sialyltransferases modify characteristic target proteins and regulate cell biological functions in different ways.

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Intestinal Muc2 mucin O-glycosylation is affected by microbiota and regulated by differential expression of glycosyltranferases

Cited by 107 publications

References 43 publications

Gut microbiota: Role in pathogen colonization, immune responses, and inflammatory disease

Gut microbiota: Role in pathogen colonization, immune responses, and inflammatory disease

The pleiotropic effects of prebiotic galacto-oligosaccharides on the aging gut

ST3GAL3, ST3GAL4, and ST3GAL6 differ in their regulation of biological functions via the specificities for the α2,3‐sialylation of target proteins

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