169 Discussion In this study, we demonstrate that a variety of IgG immune responses are directed against the majority of the main fecal bacterial genera in both patients with IBD and healthy individuals. The IgG-coated samples showed a great overlap in enrichment of specific IgG-coated bacterial genera between both groups. In particular, serum IgG was directed against the bacterial genera Streptococcus, Lactobacillus, Lactococcus, and Veillonella. In contrast, bacterial genera like Faecalibacterium, Roseburia, and Blautia were decreased after the IgG-coating procedure, which are members of the families Lachnospiraceae and Ruminococcaceae, representing two dominant colonic microbial groups (Figure 3). This may suggest that there is less IgG reactivity against commensal (butyrate-producing) bacteria, however other Lachnospiraceae members, e.g. Dorea and Coprococcus, were significantly enriched after IgG-coating. This indicates that there were IgG immune responses against several types of commensal anaerobic microbiota. Furthermore, we showed that IgG-coating had a small but statistically significant impact on sample microbial diversity, which was to be expected as several types of bacteria were separated out after the MACS procedure. No significant differences in IgG-coated bacteria were observed between patients with CD and UC, patients with quiescent or active disease or patients with different disease locations, although numbers were actually too small to allow for reliable subgroup analyses. Collectively, these findings emphasize that both patients with IBD and HC have IgG immune responses against the fecal microbiota, many of which are rather prominent in patients with IBD. The observed IgG immune responses, particularly in patients with IBD, were preferentially directed against typical members of the small intestinal microbiota, including Streptococcus, Lactobacillus, Lactococcus, and Veillonella. These findings are in line with what is known on the composition of the small intestinal microbiota in the context of IBD. Bacteria that are typically enriched in the small intestine of patients with IBD as compared with population controls comprise, among others, Streptococcus, Veillonella, Clostridium, Lactobacillus, Klebsiella, Enterococcus, Lactococcus, and Actinomyces species.25-27 Moreover, some of these bacteria, especially Streptococcus and Lactobacillus, have also been found to be abundantly present within the mucosa-associated microbiota in inflamed biopsies from patients with IBD, residing within a thinner mucus layer compared to healthy controls.28 Considering these observations, one may speculate that a compromised small intestinal barrier integrity may lead to higher exposure of these bacteria to the mucosal immune system as they are in close proximity, resulting in increased specific IgG immune responses. However, this speculation was not sustained by our data as it can be anticipated that patients with CD, who often have small intestinal disease involvement, would exhibit increased IgG responses towards these bacteria compared to patients with UC, which was however not observed. In addition, our study was not sufficiently powered to reliably establish these potential differences between subtypes of IBD, and thus warrants further investigation. In keeping with this, the decreased IgG immune responses against commensal, anaerobic, butyrateproducing bacteria like Roseburia and Faecalibacterium may be explained by the fact that these bacteria confer barrier-protective and anti-inflammatory properties.29,30 Butyrate is known for its anti-inflammatory and anti-carcinogenic effects, and it contributes to the preservation of the intestinal barrier by acting as an energy source for epithelial cells.30-32 Furthermore, these butyrateproducing bacteria are characterized by high oxygen sensitivity, which limits their passage of Antimicrobial IgG immune responses in IBD
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