DISTINCTIVE MOLECULAR SIGNATURE AND STRUCTURAL ALTERATIONS OF THE COLONIC BRUSH BORDER IN MICROSCOPIC COLITIS

BACKGROUND: Collagenous colitis (CC) and lymphocytic colitis (LC) are chronic inflammatory diseases of the colon of unknown etiology. We aimed to explore the underlying mechanisms of the colonic barrier dysfunction in MC by analysing the molecular pathways involved in the colonic epithelial brush border. METHODS: We obtained colonic biopsies from CC and LC patients and from healthy controls (H) and irritable bowel syndrome with predominance of diarrhea (IBS-D) patients, as control groups. Transcriptomic and proteomic analysis by RNA-seq and liquid chromatography mass spectrometry, respectively, and an ultrastructural assessment or the epithelium by electron microscopy were performed. The impact of budesonide therapy on the epithelial structure was also evaluated in samples from CC patients Integrated clinical and biological data analysis was performed using R. FINDINGS: A paired-omic analysis focused on the brush border identified a reduced expression of the inter-microvilli adhesion complex and the actin-bundling proteins in parallel to an increased expression of the actin-membrane connection of microvilli in MC patients compared to control groups. Moreover, colonic microvilli were shorter in length and reduced in number in CC and LC respect to controls. Treatment with oral budesonide partially recovered the ultrastructural alterations in parallel to clinical improvement. INTERPRETATION: Differentiated molecular and structural dysregulation of the colonic brush border features the colonic epithelium in MC. Given the fundamental role of the brush border in maintaining homeostasis, these previously undescribed findings open new perspectives to further define MC etiopathogenesis and the search of targeted therapies. Overall design: RNA expression was determinedby RNAseq in colonic biopsies in three types of colitis ( 12 CC ,12 LC and 13 IBS-D) and 11 Healthy subjects . We performed sequencing using Illumina NovaSeq 6000 system, paired-end reads and 101 length.