197 Mucosal Bacteroides associate with host interleukin signaling and metal ion response pathways The third pair of significantly correlated components (component pair 7, P=1.28x10-4, FDR<0.05) is represented by Bacteroidetes. Twenty-four different pathways were significantly associated with this microbial component (Supplementary Tables S11-S12). A number of interferon signaling pathways (e.g. IFN-α, IFN-β and IFN-γ as well as the IL-2, IL-4, IL-6, IL-10, IL-12 and IL-13 signaling pathways) are all inversely associated with the microbial component. In addition, metal ion response and metallothionein pathways (e.g. metal ion transcription factors MT1A, MT1E, MT1F, MT1G and others) are positively associated with the microbial component. Taken together, these observations could suggest a predominance of potentially beneficial Bacteroides species associated with this component. Previous studies have shown that Bacteroides can exert either beneficial, mutualistic, or pathogenic effects on the host, depending on local interactions, intestinal location and nutrient availability.21,33 The co-occurrence of Bacteroides with lower expression of interleukin signaling pathways is supported by experimental work that found potential anti-inflammatory and protective roles for these bacteria in the context of intestinal inflammation.34,39,40 Still, the relative contributions of each of these species, as well as their behavior in the context of intestinal inflammation, remain elusive, although our data might reflect an overrepresentation of anti-inflammatory members.34-39,43 The positive associations between Bacteroides and expression of metal ion response genes and metallothioneins (MTs) are intriguing in the context of IBD because aberrant MT homeostasis and intracellular zinc metabolism have been implicated in disease pathophysiology.44-48 Mucosal Erysipelotrichaceae bacteria interact with collagen biosynthesis pathways In the fourth pair of significantly correlated components (component pair 8, P=1.22x10-4, FDR<0.05), the microbial component, represented by the family Erysipelotrichaceae, is inversely associated with the expression of genes belonging to a wide range of ECM and collagen genes that are involved in collagen biosynthesis, integrin cell surface interactions, collagen chain trimerization, collagen fibril cross-linking, collagen fibril assembly, ECM proteoglycans, collagen degradation and related pathways (Supplementary Tables S13-S14). Similar to Bacteroides, the precise role of Erysipelotrichaeae in the context of IBD has not yet been fully elucidated. Some studies found lower abundances of Erysipelotrichaceae in patients with new-onset CD49 and postoperative active CD,50 whereas others reported higher levels of Erysipelotrichaceae in the context of ileitis51 and TNF-regulated CD-like transmural inflammation.52 These inconsistencies have been suggested to be due to Erysipelotrichaceae behaving differently in response to intestinal inflammation, but they may also reflect incomplete characterization of the precise species that belong to the family of Erysipelotrichaceae.53 Interactions between Erysipelotrichaceae and ECM/collagen remodeling pathways have not yet been reported in the context of IBD, but they would be particularly relevant because fibrosis occurs in a large fraction of patients with CD and Erysipelotrichaceae bacteria have been associated with fibrotic conditions beyond IBD.54-60 Mucosal host-microbe interactions in IBD
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