Glycosylation in a Common Mechanism of Colitis and Sepsis

Abstract

Glycosylation is a post‐translation modification common to proteins produced in the secretory pathway. In the bloodstream and at cell surfaces, glycan structures operate in multiple processes including the determination of protein half‐life, abundance, and function. Disruption of the normal mammalian N‐glycan repertoire can occur in part from acquired environmental and metabolic factors, and are responsible for the pathogenesis of multiple common diseases including autoimmunity, diabetes, colitis, and sepsis. Microbial infections are common throughout mammalian lifespan and can be life‐threatening as in the case of sepsis. Bacterial pathogens have also been considered as a possible environmental triggers precipitating chronic diseases including the human inflammatory bowel diseases (IBDs). For example, seasonal bacterial infections have been associated with increases in clinical diagnoses of IBD. To test the possibility that recurrent self‐resolving bacterial infections may trigger chronic disease, we developed a mouse model of recurrent human food poisoning using low‐titer non‐lethal gastric infections of Gram‐negative Salmonella enterica Typhimurium (ST). The ST pathogen produces a greater human disease burden than any other foodborne bacterial pathogen in the United States and is endemic throughout the world. Although the mouse rapidly cleared multiple recurrent low titer ST infections, colitis developed after several months, escalating in severity and failing to resolve after the cessation of infection. ST progressively disabled a mechanism of host protection by inducing intestinal neuraminidase activity with Neu3 gene induction among duodenal enterocytes. This accelerated the rate of molecular aging of intestinal alkaline phosphatase (IAP) measured by extent of de‐sialylation and led to its rapid endocytic clearance, thereby diminishing IAP levels in the small intestine and colon. Pathogenesis required host Tlr4 function through neuraminidase induction which was deleterious to the host as IAP deficiency increased the abundance of the LPS‐phosphate endotoxin in the colon. Oral administration of IAP or the marketed anti‐viral neuraminidase inhibitor Zanamivir were therapeutic reducing both LPS‐phosphate and inflammatory tissue damage. Humans with IBD have been reported with low IAP levels, while IAP‐null humans develop IBD. In both mouse and human colitis studies, IAP augmentation is remarkably therapeutic. This pathogenic mechanism emanating from altered protein glycosylation may be a trigger of one or more forms of IBD among the human population. In related studies where the ST pathogen gains access to the bloodstream in sepsis, we discovered a similar mechanism operating among Gram‐negative pathogens including ST and E. coli (EC). Both pathogens operated through Tlr4 to increase host neuraminidases Neu1 and Neu3 in the bloodstream, and thereby diminished alkaline phosphatase activities via endocytic clearance by the Ashwell‐Morell receptor of hepatocytes. These findings reveal a similar pathogenic process operating among ST and EC pathogens to subvert host protection by diminishing the expression of anti‐inflammatory enzymes. These findings further support published data and rationale for clinical trials augmenting alkaline phosphatase activity in sepsis and IBD patients.Support or Funding InformationNIH DK048247; HL131474; HL125352; AI141394