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Link to original content: https://pubmed.ncbi.nlm.nih.gov/37874904
Dysregulated Immunity to Clostridioides difficile in IBD Patients Without a History of Recognized Infection - PubMed Skip to main page content
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. 2024 May 2;30(5):820-828.
doi: 10.1093/ibd/izad238.

Dysregulated Immunity to Clostridioides difficile in IBD Patients Without a History of Recognized Infection

Laura Cook  1   2   3 , May Q Wong  1   2 , William D Rees  1   2 , Alana Schick  4 , Daniel J Lisko  1   2 , Genelle R Lunken  5 , Xiaojiao Wang  1   2 , Hannah Peters  1 , Laura Oliveira  1 , Torey Lau  1 , Regan Mah  1 , Brian Bressler  6 , Megan K Levings  2   7   8 , Theodore S Steiner  1   2
Affiliations

Dysregulated Immunity to Clostridioides difficile in IBD Patients Without a History of Recognized Infection

Laura Cook et al. Inflamm Bowel Dis. .

Abstract

Background & aims: Clostridioides difficile is a toxin-secreting bacteria that is an urgent antimicrobial resistance threat, with approximately 25% of patients developing recurrent infections. Inflammatory bowel disease (IBD) patients are at increased risk of severe, recurrent C. difficile infection.

Methods: To investigate a role for C. difficile infection in IBD pathogenesis, we collected peripheral blood and stool from 20 each of ulcerative colitis patients, Crohn's disease patients, and healthy control subjects. We used a flow cytometric activation induced marker assay to quantify C. difficile toxin-specific CD4+ T cells and 16S ribosomal RNA sequencing to study microbiome diversity.

Results: We found IBD patients had significantly increased levels of C. difficile toxin B-specific CD4+ T cells, but not immunoglobulin G or immunoglobulin A, compared with healthy control subjects. Within antigen-specific CD4+ T cells, T helper type 17 cells and cells expressing the gut homing receptor integrin β7 were reduced compared with healthy control subjects, similar to our previous study of non-IBD patients with recurrent C. difficile infection. Stool microbiome analysis revealed that gut homing, toxin-specific CD4+ T cells negatively associated with microbial diversity and, along with T helper type 17 cells, positively associated with bacteria enriched in healthy control subjects.

Conclusions: These data suggest that IBD patients, potentially due to underlying intestinal dysbiosis, experience undiagnosed C. difficile infections that result in impaired toxin-specific immunity. This may contribute to the development of inflammatory T cell responses toward commensal bacteria and provide a rationale for C. difficile testing in IBD patients.

Keywords: C. difficile; CD4+ T cell; T cell memory; antimicrobial resistance; microbiome.

Plain language summary

Crohn’s disease and ulcerative colitis patients with no history of Clostridioides difficile infection had dysregulated T cell immunity to C. difficile toxin B. This was significantly different from healthy control subjects but similar to non–inflammatory bowel disease patients with recurrent C. difficile infection.

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Conflict of interest statement

M.K.L. has received research funding from Bristol Myers Squibb and Takeda for work not related to this study. T.S.S. has received research funding from Rebiotix, Seres, NuBiyota, Actelion, Sanofi Pasteur, and Pfizer for studies in Clostridioides difficile infection not related to this study. All other authors report no conflicts of interest.

Figures

Figure 1.
Figure 1.
Inflammatory bowel disease patients have increased frequency of circulating TcdB-specific CD4+ T cells. A, Representative unstimulated and TcdB-stimulated CD25/OX40 assay wells for a Crohn’s disease (CD) patient, showing gating strategy as previously described for CD25+OX40+ cells and T helper type 1 (Th1), Th2, and Th17 cells, gates set on CD4+ T cells and CD3neg cells. B, Comparison of TcdB-specific CD4+ T cell responses normalized as a percent of Pediacel vaccine responses for healthy control (HC) subjects (n = 20), CD (n = 20), and ulcerative colitis (UC) patients (n = 20). C, Spearman’s rho correlation between Harvey-Bradshaw index (HBI) for CD and Simple Clinical Colitis Activity Index (SCCAI) for UC; and TcdB-specific CD4+ T cells (n = 20 CD and n = 20 UC). D, Levels of anti-TcdB and anti-TcdBCROPS immunoglobulin G (IgG) and IgA for cohorts in panel B measured by enzyme-linked immunosorbent assay. Statistical analysis in panels B and D used Kruskal-Wallis tests.
Figure 2.
Figure 2.
Inflammatory bowel disease patients have a reduced frequency of TcdB-specific T helper type 17 (Th17) cells. A, Analysis of TcdB-specific T cell proportions of Th1 cells (n = 14 healthy control [HC] subjects, n = 11 Crohn’s disease [CD] patients, n = 18 ulcerative colitis [UC] patients), Th2 cells (n = 14 HC, n = 11 CD patients, n = 16 UC patients), and Th17 cells (n = 13 HC subjects, n = 11 CD, n = 16 UC). B, Proportions of integrin β7+ cells within TcdB-specific responses for n = 12 CD and n = 17 UC. C, TcdB-specific CD4+ T cells were analyzed using unbiased clustering analysis (FlowSOM). Two clusters with statistically significant differences between cohorts after individual hierarchical gating analyses are shown on tSNE plots. Proportions of each cluster within TcdB-specific CD4+ T cells are shown for all groups (n = 16 HC subjects, n = 12 CD patients, n = 16 UC patients) and compared with proportions within Pediacel-specific responses. Statistical analysis used Kruskal-Wallis tests, patients receiving vedolizumab are colored pink in all plots.
Figure 3.
Figure 3.
Correlations of TcdB-specific immune responses and microbiome. A, Proportion of variation in overall microbiome composition (R2) explained by the y-axis variable using permutational multivariate analysis of variance. Spearman rank correlations with microbiome alpha diversity (estimated using Shannon index) and TcdB-specific (B) antibodies and (C) T cells (n = 39; being n = 13 from each cohort). D, Heat map showing Spearman correlation analyses between the relative abundance of differentially expressed bacterial taxa and anti-TcdB immune responses (n = 39). *P < .05. Ab, antibody; CD, Crohn’s disease; Ig, immunoglobulin; Th, T helper; UC, ulcerative colitis.
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