Alteration of microbiota antibody‐mediated immune selection contributes to dysbiosis in inflammatory bowel diseases

Abstract

Human secretory immunoglobulins (SIg) A1 and SIgA2 guide mucosal responses toward tolerance or inflammation, notably through reverse‐transcytosis, the apical‐to‐basal transport of IgA2 immune complexes via M cells of gut Peyer's patches. As such, the maintenance of a diverse gut microbiota requires broad affinity IgA and glycan–glycan interaction. Here, we asked whether IgA1 and IgA2‐microbiota interactions might be involved in dysbiosis induction during inflammatory bowel diseases. Using stool HPLC‐purified IgA, we show that reverse‐transcytosis is abrogated in ulcerative colitis (UC) while it is extended to IgA1 in Crohn's disease (CD). 16S RNA sequencing of IgA‐bound microbiota in CD and UC showed distinct IgA1‐ and IgA2‐associated microbiota; the IgA1+ fraction of CD microbiota was notably enriched in beneficial commensals. These features were associated with increased IgA anti‐glycan reactivity in CD and an opposite loss of reactivity in UC. Our results highlight previously unknown pathogenic properties of IgA in IBD that could support dysbiosis.

Single-cell RNA sequencing reveals dysregulated cellular programmes in the inflamed epithelium of Crohn’s disease patients

“…Among the most up regulated genes in Crohn’s disease across epithelial cell types was PIGR , which showed highly concordant dysregulation across both cohorts (Figure S5A). PIGR encodes a protein that plays a crucial role in transporting immunoglobulin A (IgA) into the intestinal lumen, where IgA shapes the intestinal microbiota through binding to a range of bacteria, which is thought to be associated with the dysbiosis of IBD (Michaud et al 2022, Shapiro et al 2021). Furthermore, within epithelial cells we confirmed a consistent activation of genes previously reported as being upregulated in IBD, including biomarkers IFI27, LCN2, B2M (Dooley et al 2004, Yılmaz et al 2014), and regenerating family member (REG) genes REG1A/B responsible for intestinal cell proliferation and differentiation (Zhang et al 2003) (Figure S5A).…”

“…PIGR is a basolateral transporter for dimeric immunoglobulin A (IgA) into epithelial cells, from where it undergoes a process of reverse transcytosis into the intestinal lumen as secretory IgA (sIgA). sIgA plays an important role in shaping the intestinal microbiota and binds a range of bacteria associated with the dysbiosis of IBD (Michaud et al 2022, Shapiro et al 2021). We, and others, have previously shown that somatic mutations predicted to lead to a loss of function of PIGR are under positive selection in the epithelium of some patients with IBD (Olafsson et al 2020, Kakiuchi et al 2020), whilst PIGR transcription is increased in the presence of IBD-associated cytokines, including IL-17A and IFN-γ, in line with our observation of an interferon signalling signature in CD epithelial cells in our analysis of DGE.…”

Intestinal fungi and antifungal secretory immunoglobulin A in Crohn’s disease

“…With a shorter hinge region than IgA1, IgA2 seems more advantageous in the microbe-rich environment of the colon owing to its higher stability ( 86 , 87 , 89 , 90 ). A recent study showed that the IgA1 + microbiota fraction in patients with CD was notably enriched in beneficial commensals and that local IgA2 selection of the microbiota correlated with disease activity in CD, suggesting that IgA1 has a pathogenic role in the lumen in CD, whereas IgA2 has a pathogenic role in tissues ( 91 ).…”

Intestinal IgA-Coated Bacteria in Healthy- and Altered-Microbiomes (Dysbiosis) and Predictive Value in Successful Fecal Microbiota Transplantation

“…In another study, binding of bacteria to IgA subclasses in patients with IBD was examined to see if the bacteria could contribute to the dysbiosis in these conditions [ 36 ]. The study found IgA-bound bacteria in CD and UC showed distinct IgA1- and IgA2-associated microbiota.…”