P0123 The immune system of patients with immune-mediated diseases perceives dysbiotic intestinal microbial species, and IgG reactivity uncovers shared and non-shared responses across diseases
Authors: Barendregt D , Gacesa R , Plomp N , Calado B , Bourgonje A R , van Heck J I P , van Mourik A G , van der Woude D , Weersma R K , Joosten L A B , Lubberts E , Rizopoulos D , Chandler F , Sikkema R S , Harmsen H J M , de Ridder L , Samsom J N 
Published: January 2025

Abstract

Background
Immune-mediated diseases (IMIDs), like Crohn’s disease (CD), ulcerative colitis (UC), psoriatic arthritis (PsA) and type I diabetes (T1D), have common features, including intestinal microbial dysbiosis. However, it is unclear whether dysbiosis contributes to IMID pathogenesis and whether the host immune system perceives dysbiotic commensals. In CD, high IgG and T-cell responses to Lachnospiraceae-derived flagellins associate with complex disease, while Lachnospiraceae fecal abundance is decreased in CD, suggesting that individual variation in the host-microbial mutualism is important. We studied IgG responses to dysbiotic microbial species across IMIDs, and questioned whether changes in these IgG responses are homogeneous within each IMID and shared among IMIDs.

Methods
Using shotgun metagenomic sequencing of feces from 6 IMID cohorts (n=5650), dysbiosis was extrapolated to species level. Plasma IgG reactivity to lysates of 71 dysbiotic species was measured in adult CD (aCD, n=50), adult UC (aUC, n=50), PsA (n=100), rheumatoid arthritis (RA, n=74), T1D (n=75), healthy controls (aHC, n=97), pediatric CD (pCD, n=103), pediatric UC (pUC, n=48), pediatric HC (pHC, n=58), pediatric celiac disease (CeD, n=103) and no-CeD HC (n=68). Multiple ordinal regression analysis was performed corrected for age, sex and multiple testing.

Results
Anti-microbial IgG responses compared to age-matched HC were increased in aCD (2/71); pCD (46/71); PsA (3/71); RA (1/71); decreased in T1D (10/71) and pUC (1/71), and not different in CeD and aUC. Shared increased responses occurred to: Klebsiella oxytoca and Roseburia inulinivorans in aCD and pCD, Streptococcus parasanguinis and Streptococcus vestibularis in PsA and pCD, and Acidaminococcus intestini in both arthritic diseases PsA and RA. As changes were heterogeneous within each IMID, hierarchical clustering of all anti-microbial responses across adult IMIDs was performed. Clusters had a mix of IMIDs, uncovering shared response patterns across IMIDs. Although aCD and aUC patients had disease-specific responses, their overall anti-microbial response pattern was not different from other IMIDs. In contrast, pCD patients were clearly distinct from pUC and pHC, with high number of significantly increased anti-microbial IgG responses and separate hierarchical clustering, demonstrating overall increased anti-microbial responses in pCD versus aCD. Interestingly, clustering grouped pCD patients with similar clinicopathological parameters, arguing that anti-microbial IgG response patterns may relate to disease pathogenesis.

Conclusion
We show that the immune system perceives dysbiotic commensals and uncover shared and non-shared anti-microbial IgG responses among adult and pediatric IBD and other IMID patients.