Integrated Multi-Omic Analysis Identifies Altered Colonic Brush Border Profile as a Key Feature of Microscopic Colitis.

BACKGROUND: Microscopic colitis (MC), comprising lymphocytic colitis (LC) and collagenous colitis (CC), is an inflammatory bowel disease with increasing incidence. MC etiopathogenesis remains unknown; however, altered colonic epithelial integrity may underlie uncontrolled luminal antigen passage, triggering immuno-inflammatory responses. OBJECTIVE: The aim of this study was to further define the involvement of the colonic epithelium in MC. METHODS: A paired transcriptomic and proteomic analysis followed by epithelial ultrastructural examination was performed on colonic biopsies from LC and CC patients, and from irritable bowel syndrome with a predominance of diarrhoea (IBS-D) and healthy subjects (H) as control groups. The impact of budesonide therapy on the epithelial structure was also evaluated in CC. RESULTS: MC patients exhibited decreased expression of inter-microvilli adhesion and actin-bundling proteins, accompanied by increased expression of actin-membrane connection proteins compared to both control groups. Distinct molecular differentiated CC and LC, which translated into differential ultrastructure abnormalities. The colonic microvilli in CC patients were shorter in length and fewer in number, with partial restoration following budesonide treatment, whereas LC showed a reduction solely in microvilli number. A negative correlation was found between daily stool frequency and SPATN1 and ATP8B1 protein levels in CC patients. CONCLUSIONS: Molecular dysregulation and aberrant ultrastructure of the colonic brush border feature the colonic epithelium in LC and CC. These previously undescribed findings provide new perspectives for further defining MC pathogenesis and identifying biomarkers for diagnosis, prognosis and treatment of this debilitating and prevalent disease.