Helicobacter pylori chronic infection and mucosal inflammation switches the human gastric glycosylation pathways

Abstract

Helicobacter pylori exploits host glycoconjugates to colonize the gastric niche. Infection can persist for decades promoting chronic inflammation, and in a subset of individuals lesions can silently progress to cancer. This study shows that H. pylori chronic infection and gastric tissue inflammation result in a remodeling of the gastric glycophenotype with increased expression of sialyl-Lewis a/x antigens due to transcriptional up-regulation of the B3GNT5, B3GALT5, and FUT3 genes. We observed that H. pylori infected individuals present a marked gastric local proinflammatory signature with significantly higher TNF-α levels and demonstrated that TNF-induced activation of the NF-kappaB pathway results in B3GNT5 transcriptional up-regulation. Furthermore, we show that this gastric glycosylation shift, characterized by increased sialylation patterns, favors SabA-mediated H. pylori attachment to human inflamed gastric mucosa. This study provides novel clinically relevant insights into the regulatory mechanisms underlying H. pylori modulation of host glycosylation machinery, and phenotypic alterations crucial for life-long infection. Moreover, the biosynthetic pathways here identified as responsible for gastric mucosa increased sialylation, in response to H. pylori infection, can be exploited as drug targets for hindering bacteria adhesion and counteract the infection chronicity.

Altered (neo-) lacto series glycolipid biosynthesis impairs α2-6 sialylation on N-glycoproteins in ovarian cancer cells

“…In regards to pathogenic infections, it has been previously shown that Helicobacter pylori induces B3GNT5 expression and that the ABO(H)/Lewis blood group antigens expressed in H. pylori - infected individuals act as receptors for BabA, thereby facilitating colonization of the gastric niche33. Likewise, the Shiga toxin from urinary tract infection-causing enterohemorrhagic E. coli was shown to recognize the terminal epitope of P 1 , Galα1-4Galβ1-4 following internalization of the toxin by receptor-mediated endocytosis34.…”

Glycosylation in cancer: mechanisms and clinical implications

“…The antigen-binding adhesin BabA binds to fucosylated antigens normally expressed by secretor individuals 212 , and the sialic acid-binding adhesin SabA recognizes sialylated Lewis glycans (sialyl Lewis a (SLe a ) and SLe x ) expressed in gastritis 213 . Inflammation-induced glycosylation alterations, such as the aberrant overexpression of SLe x , occur because of changes in glycosyltransferases expression 59,60,214 . Changes in glycosylation have also been studied in acute-phase proteins, such as α1 antitrypsin, as potential biomarkers in cancer and in acute and chronic inflammatory conditions 215 .…”

The Densely O-Glycosylated MUC2 Mucin Protects the Intestine and Provides Food for the Commensal Bacteria

“…The glycan changes are caused by transcriptional up-regulation of the B3GNT5, B3GALT5, and FUT3 genes [73]. …”