Letter to the Editor: Too Soon to Dismiss Inflammation-Related Differences in the Mucosa-Associated Microbiota in Crohn’s Disease Patients

To the Editors:

We read with great interest the paper by Olaisen et al¹ reporting the characterization of mucosa-associated microbiota in inflamed distal ileum compared with more proximal noninflamed ileum in patients with Crohn’s disease (CD). We commend the authors for examining the mucosa-associated microbiota in CD patients, as most studies investigating microbiome changes in inflammatory bowel disease have focused on fecal samples. We also welcome the opportunity to compare the authors’ findings in ileal disease with our earlier findings in colonic CD.²

Olaisen et al conclude, based on 16S ribosomal RNA gene sequencing, that the ileal mucosa-associated microbiota characteristic of CD patients is not affected by inflammatory status or sublocation. This is consistent with our report, in 2018, that the colonic mucosa-associated microbiota in inflamed and adjacent noninflamed regions of CD patients had similar microbial communities, and no statistically significant differences in operational taxonomic units were detected between these adjacent regions in the same patient.² However, in our study, further investigation of bacterial encroachment using fluorescent in situ hybridization revealed distinctly different microbial attachment patterns; inflamed regions were marked by close mucosal attachment compared with noninflamed regions, the latter showing a clear separation between host mucosa and the microbiota. Inflamed regions also demonstrated increased permeability affecting both vascular and paracellular pathways. Thus, sequencing alone is insufficient to characterize the complexity of the mucosa-microbiota interface, and this concept has been shown previously in both feces³ and sputum.⁴ Further studies are needed to determine how microbial communities differ between inflamed and noninflamed regions with respect to strain or function, as these differences, leading to differences in mucosal injury, are not detected by 16S ribosomal RNA gene sequencing alone. For example, we have recently shown that individuals at risk for inflammatory bowel disease have an altered microbial proteolytic signature that was proinflammatory in germ-free mice that were colonized with patient microbiota.⁵

In view of this, a more detailed assessment of ileal mucosa-microbiota interactions, accounting for local differences in inflammation, structure, and function, similar to those reported for the colon,² may reveal important clues as to the cause of mucosal injury in CD. We suggest, therefore, that it is premature to conclude that that the mucosa-associated microbiota in CD is similar in inflamed and noninflamed regions and that studies should continue to investigate regional, inflammation-related differences in mucosa-associated microbiota to elucidate the pathogenesis of CD.

Funding

J.L. is a recipient of the IMAGINE-CAG-CIHR fellowship. D.A. is the Douglas Family Chair in Nutrition Research.

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