Fecal MicroRNAs Show Promise as Noninvasive Crohn's Disease Biomarkers.

BACKGROUND: Short non-coding microRNAs (miRNAs) are involved in various cellular processes during disease progression of Crohn's disease (CD) and remarkably stable in feces, which make them attractive biomarker candidates for reflecting intestinal inflammatory processes. Here we investigated the potential of fecal miRNAs as noninvasive and translational CD biomarkers. METHODS: MiRNAs were screened in feces of 52 patients with CD and 15 healthy controls using RNA sequencing and the results were confirmed by PCR. The relationship between fecal miRNA levels and the clinical CD activity index (CDAI) or CD endoscopic index of severity (CDEIS) was explored, respectively. Additionally, fecal miRNAs were investigated in dextran sodium sulfate, adoptive T-cell transfer, and Helicobacter typhlonius/stress-induced murine colitis models using the NanoString platform. RESULTS: Nine miRNAs (miR-15a-5p, miR-16-5p, miR-128-3p, miR-142-5p, miR-24-3p, miR-27a-3p, miR-223-3p, miR-223-5p, and miR-3074-5p) were significantly (adj. P < 0.05, >3-fold) increased whereas 8 miRNAs (miR-10a-5p, miR-10b-5p, miR-141-3p, miR-192-5p, miR-200a-3p, miR-375, miR-378a-3p, and let-7g-5p) were significantly decreased in CD. MiR-192-5p, miR-375, and miR-141-3p correlated (P < 0.05) with both CDAI and CDEIS whereas miR-15a-5p correlated only with CDEIS. Deregulated expression of miR-223-3p, miR-16-5p, miR-15a-5p, miR-24-3p, and miR-200a-3p was also observed in murine models. The identified altered fecal miRNA levels reflect pathophysiological mechanisms in CD, such as Th1 and Th17 inflammation, autophagy, and fibrotic processes. CONCLUSIONS: Our translational study assessed global fecal miRNA changes of patients with CD and relevant preclinical models. These fecal miRNAs show promise as translational and clinically useful noninvasive biomarkers for mechanistic investigation of intestinal pathophysiology, including monitoring of disease progression.

Molecular Imaging in Preclinical Models of IBD with Nuclear Imaging Techniques: State-of-the-Art and Perspectives.

Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is characterized by chronic unregulated inflammation of the intestinal mucosa of the gastrointestinal tract. To date, this pathology has no cure. Colonoscopy and biopsies are the current gold standard diagnostic tools. However, being a chronic disease, IBD requires continuous follow-up to check for disease progress, treatment response, and remission. Unfortunately, these 2 diagnostic procedures are invasive and generally unable to show the cellular and molecular changes that take place in vivo. In this context, it is clear that there is a strong need for optimized noninvasive imaging techniques able to overcome the aforementioned limitations. This review aims to bring to light the scientific advancements that have been achieved so far in nuclear medicine in relation to tracking of immune cells involved in the preclinical models of IBD. In particular, this review will explore the advantages and limitations of the radiopharmaceuticals that aim to track whole cells like neutrophils, those that involve the radiolabeling of immune cell substrates or available human IBD medical therapies, and those that aim to track cell signaling molecules (e.g., cytokines and cell adhesion molecules). After a detailed critical summary of the state-of-the art, the challenges and perspectives of molecular imaging applied to IBD studies will be analyzed. Special attention will be paid to the translational potential of the described techniques and on the potential impact of these innovative approaches on the drug discovery pipelines and their contribution to the evolution of personalized medicine.

Noninvasive Longitudinal Study of a Magnetic Resonance Imaging Biomarker for the Quantification of Colon Inflammation in a Mouse Model of Colitis.

BACKGROUND: Colonoscopy is the gold standard to diagnose and follow up the evolution of inflammatory bowel diseases. However, this technique can still present a risk of severe complications, a general discomfort in patients, and its diagnostic value is limited to the visualization of the colon mucosal changes. Magnetic resonance imaging (MRI) is emerging as a noninvasive imaging technique of choice to overcome these limitations. The aim of this work was to evaluate the potential of colon wall thickness measured using MRI as an in vivo imaging biomarker of inflammation for inflammatory bowel disease in an animal model of this disease. METHODS: On day 0, 2% or 3% Dextran sodium sulfate was added to the drinking water of mice (n = 10/group) for 5 days. Six mice were left as controls. Animals were imaged with colonoscopy and MRI on days 7, 11, and 21 to study the colitis progression. Histology was performed at the end of the protocol. RESULTS: The colon wall thickness measured in Dextran sodium sulfate-treated animals was shown to be significantly and dose dependently increased compared to controls. Colonoscopy showed similar results and excellently correlated with MRI measurements and histology. The proposed protocol showed high robustness, with negligible interoperator and intraoperator variability. CONCLUSIONS: The findings of this investigation suggest the feasibility of using MRI for the noninvasive assessment of colon wall thickness as a robust surrogate biomarker for colon inflammation detection and follow-up. The data presented show the potential of MRI in in vivo preclinical longitudinal studies, including testing of new drugs or investigation of inflammatory bowel disease development mechanisms.