Abstract
Bacteroides fragilis has previously been linked to Crohn’s disease (CD) exacerbations, but results are inconsistent and underlying mechanisms unknown. This study investigates the epidemiology of B. fragilis and its virulence factors bft (enterotoxin) and ubiquitin among 181 CD patients and the impact on the intestinal epithelial barrier in vitro. The prevalence of B. fragilis was significantly higher in active (n = 69/88, 78.4%) as compared to remissive (n = 58/93, 62.4%, p = 0.018) CD patients. Moreover, B. fragilis was associated with intestinal strictures. Interestingly, the intestinal barrier function, as examined by transepithelial electrical resistance (TEER) measurements of Caco-2 monolayers, increased when exposed to secretomes of bft-positive (bft-1 and bft-2 isotype; increased TEER ∼160%, p < 0.001) but not when exposed to bft-negative strains. Whole metagenome sequencing and metabolomics, respectively, identified nine coding sequences and two metabolites that discriminated TEER-increasing from non-TEER-increasing strains. This study revealed a higher B. fragilis prevalence during exacerbation. Surprisingly, bft-positive secretomes increased epithelial resistance, but we excluded Bft as the likely causative factor.
Highlights
Crohn’s disease (CD) is a chronic inflammatory disease, characterized by patchy inflammation of the intestinal mucosa with or without extra-intestinal manifestations (Baumgart and Sandborn, 2012)
We subsequently determined the prevalence of the B. fragilis virulence factors bft CD remission (n = 93) CD exacerbation (n = 88)
We hypothesized that B. fragilis and its virulence factors bft and ubb are associated with exacerbations and may contribute to exacerbations by disruption of the intestinal epithelial barrier (Wells et al, 1996; Chambers et al, 1997; Obiso et al, 1997; Wu et al, 1998; Riegler et al, 1999)
Summary
Crohn’s disease (CD) is a chronic inflammatory disease, characterized by patchy inflammation of the intestinal mucosa with or without extra-intestinal manifestations (Baumgart and Sandborn, 2012). Microbial dysbiosis gained increasing attention as a factor contributing to exacerbations (Baumgart and Sandborn, 2012; Tedjo et al, 2016). In CD, an impaired intestinal epithelial barrier function has increasingly been recognized as a hallmark of exacerbations (Baumgart and Sandborn, 2012). The impaired barrier function has been associated with alterations in the epithelial junctional complex (Zeissig et al, 2007; Lameris et al, 2013). It remains unknown whether the observed altered microbiota composition and functionality during CD exacerbations can contribute to this impaired epithelial barrier
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