Main text
Sialylation is a post-translational modification, catalyzed by
sialyltransferases, that consists of the addition of sialic acid to
oligosaccharides, glycoproteins or glycosphingolipids. ST6GALNAC1 (ST6)
is a sialyltransferase predominantly expressed in intestinal goblet
cells. Goblet cells produce intestinal mucus, which has emerged as a key
player in oral tolerance to food antigens1. The
hyperglycosylated Mucin-2 (MUC2) is the major component of intestinal
mucus2 and is susceptible to undergoing
post-translational modifications. Along this line, Yao et
al. 3 studied the contribution of ST6-mediated glycan
sialylation of intestinal mucus to barrier integrity, host-commensal
homeostasis and inflammation.
Certain gut bacteria, mainly
pathogens, can evolve to produce a range of mucin-hydrolyzing enzymes
(i.e. , mucinases)4. Yao et
al. 3 demonstrated that ST6-mediated sialylation
protects MUC2 against degradation by certain bacterial-secreted
mucinases (i.e., Escherichia coli and Akkermansia
muciniphila proteases), thus maintaining mucus integrity
(Figure 1 ). Unraveling the stability of sialylated mucus
against different gut bacteria may lead to the identification of
potentially harmful species. Furthermore, it could be interesting to
assess if this modification protects against mucinases secreted by
pathogens such as the enterotoxigenic Escherichia coli orVibrio cholerae .
This work also revealed
that St6- deficient mice were more susceptible to dextran sulfate
sodium (DSS)-induced colitis as compared to wild-type (WT) mice.
Thickening of the mucus barrier accompanied by a marked improvement in
colitis markers was observed in St6 -deficient mice following
mucin administration. Moreover, antibiotic treatment ofSt6 -deficient mice prior to DSS administration eliminated the
difference in disease severity between WT and St6- deficient mice.
The authors concluded that ST6 is essential for the mucus barrier that
prevents bacterial translocation and inflammation. By comparing the
fecal microbiota in WT and St6 -deficient mice, it was observed
that the latter had a less diverse microbiome with increasedAkkermansiaceae and Ruminococcaceae taxa (Figure
1 ). These taxa are important producers of short-chain fatty acids
(SCFA) (i.e. , butyrate, acetate, propionate), metabolites mainly
produced by bacterial fermentation of dietary fibers and resistant
starch. The excess of butyrate in stool samples, as a result of the
alteration of the gut microbiota, impaired intestinal stem cell
proliferation delaying mucus reparation during DSS colitis inSt6- deficient mice. Further investigation on the levels of
butyrate could inform of its importance in the severity of mucus damage;
however, it should bear in mind that fecal SCFA levels are not
necessarily representative of intestinal luminal SCFA content.
Moreover, to investigate the role of ST6 in humans, Yao et
al3 examined individuals from three families with
very early-onset intestinal bowel disease (i.e ., colitis).
Remarkably, different mutations were found in all families affecting
conserved amino acids in ST6 that likely compromise its activity.
Additional studies with larger cohorts of autoimmune and allergic
patients could shed some light on potential correlations between ST6
mutations and clinical outcome.
Due to the important role of ST6 in barrier integrity and the novel
hypothesis on the epithelial barrier and type 2
responses,5 it would be relevant to investigate the
role of ST6 in allergic sensitization. A deficiency or mutation on ST6
jeopardizes mucus barrier reparation during DSS colitis, so this
scenario could be prone to induce sensitization to bystander allergens
(Figure 1 ). Finally, IgE sialylation has been reported as an
important regulator of anaphylaxis6,7. Given that
sialylation is a highly specific and local glycomodification, it would
be interesting to investigate ST6 expression in other tissues, and its
protective role in other mucosal tissues.
Figure 1 legend . ST6-mediated sialylation protects MUC2 against
mucinase degradation maintaining mucus integrity. ST6-deficiency impairs
the microbiome homeostasis and promotes an increase ofAkkermansiaceae and Ruminococcaceae taxa, reducing the
microbiome diversity. These bacteria are producers of butyrate, which
delays intestinal stem cell proliferation. This also induces mucus
damage which may promote a release of cytokines and alarmins. The
interrogation in the label of food allergens refers to the unknown role
of ST6 in allergic sensitization. Wild-type, WT; ST6GALNAC1, ST6;
mucin-2, MUC-2; short-chain fatty acids, SCFAs.