Increased Antibody Response to Fucosylated Oligosaccharides and Fucose-Carrying Bacteroides Species in Crohn’s Disease

Abstract

Inflammatory bowel disease is associated with intestinal dysbiosis and with elevated antibody production toward microbial epitopes. The underlying processes linking the gut microbiota with inflammation are still unclear. Considering the constant induction of antibodies by gut microbial glycans, the aim of this study was to address whether the repertoire of carbohydrate-specific antibodies is altered in Crohn's disease or ulcerative colitis. IgG and IgM reactivities to oligosaccharides representative of mucosal glycans were tested in blood serum from 20 healthy control subjects, 17 ulcerative colitis patients, and 23 Crohn's disease patients using glycan arrays. An increased IgG and IgM reactivity toward fucosylated oligosaccharides was detected in Crohn's disease but not in ulcerative colitis. To address the antibody reactivity to the gut microbiota, IgG binding to members of a complex intestinal microbiota was measured and observed to be increased in sera of patients with Crohn's disease. Based on the elevated reactivity to fucosylated oligosaccharides, gut bacteria were tested for recognition by the fucose-binding Aleuria aurantia lectin. Bacteroides stercoris was detected in IgG-and lectin-positive fractions and reactivity of A. aurantia lectin was demonstrated for additional Bacteroides species. IgG reactivity to these Bacteroides species was significantly increased in inflammatory bowel disease patients, indicating that the increased reactivity to fucosylated oligosaccharides detected in Crohn's disease may be induced by fucose-carrying intestinal bacteria. Enhanced antibody response to fucosylated epitopes may have systemic effects by altering the binding of circulating antibodies to endogenous glycoproteins.

Finding the sweet spot: glycosylation mediated regulation of intestinal inflammation

“…Interestingly, 5 of the 16 genes that regulate IgG glycosylation contain SNPs linked to increased risk for IBD identified by GWAS 39 . Reduced levels of serum IgG sialylation is observed in both UC and Crohn’s disease 112 – 114 as well as altered fucosylation, with increased levels detected in Crohn’s disease and lower levels in people with UC 112 , 115 . While the functional role of IgG fucosylation in regulating intestinal inflammation is not understood, afucosylated IgG has been shown to enhance pro-inflammatory cytokine production by monocytes in the lungs of individuals with severe COVID-19 116 , suggesting that altered IgG fucosylation could also contribute to IBD pathobiology.…”

“…Overall, a clear functional role for IgG glycosylation in IBD pathophysiology has yet to be determined. However given that current strategies for differential diagnosis and monitoring of IBD can lack sensitivity and are often invasive 122 , 123 , measurement of serum IgG glycosylation could potentially represent an attractive and minimally invasive option for IBD patient stratification 114 , 115 .…”

Emergence and significance of carbohydrate-specific antibodies

“…These antibodies recognize oligosaccharides that are frequently found on the surface of gut microbes, such as laminaribioside, laminarin, mannobioside, chitobioside, and chitin [ 190 – 193 ]. In our own studies, we observed an increased antibody response to carbohydrates in blood serum of patients with Crohn’s disease compared with healthy controls, which was mainly reflected by a higher antibody reactivity to fucosylated oligosaccharides and could be linked to increased antibody recognition of intestinal Bacteroides species [ 194 ]. Given the association between intestinal dysbiosis and altered anti-bacterial antibodies, the question arises whether these antibodies targeting bacterial antigens contribute to the etiology of inflammatory bowel disease.…”

Acceptive Immunity: The Role of Fucosylated Glycans in Human Host–Microbiome Interactions

“…This can indicate the active degradation of mucins. At the same time, many glycans have the same composition, but clearly differ structurally; therefore, the study of their structure is of interest from the viewpoint of the patterns they form [ 246 ]. The role of 1,2-Fuc–containing patterns is not clear.…”