The intestinal mucosa-associated microbiota in IBD-associated arthritis displays lower relative abundance of Roseburia intestinalis

Abstract

The most common extra-intestinal manifestation (EIM) of inflammatory bowel disease (IBD), IBD-associated arthritis (IAA), occurs in 25-40% of patients and can be debilitating. In IBD, mucosal and stool microbiota richness is decreased, and compositional changes can precede or accompany disease onset. Likewise, spondyloarthritides are associated with altered gut microbiota, with overlapping bacterial signatures observed in IBD, suggesting key shared microbial factors are involved in both conditions. Much has been learned about the role of the intestinal microbiome in IBD, but less is known regarding its role in IAA. To address this knowledge gap, we analyzed the mucosa-associated intestinal microbiota of participants enrolled in the LOCATION-IBD cohort. Microbiota composition was established using 16S rRNA gene amplicon sequencing of intestinal biopsy samples taken from participants with IBD, with or without arthropathy. Microbiota samples clustered predominantly by participant, and similar taxa were present across the colon. The mucosal intestinal microbiota of females with IAA displayed a lower relative abundance of R. intestinalis, while males with IAA had a higher relative abundance of Corynebacterium, even when controlling for IBD-type, whether samples were taken from a site of inflammation and intestinal location. These findings indicate the mucosa-associated intestinal microbiota is associated with IAA in a sex-specific manner.

Keywords: Crohn’s disease; IBD-associated arthritis; Spondyloarthritis; enteropathic arthritis; mucosal gut microbiome; ulcerative colitis.

Figure 1.

PCA based clustering of relative abundance normalized intestinal mucosal microbiota compositional data. (a) sampling locations, (b) presence and absence of inflammation at sampling site, (c) sex, (d) IBD type, and (e) joint EIM status. DDC = distal descending colon, HF = hepatic flexure, TI = terminal ileum, CD = Crohn’s disease, IC = IBD-type undetermined, UC = ulcerative colitis.

Figure 2.

Stacked bar plots of bacterial taxa relative abundance in the intestinal mucosal microbiota of the TI (a), HF (b), and DDC (c), as well in all samples collected (d).

Figure 3.

Intestinal mucosal microbiome alpha diversity comparison by sampling location (a), IBD type (b), whether or not a sample was taken from a site of inflammation (c), whether or not erythema/inflammation was present on endoscopic exam (d), sex (e), joint EIM status (f), and joint EIM status sub-stratified based on whether or not a sample was taken from a site of inflammation (g). DDC = distal descending colon, HF = Hepatic flexure, TI = Terminal ileum, CD = Crohn’s disease, IC = IBD-type undetermined, UC = Ulcerative colitis, F = Female, M = Male. Boxes represent the IQR. ***p ≤ 0.001.

Figure 4.

Intestinal mucosal microbiota mean beta diversity (JSD) across samples for each individual, stratified by multiple clinical factors. JSDs were calculated between each site and averaged for a given individual to assess beta diversity across samples for each participant, and values were compared based on whether or not inflammation was present on endoscopic exam (a), biological drug use (b), sex (c), extent of disease (UC, IC) or disease location (CD) (d), IBD type (e), and joint EIM status (f). CD = Crohn’s disease, IC = IBD-type undetermined, UC = Ulcerative colitis, F = Female, M = Male. Boxes represent the IQR.

Figure 5.

Differences in bacterial taxa relative abundance in the intestinal mucosal microbiota in those with or without joint EIMs. Univariate assessment of differences in relative abundance between bacterial taxa in those with or without joint EIMs were performed using ALDEx2. Y = IAA present, N = IAA absent. Red points = Welch’s t-test q-value ≤0.10, gray points = Wilcoxon rank test q-value ≤0.10 with Welch’s t-test q-value >0.10.

Figure 6.

Relative abundance of R. intestinalis and Corynebacterium by sex, joint EIM status, and joint EIM status sub-stratified by sex. CLR transformed relative abundance values were compared, and t-test was used for 2-group comparisons of R. intestinalis and sex (a), R. intestinalis and joint EIM status (b), Corynebacterium and sex (d), and Corynebacterium and joint EIM status (e), while one-way ANOVA was used for multi-group comparisons with R. intestinalis (c) and Corynebacterium (f). M = male, F = female, Y = arthritis, N = no arthritis. *p ≤ 0.05, ***p ≤ 0.001. Boxes represent the IQR.

Figure 7.

Relative abundance of R. intestinalis and Corynebacterium by sex and joint disease activity status. CLR-transformed relative abundance values were compared, and one-way ANOVA was used for comparisons of R. intestinalis (a), Corynebacterium (b), Moraxella (c), and Butyricicoccus (d), in participants sub-stratified by sex and joint disease activity (active vs inactive) for those with joint EIMs (n = 51 total, 6 males without (M/N), 9 males with (M/Y), 15 females without (F/Y), and 14 females with (F/Y) active joint disease). M = male, F = female, Y = active joint EIMs, N = inactive joint EIMs. *p ≤ 0.05, **p ≤ 0.01. Boxes represent the IQR.