Defining a timeline of colon pathologies after keratin 8 loss: Rapid crypt elongation and diarrhea are followed by epithelial erosion and cell exfoliation

Maria Ilomäki, Lauri Polari*, Carl-Gustaf A Stenvall, Mina Tayyab, Kirah Kähärä, Karen M Ridge, Diana M Toivola

*Korresponderande författare för detta arbete

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

45 Nedladdningar (Pure)

Sammanfattning

Keratins are epithelial intermediate filament proteins that play a crucial role in cellular stress protection, with K8 being the most abundant in the colon. The intestinal epithelial-specific K8-deficient mouse model (K8 flox/fl ox;Villin-Cre) exhibits characteristics of inflammatory bowel disease, including diarrhea, crypt erosion, hyperproliferation, and decreased barrier function. Nevertheless, the order in which these events occur and whether they are a direct cause of K8 loss or a consequence of one event inducing another remains unexplored. Increased knowledge about early events in the disruption of colon epithelial integrity would help to understand the early pathology of inflammatory and functional colon disorders and develop preclinical models and diagnostics of colonic diseases. Here, we aimed to characterize the order of physiological events after Krt8 loss by utilizing K8 flox/fl ox;Villin-CreER t2 mice with tamoxifen-inducible Krt8 deletion in intestinal epithelial cells, and assess stool analysis as a noninvasive method to monitor real-time gene expression changes following Krt8 loss. K8 protein was significantly decreased within a day after induction, followed by its binding partners, K18 and K19 from day 4 onward. The sequential colonic K8 downregulation in adult mice leads to immediate diarrhea and crypt elongation with activation of proliferation signaling, followed by crypt loss and increased neutrophil activity within 6–8 days, highlighting impaired water balance and crypt elongation as the earliest colonic changes upon Krt8 loss. Furthermore, epithelial gene expression patterns were comparable between colon tissue and stool samples, demonstrating the feasibility of noninvasive monitoring of gut epithelia in preclinical research utilizing Cre-LoxP-based intestinal disease models. NEW & NOTEWORTHY Understanding the order in which physiological and molecular events occur helps to recognize the onset of diseases and improve their preclinical models. We utilized Cre-Lox-based inducible keratin 8 deletion in mouse intestinal epithelium to characterize the earliest events after keratin 8 loss leading to colitis. These include diarrhea and crypt elongation, followed by erosion and neutrophil activity. Our results also support noninvasive methodology for monitoring colon diseases in preclinical models.

OriginalspråkEngelska
Sidor (från-till)G67-G77
Antal sidor11
TidskriftAJP - Gastrointestinal and Liver Physiology
Volym326
Nummer1
DOI
StatusPublicerad - 1 jan. 2024
MoE-publikationstypA1 Tidskriftsartikel-refererad

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