Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 28, 2017; 23(28): 5115-5126
Published online Jul 28, 2017. doi: 10.3748/wjg.v23.i28.5115
Myo-inositol reduces β-catenin activation in colitis
Emily M Bradford, Corey A Thompson, Tatiana Goretsky, Guang-Yu Yang, Luz M Rodriguez, Linheng Li, Terrence A Barrett
Emily M Bradford, Corey A Thompson, Tatiana Goretsky, Terrence A Barrett, Division of Gastroenterology, Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, United States
Guang-Yu Yang, Department of Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
Luz M Rodriguez, Division of Cancer Research, National Cancer Institute, DCP/GOCRG, Bethesda, MD 20892, United States
Luz M Rodriguez, Department of Surgery, Walter Reed National Military Medical Center, Bethesda, MD 20889, United States
Linheng Li, Department of Pathology and Laboratory Medicine, University of Kansas School of Medicine and Stowers Institute for Medical Research, Kansas, MO 64110, United States
Author contributions: Bradford EM, Thompson CA and Goretsky T performed experiments and analyzed data; Yang GY provided assistance with pathology; Rodriguez LM and Barrett TA supported the design and execution of the clinical trial; Li L provided reagents and contributed to the experimental design; Bradford EM and Barrett TA wrote the manuscript.
Supported by Veterans Affairs Merit Award, No. IO1CX001353 (to Barrett TA); National Institutes of Health, No. 2R01DK095662-06A1 (to Barrett TA); the National Cancer Institute at the National Institutes of Health, No. N01-CN-35157 (to Bergan R); the Training Program in Oncogenesis and Developmental Biology through the National Cancer Institute, No. NCI T32 CA080621 (to Bradford EM); an Institutional Development Award from the National Institute of General Medical Sciences of the National Institutes of Health, No. 8 P20GM103527-05; and American Physiological Society STEP-UP Fellowship (to Thompson CA).
Institutional review board statement: For all human studies, informed consent was obtained from every patient and samples were coded. Collection of all material was approved by the Northwestern University or University of Kentucky Institutional Review Boards. Some biopsies were collected under the NCI Myo-Inositol Chemoprevention in Colitis-Associated Dysplasia trial, #NWU09-13-02. The ClinicalTrials.gov identifier for the Myo-Inositol Chemoprevention trial is NCT01111292.
Institutional animal care and use committee statement: All animal studies were approved by the University of Kentucky Institutional Animal Care and Use Committee (IACUC).
Conflict-of-interest statement: The authors have no conflicts-of-interest to report.
Data sharing statement: All patients gave informed consent to allow their samples to be used in this study. These samples were coded and no patient information is identifiable.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Terrence A Barrett, MD, Division of Gastroenterology, Department of Internal Medicine, University of Kentucky, 800 E. Rose St. MN649, Lexington, KY 40536, United States. t.barrett@uky.edu
Telephone: +1-859-323-4887 Fax: +1-859-257-8860
Received: February 6, 2017
Peer-review started: February 8, 2017
First decision: March 16, 2017
Revised: March 31, 2017
Accepted: May 9, 2017
Article in press: May 9, 2017
Published online: July 28, 2017
Abstract
AIM

To assess dietary myo-inositol in reducing stem cell activation in colitis, and validate pβ-cateninS552 as a biomarker of recurrent dysplasia.

METHODS

We examined the effects of dietary myo-inositol treatment on inflammation, pβ-cateninS552 and pAkt levels by histology and western blot in IL-10-/- and dextran sodium sulfate-treated colitic mice. Additionally, we assessed nuclear pβ-cateninS552 in patients treated with myo-inositol in a clinical trial, and in patients with and without a history of colitis-induced dysplasia.

RESULTS

In mice, pβ-cateninS552 staining faithfully reported the effects of myo-inositol in reducing inflammation and intestinal stem cell activation. In a pilot clinical trial of myo-inositol administration in patients with a history of low grade dysplasia (LGD), two patients had reduced numbers of intestinal stem cell activation compared to the placebo control patient. In humans, pβ-cateninS552 staining discriminated ulcerative colitis patients with a history of LGD from those with benign disease.

CONCLUSION

Enumerating crypts with increased numbers of pβ-cateninS552 - positive cells can be utilized as a biomarker in colitis-associated cancer chemoprevention trials.

Keywords: Chemoprevention, Dysplasia, Biomarker, Stem cell, Colitis-associated cancer

Core tip: We report that dietary myo-inositol reduced inflammation and intestinal stem cell activation in both genetic and chemically-induced mouse models of colitis. In a limited clinical trial of colitis patients with a history of recurrent low grade dysplasia (LGD), myo-inositol reduced the number of intestinal crypts with activated stem cells. This study demonstrated for the first time that nuclear pβ-cateninS552 staining discriminates between patients with inflammation and those with a history of LGD, suggesting that nuclear pβ-cateninS552 staining may reflect local expansions of activated stem cells with neoplastic potential. Based on these data, we propose a more extensive clinical trial.