Thapa Himadri B, Passegger Christina A, Fleischhacker Dominik, Kohl Paul, Chen Yi-Chi, Kalawong Ratchara, Tam-Amersdorfer Carmen, Gerstorfer Michael R, Strahlhofer Jana, Schild-Prüfert Kristina, Zechner Ellen L, Blesl Andreas, Binder Lukas, Busslinger Georg A, Eberl Leo, Gorkiewicz Gregor, Strobl Herbert, Högenauer Christoph, Schild Stefan
Institute of Molecular Biosciences, University of Graz, Graz, Austria.
Division of Immunology, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria.
Nat Commun. 2025 Apr 29;16(1):3995. doi: 10.1038/s41467-025-59354-5.
The gut microbiome contributes to chronic inflammatory responses in ulcerative colitis (UC), but molecular mechanisms and disease-relevant effectors remain unclear. Here we analyze the pro-inflammatory properties of colonic fluid obtained during colonoscopy from UC and control patients. In patients with UC, we find that the pelletable effector fraction is composed mostly of bacterial extracellular vesicles (BEVs) that exhibit high IgA-levels and incite strong pro-inflammatory responses in IgA receptor-positive (CD89) immune cells. Biopsy analyses reveal higher infiltration of CD89 immune cells in the colonic mucosa from patients with UC than control individuals. Further studies show that IgA-coated BEVs, but not host-derived vesicles nor soluble IgA, are potent activators of pro-inflammatory responses in CD89 cells. IgA-coated BEVs also exacerbate intestinal inflammation in a dextran sodium sulfate colitis model using transgenic mice expressing human CD89. Our data thus implicate a link between IgA-coated BEVs and intestinal inflammation via CD89 immune cells, and also hint a potential new therapeutic target for UC.
肠道微生物群在溃疡性结肠炎（UC）中促成慢性炎症反应，但分子机制和与疾病相关的效应物仍不清楚。在此，我们分析了在结肠镜检查期间从UC患者和对照患者获取的结肠液的促炎特性。在UC患者中，我们发现可沉淀的效应物部分主要由细菌细胞外囊泡（BEV）组成，这些囊泡呈现高IgA水平，并在IgA受体阳性（CD89）免疫细胞中引发强烈的促炎反应。活检分析显示，UC患者结肠黏膜中CD89免疫细胞的浸润高于对照个体。进一步研究表明，IgA包被的BEV而非宿主来源的囊泡或可溶性IgA是CD89细胞中促炎反应的有效激活剂。使用表达人CD89的转基因小鼠，IgA包被的BEV在葡聚糖硫酸钠结肠炎模型中也会加剧肠道炎症。因此，我们的数据表明IgA包被的BEV与通过CD89免疫细胞介导的肠道炎症之间存在联系，也提示了UC潜在的新治疗靶点。
