Duodenal bacterial proteolytic activity determines sensitivity to dietary antigen through protease-activated receptor-2.
Caminero A, McCarville JL, Galipeau HJ, Deraison C, Bernier SP, Constante M, Rolland C, Meisel M, Murray JA, Yu XB, Alaedini A, Coombes BK, Bercik P, Southward CM, Ruf W, Jabri B, Chirdo FG, Casqueiro J, Surette MG, Vergnolle N, Verdu EF
Nat Commun. 03 2019. doi: 10.1038/s41467-019-09037-9
COMMENT: Celiac disease (CeD) is an autoimmune disorder of the small intestine caused by gluten induced inflammation in some individuals susceptible to genetic and environmental influences. Some pathogenic bacteria isolated from the duodenum of CeD patients have the ability to metabolize gluten into shorter immunogenic peptides that could promote sensitivity in a predisposed host. Authors in this work analyze if the proteases produced by these pathogens can independently disrupt host inflammatory pathways relevant for the generation of sensitivity to dietary protein antigens.
To study the proteolytic activity against gluten peptides in duodenal biopsies from patiens with active celiac disease (CeD) and healthy controls.
Biopsies from CeD patients produced a larger hydrolytic halo in solid gluten-containing media compared with biopsies from controls (...). At the genus level, increased glutenasic activity correlated with an increase in Proteobacteria such as Pseudomonas and Janthinobacterium and a reduction in core members of the duodenal microbiota, such as Lactobacillus and Clostridium. These results suggest an association between the small intestinal glutenasic profile in patients with CeD and the relative abundance of certain duodenal microbial groups, notably gluten degrading bacteria such as Pseudomonas.
In C57BL/6 mice, LasB (gluten-degrading protease elastase) is associated with higher IEL counts and altered small intestinal microbiota profiles, in the absence of significant mucosal damage.
LasB-producing P. aeruginosa is sufficient to promote a widespread pro-inflammatory molecular signature in the IEL compartment of the duodenum.
Proteolytic cleavage of PAR-2 receptor is key for the IEL responses induced by bacterial elastase.
The increased small intestinal microbial glutenasic activity in CeD patients can be transferred to germ-free mice where it associates with higher IEL counts.
Correction of bacterial proteolytic imbalance in the small intestine may constitute a new therapeutic target to prevent or ameliorate food sensitivities triggered by specific protein antigens.