Anti-<i>Helicobacter pylori</i>effect of CaG-NANA, a new sialic acid derivative

Rhee, Yun-Hee; Ku, Hyun-Jeong; Noh, Hye-Ji; Cho, Hyang-Hyun; Kim, Hee-Kyong; Ahn, Jin‐Chul

doi:10.4291/wjgp.v7.i4.300

Cited by 4 publications

(6 citation statements)

References 21 publications

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“…Several lines of evidence point to a central role for bacteria of the Helicobacter genus in our data. A greater abundance of Helicobacter in ST6GAL1-deficient animals is consistent with a number of previous reports demonstrating that soluble sialic acid preparations have direct antibacterial properties towards Helicobacter species both in vitro and in vivo [91][92][93][94] . Although a physiological role for milk-derived sialic acid in protecting the neonate from Helicobacter colonization is plausible, human studies in multiple populations have failed to demonstrate any association between breastfeeding and Helicobacter colonization [131][132][133][134] .…”

Section: Subsequent Work Indicated That Fucosylation Of Enterocytes Psupporting

confidence: 91%

“…In contrast, several Proteobacteria genera were expanded in ST6GAL1-deficient animals, including Helicobacter and Bilophila OTUs (Fig 3e). Helicobacter species, which are wellstudied pathogens in both animals and humans, have been shown to be inhibited by free sialic acid [91][92][93][94] . The bile-metabolizing genus Bilophila, which expands in response to dietary fat intake, was recently identified as a pathobiont, capable of promoting colitis 95,96 .…”

Section: St6gal1 Patterns the Postnatal Gut Microbiomementioning

confidence: 99%

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Bacterial Colonization and Th17 Immunity are Shaped by Intestinal Sialylation in Neonatal Mice

Irons

Gomez

Andersen

et al. 2020

Preprint

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Background: Interactions between the neonate host and its gut microbiome are central to the development of a healthy immune system. However, the mechanisms by which animals alter early colonization of microbiota for their benefit remain unclear. Host-derived carbohydrates, which can serve as metabolic substrates for the expansion of specific commensal and pathogenic bacteria, are one method by which the host may influence interspecies competition in the microbiome. Here, we investigated the role of early-life expression of the α2,6-sialyltransferase ST6GAL1 in microbiome phylogeny and mucosal immunity. Methods: Intestinal sialylation was characterized by RT-qPCR, immunoblot, microscopy, and sialyltransferase enzyme assays in genetic mouse models at rest or with glucocorticoid receptor modulators. The fecal, upper respiratory, and oral microbiomes of pups expressing or lacking St6gal1 were analyzed by 16S rRNA sequencing. Pooled fecal microbiomes from syngeneic donors were transferred to antibiotic-treated wild-type mice, before analysis of recipient mucosal immune responses by flow cytometry, RT-qPCR, microscopy, and ELISA. Results: ST6GAL1 was highly expressed in duodenal enterocytes between birth and weaning, driving temporary sialylation of the associated glycocalyx and secretion of active ST6GAL1 into the intestinal lumen, with subsequent uptake by colonic goblet cells. Expression was mediated by the P1 promoter of the St6gal1 gene, which was efficiently inhibited by intraperitoneal dexamethasone. At weaning, the fecal microbiome of St6gal1-KO pups was unchanged in diversity but exhibited reductions in Clostridium, Coprobacillus, and Adlercreutzia, along with increased Helicobacter and Bilophila. Transfer of St6gal1-KO microbiome induced an AhR-dependent Th17 response, with expression of T-bet and IL-17, and IL-22-dependent gut lengthening. Conclusions: Intestinal sialylation by the sialyltransferase ST6GAL1 in the neonatal period is a developmentally regulated host mechanism coordinating bacterial colonization in the early gut microbiome. The inability to produce α2,6-sialyl ligands results in microbiome-dependent Th17 inflammation, highlighting a pathway by which intestinal epithelium regulates mucosal immunity. Considering the prevalence of intestinal fucosylation in adult animals, sialic acid may promote an early stage of ecological succession in the developing gut. Trial registration: N/A

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Section: Subsequent Work Indicated That Fucosylation Of Enterocytes Psupporting

confidence: 91%

Section: St6gal1 Patterns the Postnatal Gut Microbiomementioning

confidence: 99%

Bacterial Colonization and Th17 Immunity are Shaped by Intestinal Sialylation in Neonatal Mice

Irons

Gomez

Andersen

et al. 2020

Preprint

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“…properties both in vitro and in vivo [101][102][103][104][105][106] . Bile-metabolizing bacteria of the Bilophila genus, which expand in response to dietary fat intake, were recently identified as pathobionts, capable of promoting colitis 99,100 .…”

