171 Strengths of the present study include the fact that this study presents a unique characterization of antimicrobial immune responses against fecal bacteria in patients with IBD. Furthermore, the concurrent availability of an age- and sex-matched cohort of population controls enabled us to directly compare autologous IgG-coated fractions of fecal bacteria to determine their specificity for IBD. However, several limitations also warrant recognition. For instance, we could not confirm enrichment after IgG-coating for all fecal samples of patients with IBD (or we could not demonstrate this by flow cytometry), and the relative enrichment was also not that high when compared to earlier reports.51 One explanation to the limited enrichment observed in fecal samples of patients with IBD could be that anti-IgG-FITC is less effective when bacteria are already pre-treated with anti-IgG-biotin antibodies, which may in turn lead to underestimation of enrichment by anti-IgG-biotin/streptavidin-coated magnetic beads. In addition, the bacterial diversity in fecal samples from patients with IBD was significantly reduced after IgG-coating, suggesting that some degree of selection had occurred during the MACS-procedure, which might indicate the existence of selective immune responses towards specific bacteria in the context of IBD. Indeed, bacterial sequence results of the different sorted fractions demonstrated that there was a selection of specific bacterial groups. Another limitation to this study pertains to the relatively small sample size, which did not permit us to perform reliable subgroup analyses (e.g. a comparison between patients with CD and UC) as statistical power was very limited for this. In addition, we had to rely on clinical assessment of disease activity, as data on fecal calprotectin levels or endoscopic disease activity were not recorded at time of sampling. However, themajority of our cohort (~75%) was in disease remission and previous efforts already indicated that the degree of IgG-coating does not seem to be affected by disease activity.13 In conclusion, this study demonstrates that patients with IBD exhibit distinct IgG immune responses directed towards a smaller group of specific types of bacteria compared with healthy controls. More specifically, this IgG immune response seems to be directed against Streptococcus, Lactobacillus, and Lactococcus, among others, as well as bacteria belonging to the family of Lachnospiraceae and other Clostridium cluster XIVa bacteria (e.g. Coprococcus, Dorea, and Ruminococcus gnavus-group). In contrast, there was some degree of IgG reactivity against typical colonic microbiota including several members of Lachnospiraceae (e.g., Roseburia and Blautia), Ruminococcaceae (e.g., Faecalibacterium), and Bacteroides, whichwas not clearly different between patients with IBD and HC. In addition, no significant differences in IgG reactivity were observed between CD and UC, quiescent and active disease or different disease locations. Future research is warranted to further unravel the pathophysiological role of these IgG-bound bacterial groups within the context of IBD. Further investigation into the exact antigenic nature of these specific bacteria is paramount to better characterize host-microbiota interactions that are relevant to IBD. Antimicrobial IgG immune responses in IBD
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