199 Use of TNF-α-antagonists is associated with Ruminococcaceae-associated gene interactions related to fatty acid metabolism Subsequently, we investigated the impact of TNF-α-antagonist use on mucosal host–microbe interactions. Pairwise comparisons revealed that TNF-α-antagonist use was significantly associated with three different bacterial taxa, Faecalibacterium, Ruminococcaceae_UCG-002, and Ruminococcaceae_UCG-005 (all showing reduced abundances in users), and 513 different genes (FDR<0.05, Supplementary Table S22). For instance, one of the top genes associated with TNF-αantagonist usewas CXCL13, which encodes B cell attracting chemokine 1. By comparing each taxaassociated gene cluster between patients using and not using TNF-α-antagonists, we identified a single cluster represented by mucosal Ruminococcaceae_UCG-002 that was significantly altered in users vs. non-users (FDR<0.05, Supplementary Table S23). Ruminococcaceae_UCG-002 bacteria were associated with 135 genes in non-users, and these genes were mainly enriched in cell cycle–associated pathways (e.g. PRIM1 and PRIM2), including mitosis-, prometaphase- and DNAreplication-associated genes (Figure 5C-D). However, the Ruminococcaceae_UCG-002-associated genes in TNF-α-antagonist users (FDR<0.05) were predominantly involved in lipid/fatty acid metabolism (e.g. ACAA1, ACSL5 and PDK4), glycerophospholipid biosynthesis and phospholipid metabolism. Ruminococcaceae comprise multiple distinct bacterial genera. Some of these are part of the healthy gut microbiome,68 but others are potentially pathogenic and commonly enriched in IBD.13,69 The Ruminococcaceae UCG_002 group is classified under the Oscillospiraceae family, which consists of obligate anaerobic bacteria including Faecalibacterium prausnitzii. Depending on their micro-environment, Ruminococcaceae UCG_002 bacteria can produce shortchain fatty acids due to their fiber-metabolizing capacity.70-72 The inverse associations between Ruminococcaceae_UCG_002 and genes involved in (peroxisomal) fatty acid oxidation in patients using TNF-α-antagonists might reflect a beneficial therapeutic modulation, i.e. a reduction of fatty acid oxidation and lipotoxicity, and possibly even attenuation of microbiota-induced intestinal inflammation.73-85 Mucosal host-microbe interactions in IBD
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