Dysbiosis in Crohn's disease - Joint action of stochastic injuries and focal inflammation in the gut

Abstract

Gut homeostasis involves interrelated biological networks that include the immune system, specialized cells of the epithelium, such as Paneth and goblet cells, as well as triggers derived from the microbiota. Disruption of these homeostatic interactions may lead to the pathogenesis of inflammatory bowel diseases (IBD). To develop more targeted and individual treatments in Crohn's disease and ulcerative colitis, it becomes more and more important to link key mechanisms of the disease pathogenesis to distinct IBD subsets. For the first time, our laboratory demonstrated a causal role of the microbiota for the development of Crohn's disease (CD)-like ileitis, supporting the hypothesis that a non-infectious, dysbiotic microbial ecosystem harbors aggressive traits relevant for the induction of chronic inflammation in the disease-susceptible host (i.e. TNFΔARE mouse model). Despite a growing body of evidence claiming a primary role for Paneth cells in the pathogenesis of ileal CD, we showed in the TNFΔARE mouse model that Paneth cell failure or exhaustion is a secondary event to inflammation. Therefore, additional mechanisms may act synergistically to initialize the development of CD-like pathology. Hereby, we propose a novel hypothesis suggesting that individual development of dysbiotic communities is based on stochastic injury and focal inflammation of the epithelial lining that propagate radially, finally leading to an aggressive microbial milieu.

Elevated apoptosis impairs epithelial cell turnover and shortens villi in TNF-driven intestinal inflammation

“…What causes this state to further destabilise and lead to overt clinical pathology resembling IBD in later weeks 4,14 remains to be specifically determined. Strong evidence suggests that the microbiota is an essential driver of IBD development 3,4,14 , which may explain why we detect epithelial alterations in both duodenum and ileum in our chronic setting, whereas subsequent IBD lesions are reported to affect the ileum and ileocolonic region 3,4,14 . Of note is that subclinical lesions detected by confocal endomicroscopy are reported in the duodenum of IBD patients 48 .…”

“…A single exogenous high dose of TNF induces transient intestinal damage with rapid epithelial cell apoptosis, predominantly at villus tips, villus shortening, fluid exudation into the gut lumen, and diarrhoea 8,11–13 . Animal models with persistent elevated TNF exhibit IBD-like inflammatory changes in the mucosa and are widely used to study intestinal chronic inflammatory processes 3,14,15 . Such models reveal the role of epithelial cells as targets and producers of TNF in apoptotic death, leading to barrier breach and ultimately to IBD-like pathology 16–18 .…”

Fecal transplant modifies urine chemistry risk factors for urinary stone disease

“…; Knoll et al. ; Butto and Haller ). Recently, our group provided evidence for an association between the GMB composition and USD (Stern et al.…”

5-Aminosalicylic Acid Alters the Gut Bacterial Microbiota in Patients With Ulcerative Colitis

“…Compared with healthy subjects, an increase in fecal Proteobacteria and a decrease in Firmicutes have been observed in IBD patients; additionally, compared with patients in remission, the mucosae of patients in an active stage were colonized with a higher abundance of Proteobacteria and a lower abundance of Firmicutes ( Liguori et al, 2016 ; Sokol et al, 2016 ). Apart from bacterial imbalance, there are some reports on the intestinal microbiome in IBD patients, including fungal and viral microbiomes ( Li et al, 2014 ; Norman et al, 2015 ; Liguori et al, 2016 ; Sokol et al, 2016 ; Butto and Haller, 2017 ; Hedin et al, 2017 ; Pascal et al, 2017 ).…”