Effects of Vitamin D and Calcium Supplementation on Toll-Like Receptor 4 (TLR4) Expression in the Stroma of Normal-Appearing Rectal Mucosa of Colorectal Adenoma Patients Restricted; Files Only

Ray, Stephen (2017)

Permanent URL: https://etd.library.emory.edu/concern/etds/js956g71n?locale=en


Colorectal cancer (CRC) has the third highest mortality among cancers within the United States. A variety of lifestyle and dietary factors are known to contribute to the risk of CRC, including high BMI, tobacco smoking, red or processed meat consumption, physical inactivity, low vitamin D exposure and calcium intake. TLR4 signaling pathway has been shown to contribute to the inflammatory processes in the colon. Therefore, understanding how this pathway could be beneficially modulated by dietary and lifestyle changes could have potential implications for future prevention of CRC. We conducted a biomarker adjunct study nested within a randomized clinical trial (RCT) testing the effect of vitamin D, calcium, and combined treatment on the expression of the TLR4 biomarker in the stroma of normal-appearing rectal epithelium of colorectal adenoma patients. One hundred and five participants were recruited into the adjunct biomarker sub study and had their baseline characteristics recorded and rectal biopsies taken for TLR4 expression measurement at baseline and at year one follow-up. Our results indicated that neither of the treatments had a statistically significant effect on TLR4 expression in the stroma of normal-appearing rectal epithelium of colorectal adenoma patients. There was however a modest inverse reduction in TLR4 expression that was the most profound with vitamin D treatment. Vitamin D treatment reduced TLR4 expression by 18% (p = 0.394), and the combined treatment of vitamin D and calcium resulted in a 21% reduction in TLR4 expression (p = 0.425). Additional analyses examining the associations between baseline characteristics and TLR4 expression identified being overweight (p = 0.006), being a regular aspirin user (p = 0.046), having low total calcium intake (p = 0.033) and high vitamin D intake (p = 0.003) as factors associated with TLR4 expression in the stroma of normal-appearing rectal mucosa. In conclusion, supplementation with vitamin D and to a lesser extent calcium combined with vitamin D has a modest effect at lowering TLR4 expression within the stroma of normal-appearing rectal epithelium of colorectal adenoma patients.

Table of Contents

Table of Contents

Background. 1

Colorectal Cancer. 1

Inflammation and the Toll-like Receptor 4 Pathway in Colorectal Carcinogenesis. 2

Calcium and Colorectal Neoplasms. 6

Vitamin D and Colorectal Neoplasms. 7

Other Risk Factors for Colorectal Cancer. 9

Inflammation within the Lamina Propria. 10

Methods and Materials. 13

Clinical Trial Protocol and Recruitment. 13

Rectal Biopsy Tissue Collection and TLR4 Quantification. 14

Statistical Analyses. 16

Results. 19

Selected Baseline Characteristics. 19

TLR4 Biomarker Expression by Treatment Assignment and Agent. 20

TLR4 Biomarker Expression by Baseline Characteristics. 21

Stratified Analyses. 24

Discussion. 29

Primary Findings. 29

TLR4 and Gut Barrier Health. 29

Previous Studies. 31

Strengths and Limitations. 34

Conclusion. 35

Public Health Impact and Future Directions. 36

Summary. 36

Possible Future Directions. 36

References. 38

Tables. 43

Appendices. 48

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