Section: Discussionmentioning

confidence: 99%

Bacterial colonization and TH17 immunity are shaped by intestinal sialylation in neonatal mice

et al. 2022

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Interactions between the neonate host and its gut microbiome are central to the development of a healthy immune system. However, the mechanisms by which animals alter early colonization of microbiota for their benefit remain unclear. Here, we investigated the role of early-life expression of the α2,6-sialyltransferase ST6GAL1 in microbiome phylogeny and mucosal immunity. Fecal, upper respiratory, and oral microbiomes of pups expressing or lacking St6gal1 were analyzed by 16S rRNA sequencing. At weaning, the fecal microbiome of St6gal1-KO mice had reduced Clostridiodes, Coprobacillus and Adlercreutzia, but increased Helicobacter and Bilophila. Pooled fecal microbiomes from syngeneic donors were transferred to antibiotic-treated wild-type mice, before analysis of recipient mucosal immune responses by flow cytometry, RT-qPCR, microscopy, and ELISA. Transfer of St6gal1-KO microbiome induced a mucosal Th17 response, with expression of T-bet and IL-17, and IL-22-dependent gut lengthening. Early life intestinal sialylation was characterized by RT-qPCR, immunoblot, microscopy, and sialyltransferase enzyme assays in genetic mouse models at rest or with glucocorticoid receptor modulators. St6gal1 expression was greatest in the duodenum, where it was mediated by the P1 promoter and efficiently inhibited by dexamethasone. Our data show that the inability to produce α2,6-sialyl ligands contributes to microbiome-dependent Th17 inflammation, highlighting a pathway by which the intestinal glycosylation regulates mucosal immunity.

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“…We also show an association between ST6GAL1 expression and reduced colonization of Helicobacter and Bilophila species, which are collectively implicated in the pathogenesis of infection, cancer, and metabolic dysfunction [98][99][100] . Interestingly, free sialic acid has been shown to have anti-Helicobacter properties both in vitro and in vivo [101][102][103][104][105][106] . Bile-metabolizing bacteria of the Bilophila genus, which expand in response to dietary fat intake, were recently identified as pathobionts, capable of promoting colitis 99,100 .…”

Section: Discussionmentioning

confidence: 99%

“…A greater abundance of Helicobacter in ST6GAL1-deficient animals is consistent with a number of previous reports demonstrating anti-Helicobacter activity of soluble sialic acid preparations by at least two independent mechanisms. Firstly, sialic acid has direct antibacterial properties towards Helicobacter species both in vitro and in vivo, an effect that is augmented by co-administration of antioxidant catechins [103][104][105][106] . Secondly, sialylated gastrointestinal mucins, particularly those of the stomach, act as decoys for Helicobacter strains expressing the sialic acid binding SabA adhesin by competing with sialylated structures in the gastric epithelial surface necessary for initiating infection [135][136][137][138] .…”

Section: Discussionmentioning

confidence: 99%

Bacterial Colonization and TH17 Immunity are Shaped by Intestinal Sialylation in Neonatal Mice

Irons

Gomez

Andersen

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Interactions between the neonate host and its gut microbiome are central to the development of a healthy immune system. However, the mechanisms by which animals alter early colonization of microbiota for their benefit remain unclear. Host-derived carbohydrates, which can serve as metabolic substrates for the expansion of specific commensal and pathogenic bacteria, are one method by which the host may influence interspecies competition in the microbiome. Here, we investigated the role of early-life expression of the α2,6- sialyltransferase ST6GAL1 in microbiome phylogeny and mucosal immunity. Methods: Fecal, upper respiratory, and oral microbiomes of pups expressing or lacking St6gal1 were analyzed by 16S rRNA sequencing. Pooled fecal microbiomes from syngeneic donors were transferred to antibiotic-treated wild-type mice, before analysis of recipient mucosal immune responses by flow cytometry, RT-qPCR, microscopy, and ELISA. Intestinal sialylation was characterized by RT-qPCR, immunoblot, microscopy, and sialyltransferase enzyme assays in genetic mouse models at rest or with glucocorticoid receptor modulators. Results: At weaning, the fecal microbiome of St6gal1 -KO mice exhibited reductions in Clostridiodes, Coprobacillus, and Adlercreutzia, but increased Helicobacter and Bilophila . Transfer of St6gal1- KO microbiome induced a mucosal Th17 response, with expression of T-bet and IL-17, and IL-22-dependent gut lengthening. ST6GAL1 was found to be highly expressed in duodenal enterocytes between birth and weaning, driving temporary sialylation of the associated glycocalyx and secretion of active ST6GAL1 into the intestinal lumen. Expression was mediated by the P1 promoter of the St6gal1 gene, which was efficiently inhibited by dexamethasone. Conclusions: Intestinal sialylation by the sialyltransferase ST6GAL1 in the neonatal period is a developmentally regulated host mechanism coordinating bacterial colonization in the early gut microbiome. The inability to produce α2,6-sialyl ligands results in microbiome-dependent Th17 inflammation, highlighting a pathway by which intestinal epithelium regulates mucosal immunity. Considering the prevalence of intestinal fucosylation in adult animals, sialic acid may promote an early stage of ecological succession in the developing gut. Trial registration: N/A

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Anti-Helicobacter pylorieffect of CaG-NANA, a new sialic acid derivative

Cited by 4 publications

References 21 publications

Bacterial Colonization and Th17 Immunity are Shaped by Intestinal Sialylation in Neonatal Mice

Bacterial Colonization and Th17 Immunity are Shaped by Intestinal Sialylation in Neonatal Mice

Bacterial colonization and TH17 immunity are shaped by intestinal sialylation in neonatal mice

Bacterial Colonization and TH17 Immunity are Shaped by Intestinal Sialylation in Neonatal Mice

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