Effects of Supplemental Calcium and Vitamin D on Toll-like Receptor 5 (TLR5) Expression in the Stroma of the Normal-Appearing Rectal Mucosa of Colorectal Adenoma Patients Público

Abstract

Despite major advances in screening and treatment, colorectal cancer (CRC) remains the third leading cause of death from cancer worldwide. Calcium and vitamin D have both gained appreciable interest as promising chemopreventive agents against colorectal neoplasms, likely due to their anti-inflammatory and cell cycle regulating properties. Recent studies suggest that dysregulation of Toll-like receptor 5 (TLR5), an innate immune sensor for flagellin, may trigger cytokine secretion and pro-inflammatory responses in the colon, contributing to colorectal carcinogenesis. Although some preliminary data suggest that TLR5 may be beneficially modified by calcium and vitamin D, no human data exist. Therefore, we conducted an adjunct biomarker study nested within a larger randomized, double-blind, placebo-controlled, partial 2 x 2 factorial chemoprevention trial to test the effect of supplemental calcium (1,200 mg daily) and vitamin D (1,000 IU daily) on TLR5 expression in the stroma of normal-appearing rectal mucosa of 105 colorectal adenoma patients. TLR5 expression was measured using standardized, automated immunohistochemistry and quantitative image analysis. Although not statistically significant, the preliminary results of this pilot study suggest that supplemental vitamin D3, alone or in combination with calcium, may increase TLR5 expression. Our analysis of patient characteristics and biomarker expression at baseline showed that race (P=0.01), having serrated adenomas (P=0.06), and baseline total calcium intake (P=0.04) were associated with TLR5 expression. While not statistically significant, modest associations were also observed with baseline physical activity, BMI, and alcohol consumption, providing further support for TLR5 expression in the stroma of the normal-appearing rectal mucosa as a modifiable, pre-neoplastic marker of risk for colorectal neoplasms. These initial findings are promising and support the continued investigation of modifiable risk factors that may influence inflammatory pathways related to colorectal carcinogenesis.

Table of Contents

TABLE OF CONTENTS

BACKGROUND/LITERATURE REVIEW ...................................................................... 1

Colorectal Carcinogenesis Pathway................................................................................... 1

Risk Factors for Colorectal Cancer.................................................................................... 2

Calcium and Colorectal Carcinogenesis ............................................................................ 4

Vitamin D and Colorectal Carcinogenesis ......................................................................... 5

Synergism/Antagonism of Calcium and vitamin D ............................................................. 7

Inflammation, Gut Microbiome, TLR5, and Colorectal Carcinogenesis............................ 8

Significance of the Stroma ................................................................................................ 11

METHODS ....................................................................................................................... 13

Research Aims................................................................................................................... 13

Clinical Trial Protocol...................................................................................................... 13

Rectal Biopsy Tissue Collection and Quantification of TLR5 .......................................... 15

Statistical Analysis ............................................................................................................ 17

RESULTS ......................................................................................................................... 20

Baseline Characteristics of Study Participants ................................................................ 20

TLR5 Expression by Treatment Assignment and Agent.................................................... 20

Stratified Analyses ............................................................................................................ 22

TLR5 Expression by Baseline Characteristics.................................................................. 23

DISCUSSION ................................................................................................................... 25

Discussion of Primary Findings ....................................................................................... 25

Factors Associated with TLR5 Expression ....................................................................... 26

Strengths and Limitations ................................................................................................. 30

Public Health Impact ........................................................................................................ 31

Conclusion and Future Directions.................................................................................... 32

REFERENCES ................................................................................................................. 33

TABLES ...........................................................................................................................44

FIGURES...........................................................................................................................53

APPENDIX........................................................................................................................54

About this Master's Thesis

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School	Rollins School of Public Health
Department	Epidemiology
Subfield / Discipline	Epidemiology - MPH & MSPH
Degree	M.P.H.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Epidemiology
Palavra-chave	Colorectal cancer Calcium Toll-like receptor 5 Vitamin D Inflammation TLR5
Committee Chair / Thesis Advisor	Fedirko, Veronika , Emory University
Partnering Agencies	Does not apply (no collaborating organization)

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