Oral-gut microbiome in Crohn’s disease: investigating the interplay with disease severity, progression and mucosal healing

Abstract

The oral cavity is the second most complex human microbial niche and is the conduit through which initial gut microbial colonisation occurs during early life. While many studies have implicated the gut microbiome and dysbiosis in inflammatory bowel disease (IBD), the oral microbiome remains underexplored. Within this PhD, we hypothesise that the oral microbiome is a key component in the pathogenesis of IBD, whereby oralisation from the mouth to the downstream affected gut occurs, and selective expansion of key pathobionts within inflamed tissue may drive the intestinal inflammatory processes.

In a series of original work, we profiled the oral-gut microbiota and explored its association with disease activity and complete mucosal healing (CMH), a key prognostic marker for long-term remission in IBD. We first performed an indepth meta-analysis of all the available studies (derived from an initial screen of 1367 studies) to objectively review the evidence and methodologies for studies investigating the oral microbiome in IBD. In 22 suitable studies and 6 further studies where we obtained 16S rRNA sequencing data for secondary independent analyses, we found that there are significant differences in the alpha- and beta-diversity in the oral microbiome in patients with IBD: these differences are mainly driven by Crohn’s disease (CD). Secondly, an independent analysis was conducted using samples from our IBD patients (IBD vs controls, n=58 and 25, respectively).

To further test our hypothesis, we carried out microbial source tracking using trans-anatomical oral-ileal-stool samples within the same patients at a single time-point, alongside longitudinal oral-stool sampling. Here, significant divergence was observed between IBD and HC oral microbiota, particularly in active disease, with increased oral Veillonella – a genus frequently enriched in the IBD gut. We found a trend towards higher oral microbiota abundances in inflamed ileal mucosa. Patients who achieved CMH exhibited significantly lower oral microbiota abundances in stool compared to those who did not, with significant correlations to markers of active disease. This finding suggests a potential role in the resolution of gut inflammation in IBD. Using machine learning approaches, we integrated stool microbiota taxonomic profiles with ~100 clinical variables and showed that the addition of microbial features enhanced the prediction of mucosal healing in IBD.

Together, these findings suggest that the oral microbiome may act as an upstream regulator site of IBD-inflammation, offering new insights into its role in disease progression and potential therapeutic targeting.