DOP138Anti-microbiota IgG depletes protective gut microbial symbionts in inflammatory bowel disease and precedes Crohn’s disease by years

Abstract Background The gut microbiota is significantly altered in people with inflammatory bowel disease (IBD), most notably exhibiting depletion of key health-associated gut bacteria that produce the microbial metabolite butyrate. Given butyrate’s role in dampening inflammation and bolstering gut epithelial integrity, this depletion is thought to contribute to IBD pathogenesis. However, mechanisms that govern this depletion remain unknown. Methods We used fecal metatranscriptomics and metagenomics data from a cohort of IBD (N = 72) and non-IBD subjects (N = 26) followed for up to one year (N = 739 total samples)1. We performed anti-microbiota immune repertoire profiling2 by quantifying systemic IgG levels against up to 200 of the most common human gut bacteria using serum samples from a subset of IBD patients (N = 42) and on CD pre-clinical samples from the PREDICTS cohort3 (N = 336 total samples). We performed murine colitis experiments using dextran sodium sulfate (N = 201 across experiments), T cell transfer colitis (N = 30), and IL-10-/- mice (N = 25). Results Anti-microbiota systemic IgG repertoires differed significantly between IBD and non-IBD subjects (Fig. 1A). Significantly elevated systemic IgG against butyrate-producing bacteria was observed in individuals with IBD (Fig. 1B) and was associated with significant depletion of the same butyrate-producing taxa in their fecal microbiota. Both IgG and neutrophils enter the gut lumen in IBD patients (Fig. 1C-D), a phenomenon absent in healthy controls. To test causality, we leveraged a murine commensal bacterial colonization model to demonstrate that anti-commensal systemic IgG causes gut microbe-specific depletion during colitis that is dependent on neutrophils (Fig. 1E-I). Finally, appearance of significantly elevated IgG against key butyrate-producing gut bacteria precedes onset of CD by up to 6 years (Fig. 1J). Conclusion Systemic anti-microbiota IgG selectively depletes butyrate-producing gut bacteria in a neutrophil-dependent manner in IBD. Elevated anti-microbiota IgG occurs years prior to CD disease onset, suggesting a putative causal role in the disease. References: 1. Lloyd-Curtis et al. Nature. 2019. 10.3389/fmolb.2022.949563 2. Vujkovic-Cvijin et al. Science Translational Medicine. 2023. 10.1126/scitranslmed.abl3927 3. Porter et al. Contemp Clin Trials Commun. 2019. 10.1016/j.conctc.2019.100345 Conflict of interest: Lo, Alice: No conflict of interest Gifford, Jacob: No conflict of interest Ivleva, Elena: No conflict of interest Gooder, Natalie: No conflict of interest Shiramizu, Dylan: No conflict of interest Shimahara, Christine: No conflict of interest Parvinroo, Shadi: No conflict of interest Dos Santos, Jessica: No conflict of interest Norris, Peter: No conflict of interest Esplago, Ace: No conflict of interest Wang, Daosheng: No conflict of interest Li, Jingwen: No conflict of interest Ringholz, Mia: No conflict of interest Santana, Jolcey: No conflict of interest Lundquist, Zeke: No conflict of interest Casero, David: No conflict of interest Landers, Carol: No conflict of interest Magee, Jared: No conflict of interest Ungaro, Ryan: Personal Fees: AbbVie, Bristol Myers Squibb, Genentech, Lilly, Pfizer, Janssen, Takeda Laird, Renee: No conflict of interest Braun, Jonathan: No conflict of interest Riddle, Mark: No conflict of interest McGovern, Dermot: Personal Fees: Advisory Boards for Prometheus Biosciences, Prometheus Laboratories, Takeda, Merck Other: Patents for anti-TL1A therapy in Crohn’s disease and ulcerative colitis Kubes, Paul: No conflict of interest Martins, Gislaine: No conflict of interest Porter, Chad: No conflict of interest Wannemuehler, Michael: No conflict of interest Colombel, Jean-Frédéric: Grant: AbbVie, Janssen Pharmaceuticals, Takeda, Prometheus and Bristol Myers Squibb Lectures from: AbbVie, Roche and Takeda Other: AbbVie, Amgen, AnaptysBio, Allergan, Apini, Arena Pharmaceuticals, Astellas, Boehringer Ingelheim, Bristol Myers Squibb, candidrx Celgene, Celltrion, Clearview Curogen, Eli Lilly, Envision Pharma Ferring Pharmaceuticals, Galmed Research, Glaxo Smith Kline, Roche, Janssen Pharmaceuticals, Kaleido Biosciences, Immunic, Iterative Scopes, Landos, Microba Life Science, Merck, Mirador, Novartis, Otsuka Pharmaceutical, Owkin, Pfizer, Protagonist Therapeutics, Sanofi, Sun Pharma, Takeda, Teva, TiGenix, and is holding stock options in Intestinal Biotech Development Prof. Vujkovic, Ivan: No conflict of interest