Protective links between vitamin D, inflammatory bowel disease and colon cancer

girl in sun and sunflowersArticle Written by Stacey Meeker, Audrey Seamons, Lillian Maggio-Price, and Jisun Paik
World Journal of Gastroenterology (2016); 22(3):933-948
January 21, 2016

Abstract

Vitamin D deficiency has been associated with a wide range of diseases and multiple forms of cancer including breast, colon, and prostate cancers. Relatively recent work has demonstrated vitamin D to be critical in immune function and therefore important in inflammatory diseases such as inflammatory bowel disease (IBD). Because vitamin D deficiency or insufficiency is increasingly prevalent around the world, with an estimated 30%-50% of children and adults at risk for vitamin D deficiency worldwide, it could have a significant impact on IBD. Epidemiologic studies suggest that low serum vitamin D levels are a risk factor for IBD and colon cancer, and vitamin D supplementation is associated with decreased colitis disease activity and/or alleviated symptoms. Patients diagnosed with IBD have a higher incidence of colorectal cancer than the general population, which supports the notion that inflammation plays a key role in cancer development and underscores the importance of understanding how vitamin D influences inflammation and its cancer-promoting effects. In addition to human epidemiological data, studies utilizing mouse models of colitis have shown that vitamin D is beneficial in preventing or ameliorating inflammation and clinical disease. The precise role of vitamin D on colitis is unknown; however, vitamin D regulates immune cell trafficking and differentiation, gut barrier function and antimicrobial peptide synthesis, all of which may be protective from IBD and colon cancer. Here we focus on effects of vitamin D on inflammation and inflammation-associated colon cancer and discuss the potential use of vitamin D for protection and treatment of IBD and colon cancer.

Core tip: Vitamin D is inversely related to inflammation-associated diseases such as inflammatory bowel disease (IBD) and colon cancer. As vitamin D deficiency and insufficiency are prevalent worldwide, it can significantly impact risk and progression of these diseases. Here we provide an overview of human epidemiologic and animal studies linking vitamin D, IBD and colon cancer. We also review potential mechanisms of vitamin D action that were elucidated by using animal models. Finally, we address current knowledge gaps in this field of research to help determine the potential benefits and risks of using vitamin D to prevent and/or treat IBD and cancer.

INTRODUCTION

Vitamin D is primarily known for its role in regulation of bone metabolism by controlling intestinal calcium absorption and bone remodeling[4], the importance of which is demonstrated by prolonged vitamin D deficiency resulting in delayed growth and rickets in children as well as osteoporosis and osteopenia in adults. In addition to its role in bone metabolism, it has become increasingly apparent that vitamin D participates in a variety of other physiological functions, including immune responses. Consequently, vitamin D deficiency is also associated with a wide range of diseases including: asthma, multiple sclerosis, rheumatoid arthritis, type 1 diabetes, heart disease, depression, and tuberculosis. For our interests, epidemiologic studies link low serum vitamin D levels with an increased risk of developing inflammatory bowel disease (IBD) and colon cancer. As vitamin D deficiency or insufficiency is increasingly prevalent around the world, with estimates of 30%-50% of children and adults at risk of vitamin D deficiency worldwide, it could significantly influence incidence and progression of IBD and colon cancer. In this paper, we will review current evidence linking vitamin D, IBD, and colitis-associated colon cancer (CAC) and summarize the potential benefits and risks of using vitamin D to prevent or treat these diseases. Several reviews have been published recently concerning vitamin D and the immune system and cancer.

OVERVIEW OF IBD, CAC AND VITAMIN D

IBD is a group of diseases characterized as chronic remittent or progressive inflammation of the gastrointestinal tract. The two primary conditions in humans are Crohn’s disease (CD) and ulcerative colitis (UC), and the prevalence of both conditions have been increasing in western countries over the past 50 years with CD affecting 50-200/100000 people and UC affecting 120-200/100000 people per year[29]. Though the precise etiology underlying IBD remains unclear, dysregulation of the mucosal immune system in response to enteric antigens is believed to be one of the initiators of the chronic inflammation[30]. Patients diagnosed with IBD are at increased risk for developing CAC compared to the general population, especially if the colitis is not well controlled. Inflammation is believed to play a role in the development of CAC through promotion of angiogenesis, tumor-promoting cytokine production, tumor cell invasive behavior, cellular proliferation and alterations in immune responses. Treatments to limit inflammation may be beneficial in reducing the incidence of CAC in these high-risk populations. Because vitamin D has been shown to alter many of the pathways involved in inflammation as well as tumorigenesis, the potential to use vitamin D supplementation as an adjunct therapy in IBD patients is being explored.

We have recently shown that dietary vitamin D supplementation provides protection against IBD and subsequent inflammation-induced colon cancer in the Smad3-/- mouse model of CAC. Our data suggest that the chemoprotective effect of vitamin D is likely due to decreased colitis prior to tumor development. Our findings are consistent with other studies demonstrating association between vitamin D supplementation and decreased colitis, disease activity and/or alleviated symptoms of IBD in both mice and humans. Additionally, both our work and others have demonstrated that vitamin D decreases the incidence of dysplasia, a precursor to cancer, in models of IBD-associated colon cancer. These data support the notion that vitamin D may be a beneficial adjunct therapy for IBD and CAC. Because there is currently no cure for IBD, patients typically require long-term immunomodulatory drug therapy to manage their symptoms with substantial economic costs over their lifetime. The use of vitamin D as a treatment in patients with IBD would be simple and inexpensive to implement. However, the specific mechanisms through which vitamin D ameliorates colitis remain unknown though vitamin D has been shown to regulate immune cell trafficking and differentiation, gut barrier function, and antimicrobial peptide synthesis, all of which may play a role in mediating protection from disease. Thus, additional studies are needed to determine the patient populations that might benefit from vitamin D therapy.

VITAMIN D METABOLISM AND SIGNALING

To explain mechanisms by which vitamin D might influence IBD and colon cancer, we will briefly review the metabolism and actions of vitamin D. More thorough reviews on this topic can be found in recent publications.

Humans obtain the majority of their vitamin D from exposure to sunlight as UVB radiation is able to convert 7-dehydrocholesterol to vitamin D3 (cholecalciferol) in the skin. Diet, however, becomes an important means of obtaining vitamin D in individuals with limited exposure to sunlight, such as might occur due to insufficient exposure to natural sunlight because of residing at higher latitudes or limited amounts of time spent outdoors, or increased protection against sun exposure through clothing and/or sunscreen. Therefore, inadequate intake of foods rich in vitamin D such as oily fish, beef liver, and fortified milk products can significantly impact vitamin D status in some individuals.

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Article Written by Stacey Meeker, Audrey Seamons, Lillian Maggio-Price, and Jisun Paik
World Journal of Gastroenterology (2016); 22(3):933-948
January 21, 2016

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