ANTI-MICROBIOTA SYSTEMIC IGG DEPLETES PROTECTIVE BUTYRATE-PRODUCING COMMENSALS IN IBD AND LONG PRECEDES CROHN’S DISEASE ONSET

Background:
Crohn’s disease (CD) is characterized by an aberrant microbiome composition – including a depletion of gut bacteria that produce short chain fatty acids (SCFA) – and by presence of anti-commensal systemic IgG. The relative depletion of SCFA in inflammatory bowel disease (IBD) has been postulated to permit pathological chronic inflammation and barrier disruption. We here explore the mechanisms driving this dysbiosis and its link with systemic anti-microbiota IgG.

Methods:
We utilized metatranscriptomics and metagenomics data generated using stool collected from a cohort of human IBD and non-IBD subjects (N=104 subjects) followed for up to one year (N=739 total samples)¹. To characterize and quantify the anti-microbiota immune repertoire, we performed SFC-IgG-seq² (Fig. 1) using serum samples from a subset of these subjects (N=42) and on pre-clinical samples from the PREDICTS cohort³ (N=336 total samples). Stool from IBD and non-IBD subjects was subjected to fecal bacterial flow cytometry (N=39 total). Metabolomics was performed to identify links with SCFA (N=42). We performed murine colitis experiments using dextran sodium sulfate (N=114 across experiments) and IL-10^-/- mice (N=25).

Results:
Anti-microbiota systemic IgG repertoires differ significantly between IBD and non-IBD subjects (Fig. 2A). Specifically, SCFA-producing bacteria are prominent targets of systemic IgG in individuals with IBD. (Fig. 2B). Consistent with prior literature, we find that these same SCFA-producing taxa are depleted in individuals with IBD (Fig. 2C). Both IgG and neutrophils enter the gut lumen in IBD patients (Fig. 2D-E), a phenomenon absent in healthy controls. The convergence of neutrophils and anti-commensal IgG associates with depletion of IgG-targeted gut taxa including most notably, SCFA producers (Fig. 2F), and associates with decreased bioavailable butyrate. To test causality, we leveraged a murine commensal bacterial colonization model to demonstrate that anti-commensal systemic IgG causes gut microbe-specific depletion that is dependent on neutrophils (Fig. 2G-H). These processes correlated with disease severity in both mice and humans. Finally, appearance of significantly elevated IgG against SCFA producing gut bacteria precedes onset of CD by up to 6 years (Fig. 2J-L).

Conclusions:
In CD, systemic anti-microbiota IgG selectively targets butyrate-producing gut bacteria in a neutrophil-dependent manner. Elevated anti-microbiota IgG occurs years prior to disease onset, suggesting a putative causal role in the disease.

¹Lloyd-Curtis et al. Nature. 2019. 10.3389/fmolb.2022.949563
²Vujkovic-Cvijin et al. Science Translational Medicine. 2023. 10.1126/scitranslmed.abl3927
³Porter et al. Contemp Clin Trials Commun. 2019. 10.1016/j.conctc.2019.100345