Regulation of CEACAM Family Members by IBD-Associated Triggers in Intestinal Epithelial Cells, Their Correlation to Inflammation and Relevance to IBD Pathogenesis.

Gonzalo Saiz-Gonzalo,Fergus Shanahan,Seamus Hussey,Valerio Rossini,Naomi Hanrahan,Ruairi O’Sullivan,Patrick T Walsh,Shane Hill,Raminder Singh,Aine Fanning,Maebh Kelleher,Caitriona M O’Driscoll,Silvia Melgar,Mary Ahern,Ken Nally

doi:10.3389/fimmu.2021.655960

Abstract

Carcinoembryogenic antigen cellular adhesion molecules (CEACAMs) are intercellular adhesion molecules highly expressed in intestinal epithelial cells. CEACAM1, -3, -5, -6, -7 are altered in patients suffering from colon cancer and inflammatory bowel diseases (IBD), but their role in the onset and pathogenesis of IBD is not well known. Herein, we aim to correlate CEACAM1, -3, -5, -6, -7 expression to the degree of inflammation in pediatric and adult IBD colon biopsies and to examine the regulation of CEACAMs on human intestinal epithelial cell lines (C2BBe1/HT29) by different IBD-associated triggers (cytokines, bacteria/metabolites, emulsifiers) and IBD-drugs (6-Mercaptopurine, Prednisolone, Tofacitinib). Biopsies from patients with pediatric Crohn’s disease (CD) and adult ulcerative colitis (UC, active/inactive disease) showed a significant increase in CEACAM3, -5, -6 expression, while CEACAM5 expression was reduced in adult CD patients (active/inactive disease). Intestinal epithelial cells cultured with a pro-inflammatory cytokine cocktail and Adherent-invasive Escherichia coli (AIEC) showed a rapid induction of CEACAM1, -5, -7 followed by a reduced RNA and protein expression overtime and a constant expression of CEACAM3, correlating with IL-8 expression. Cells cultured with the emulsifier polysorbate-80 resulted in a significant induction of CEACAM3, -5, -6, -7 at a late time point, while SCFA treatment reduced CEACAM1, -5, -7 expression. No major alterations in expression of CEACAMs were noted on cells cultured with the commensal Escherichia coli K12 or the pathogen Salmonella typhimurium. IBD drugs, particularly Tofacitinib, significantly reduced cytokine-induced CEACAM1, -3, -5, -6, -7 expression associated with a reduced IL-8 secretion. In conclusion, we provide new evidence on the regulation of CEACAMs by different IBD-associated triggers, identifying a role of CEACAMs in IBD pathogenesis.

Highlights

Inflammatory Bowel Disease (IBD), encompassing Ulcerative Colitis (UC) and Crohn’s Disease (CD), is a chronic inflammatory condition affecting the gastrointestinal tract with unknown etiology and accelerating incidence in the western world in both children and adults (0.5–24.5 per 100,000 person/year) [1]
In this study we expanded these findings by examining whether colonic Carcinoembryogenic antigen cellular adhesion molecules (CEACAMs) are altered in children with IBD without any previous treatment and whether changes in CEACAM expression correlate to the degree of inflammation
When the IBD pediatric biopsies are analyzed based on clinical disease activity, no major difference between UC versus CD is detected on the expression of the CEACAMs investigated

Summary

Introduction

Inflammatory Bowel Disease (IBD), encompassing Ulcerative Colitis (UC) and Crohn’s Disease (CD), is a chronic inflammatory condition affecting the gastrointestinal tract with unknown etiology and accelerating incidence in the western world in both children and adults (0.5–24.5 per 100,000 person/year) [1]. The overall disease course of CD is often more severe, especially in those who are diagnosed before the age of 10 years, which can affect their growth, psychological well-being, nutrition, and schooling [2]. Long-term chronic inflammation is a risk factor for the development of colon cancer, especially in patients with UC [3, 4]. There is currently no cure for IBD, and available therapies treat the symptoms of the disease and maintain patients in remission. Among anti-inflammatory drugs used in IBD patients are methylprednisolone, a potent steroid, and Tofacitinib, a Janus kinase (JAK)-inhibitor [6, 7], while drugs used for remission maintenance include the immunosuppressants azathioprine and 6-mercaptopurine (6MP) [8]

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