Mechanisms of Microbe–Host Interaction in Crohn’s Disease: Dysbiosis vs. Pathobiont Selection

Abstract

Crohn’s disease (CD) is a systemic chronic inflammatory condition mainly characterized by discontinuous transmural pathology of the gastrointestinal tract and frequent extraintestinal manifestations with intermittent episodes of remission and relapse. Genome-wide association studies identified a number of risk loci that, catalyzed by environmental triggers, result in the loss of tolerance toward commensal bacteria based on dysregulated innate effector functions and antimicrobial defense, leading to exacerbated adaptive immune responses responsible for chronic immune-mediated tissue damage. In this review, we discuss the inter-related role of changes in the intestinal microbiota, epithelial barrier integrity, and immune cell functions on the pathogenesis of CD, describing the current approaches available to investigate the molecular mechanisms underlying the disease. Substantial effort has been dedicated to define disease-associated changes in the intestinal microbiota (dysbiosis) and to link pathobionts to the etiology of inflammatory bowel diseases. A cogent definition of dysbiosis is lacking, as well as an agreement of whether pathobionts or complex shifts in the microbiota trigger inflammation in the host. Among the rarely available animal models, SAMP/Yit and TNFdeltaARE mice are the best known displaying a transmural CD-like phenotype. New hypothesis-driven mouse models, e.g., epithelial-specific Caspase8−/−, ATG16L1−/−, and XBP1−/− mice, validate pathway-focused function of specific CD-associated risk genes highlighting the role of Paneth cells in antimicrobial defense. To study the causal role of bacteria in initiating inflammation in the host, the use of germ-free mouse models is indispensable. Unraveling the interactions of genes, immune cells and microbes constitute a criterion for the development of safe, reliable, and effective treatment options for CD.

An overview of the bacterial contribution to Crohn disease pathogenesis

“…However, precisely how bacteria contribute to pathogenesis remains incompletely understood. Nevertheless, there is a consensus that the intestinal microbiome is a key factor in the development and maintenance of mucosal homeostasis, and loss of that function contributes to intestinal inflammation (Buttó et al, 2015).…”

Microbial Neuro-Immune Interactions and the Pathophysiology of IBD

“…Similarly, antibiotics and certain probiotics have shown therapeutic efficacy in certain IBD cohorts. An altered bacterial composition (dysbiosis) is associated with IBD patients, characterized by a reduction in bacterial diversity, especially the alpha diversity, which denotes the numbers of bacterial species and their abundance [168,169]. [170,171].…”

“…Among this, the adherent-invasive E. coli (AIEC), which selectively colonizes the ileum of up to 40% of CD patients, has been suggested to be a strain-specific microbial factor in the pathogenesis of CD (Figure 1). The definition of AIEC was based on the ability of the AIEC-LF82 strain to adhere and invade epithelial cells and to persist within macrophages without induction of cell death and by inducing the secretion of pro-inflammatory cytokines such as TNF-α [169,[172][173][174][175].…”

“…Patients with CD and UC are associated with impairment in SCFA production [185], which is linked to a reduction in butyrate-producing bacteria, including Roseburia inulinivorans, Ruminococcus torques, C. lavalense, B. uniformis and F. prausnitzii as well as a reduction in butyrate levels. Less butyrate is linked to changes in visceral hypersensitivity [169,200]. In contrast to dietary fibres, Westernized high-fat diet, full of refined carbohydrates, is strongly associated with the development of colitis in different IBD animal models, contrary to a diet highly based on fruits, vegetables and polyunsaturated fatty acid-3, which has a protective effect against disease progression in these models.…”

Bacterial Intestinal Superinfections in Inflammatory Bowel Diseases Beyond Clostridum difficile

“…6 Research on this topic indicates that a combination of different mechanisms (and not only one) plays a role in the immunopathogenesis of IBD. [7][8][9] Whereas the role of intestinal microbiota in IBD pathogenesis has become one of the most studied topics in IBD research in the last years, data on the role of intestinal infections occurring in patients with known IBD are still inconsistent and somehow conflicting. There is a lack of large prospective controlled studies on this topic providing reliable results.…”