Enteric bacterial proteases in inflammatory bowel diseasepathophysiology and clinical implications

Numerous reports have identified a dysbiosis in the intestinal microbiota in patients suffering from inflammatory bowel diseases(IBD),yet the mechanism(s)in which this complex microbial community initiates or perpetuates inflammation remains unclear.The purpose of this review is to present evidence for one such mechanism that implicates enteric microbial derived proteases in the pathogenesis of IBD.We highlight and discuss studies demonstrating that proteases and protease receptors are abundant in the digestive system.Additionally,we investigate studies demonstrating an association between increased luminal protease activity and activation of protease receptors,ultimately resulting in increased intestinal permeability and exacerbation of colitis in animal models as well as in human IBD.Proteases are essential for the normal functioning of bacteria and in some cases can serve as virulence factors for pathogenic bacteria.Although not classified as traditional virulence factors,proteases originating from commensal enteric bacteria also have a potential association with intestinal inflammation via increased enteric permeability.Reports of increased protease activity in stools from IBD patients support a possible mechanism for a dysbiotic enteric microbiota in IBD.A better understanding of these pathways and characterization of the enteric bacteria involved,their proteases,and protease receptors may pave the way for new therapeutic approaches for these diseases.

Development and validation of a registry-based definition of eosinophilic esophagitis in Denmark

AIM:To develop and validate a case definition of eosinophilic esophagitis(EoE) in the linked Danish health registries.METHODS:For case definition development,we queried the Danish medical registries from 2006-2007 to identify candidate cases of EoE in Northern Denmark.All International Classification of Diseases-10(ICD-10) and prescription codes were obtained,and archived pathology slides were obtained and re-reviewed to determine case status.We used an iterative process to select inclusion/exclusion codes,refine the case definition,and optimize sensitivity and specificity.We then re-queried the registries from 2008-2009 to yield a validation set.The case definition algorithm was applied,and sensitivity and specificity were calculated.RESULTS:Of the 51 and 49 candidate cases identified in both the development and validation sets,21 and 24 had EoE,respectively.Characteristics of EoE cases in the development set [mean age 35 years;76% male;86% dysphagia;103 eosinophils per high-power field(eos/hpf)] were similar to those in the validation set(mean age 42 years;83% male;67% dysphagia;77 eos/hpf).Re-review of archived slides confirmed that the pathology coding for esophageal eosinophilia was correct in greater than 90% of cases.Two registrybased case algorithms based on pathology,ICD-10,and pharmacy codes were successfully generated in the development set,one that was sensitive(90%) and one that was specific(97%).When these algorithms were applied to the validation set,they remained sensitive(88%) and specific(96%).CONCLUSION:Two registry-based definitions,one highly sensitive and one highly specific,were developed and validated for the linked Danish national health databases,making future population-based studies feasible.

Bone loss with aging is independent of gut microbiome in mice

Emerging evidence suggests a significant role of gut microbiome in bone health.Aging is well recognized as a crucial factor influencing the gut microbiome.In this study,we investigated whether age-dependent microbial change contributes to age-related bone loss in CB6F1 mice.The bone phenotype of 24-month-old germ-free(GF)mice was indistinguishable compared to their littermates colonized by fecal transplant at 1-month-old.Moreover,bone loss from 3 to 24-month-old was comparable between GF and specific pathogen-free(SPF)mice.Thus,GF mice were not protected from age-related bone loss.16S rRNA gene sequencing of fecal samples from 3-month and 24-month-old SPF males indicated an age-dependent microbial shift with an alteration in energy and nutrient metabolism potential.An integrative analysis of 16S predicted metagenome function and LC-MS fecal metabolome revealed an enrichment of protein and amino acid biosynthesis pathways in aged mice.Microbial S-adenosyl methionine metabolism was increased in the aged mice,which has previously been associated with the host aging process.Collectively,aging caused microbial taxonomic and functional alteration in mice.To demonstrate the functional importance of young and old microbiome to bone,we colonized GF mice with fecal microbiome from 3-month or 24-month-old SPF donor mice for 1 and 8 months.The effect of microbial colonization on bone phenotypes was independent of the microbiome donors’age.In conclusion,our study indicates age-related bone loss occurs independent of gut microbiome.