Micronutrients and Their Role in Inflammatory Bowel Disease: Function, Assessment, Supplementation, and Impact on Clinical Outcomes Including Muscle Health

Abstract

The incidence of inflammatory bowel disease (IBD) continues to rise worldwide, and patients with IBD are at increased risk for malnutrition and micronutrient deficiencies.1 The etiology of malnutrition and micronutrient deficiencies in IBD is multifactorial and includes reduced oral intake, increased intestinal loss, malabsorption, increased nutritional needs in the setting of a hyper catabolic state, medication effects, and altered anatomy after luminal surgery. Malnutrition can lead to deficiencies in both macronutrients (protein-energy malnutrition) and micronutrients (vitamin and mineral loss) and is estimated to affect up to 80% of patients at any point during their disease course. Micronutrient absorption occurs mostly across the epithelium of the small bowel, which is likely why patients with Crohn’s disease (CD) have a higher prevalence of nutritional deficiencies compared with those with ulcerative colitis (UC).2 Despite common misconception, malnutrition has been identified in patients with both active IBD and in those with quiescent disease.3 In all patients with IBD, malnutrition has been associated with poor clinical outcomes including poor response to biologic therapy, higher rates of hospitalization, increased postoperative complications, and reduced quality of life.4 Micronutrients play many roles in the human body: acting as cofactors in metabolism, antioxidants to reduce free radicals and oxidative stress, coenzymes in metabolism, and gene regulators.5,6 There are numerous studies evaluating micronutrient deficiencies in patients with IBD, and the current literature suggests that over 50% of patients with IBD have had at least 1 vitamin or mineral deficiency.1,2,7 The majority of these studies focus on deficiencies in vitamin B12, vitamin D, and iron, which are more commonly seen in patients with active inflammation and specifically ileal disease.2 However, other nutrients, such as vitamin C, vitamin B1, folic acid, selenium, and zinc can become deficient in IBD and are often overlooked.1,2 These deficiencies can contribute to clinically significant symptoms as well as disease-related complications; therefore, it is crucial to identify these deficiencies and intervene early in the disease course.1 It is important to highlight the importance of these less well-studied micronutrients and to provide concrete guidelines on assessment and supplementation. A recent study evaluating a nutrition care pathway in IBD identified that the majority of IBD providers did not have access to expert nutrition care in the clinic, and even with access to nutrition care, provider knowledge about nutrition testing and supplementation was limited.8 Therefore, the goal of this article is to review the literature on micronutrient deficiencies in IBD including the prevalence, risk factors, and supplementation strategies, as well as the impact of these deficiencies on IBD-related outcomes including sarcopenia. Although micronutrient deficiencies are commonly associated with undernutrition (protein calorie malnutrition), these deficiencies can similarly occur in patients who are otherwise well nourished. The term hidden hunger has been proposed to describe micronutrient deficiencies that occur without a deficit in calories or other macronutrients.9 This phenomenon is quite common, especially in Western countries, in which the diet can be energy rich but nutrient poor, and in patients with malabsorption in which vitamin and mineral absorption is impaired.9 The majority of the literature on micronutrient deficiencies in IBD centers around deficiencies in vitamin B12, vitamin D, vitamin B9 (folate), and iron. There is a significant body of literature describing the etiology and prevalence of these deficiencies as well as guidance on supplementation. Therefore, this review will instead focus on the commonly overlooked vitamins and minerals that may be deficient in patients with IBD and can contribute to clinically significant symptomatology (Tables 1 and 2, Figure 1). Summary of micronutrients, their function, sources in the diet, and symptoms of deficiency Abbreviations: IBD, inflammatory bowel disease; IV, intravenous; RBC, red blood cell; TPN, total parenteral nutrition; UC, ulcerative colitis. Interpretation of nutrition related markers in the setting of systemic inflammation42,43 Location of micronutrient absorption across the small bowel and colon. Figure created with BioRender.com. Vitamin B1, also known as thiamine, is a water-soluble vitamin that plays a role in nerve conduction and catabolism of carbohydrates and amino acids.1,44 Thiamine is generally plentiful in the diet and well absorbed in the jejunum through active and passive transport. Thiamine is commonly found in fortified breakfast cereals, breads, yogurt, eggs, and meat (pork). Although rare, thiamine deficiency in humans can cause cardiovascular, muscular, neurologic, and gastrointestinal symptoms.44 Most commonly, thiamine deficiency causes dry beriberi, which is characterized by peripheral neuropathy (loss of sensory, motor, and reflexes). Wet beriberi is similarly characterized by not only peripheral neuropathy, but also edema, tachycardia, cardiomegaly and heart failure.44 Thiamine deficiency has been reported in patients with CD; Filippi et al13 demonstrated that patients with CD in remission had lower consumption of thiamine compared with healthy control subjects and a higher incidence of thiamine deficiency (roughly 33%, as measured by high-performance liquid chromatography [HPLC]). Moreover, thiamine has been studied as a therapeutic intervention to treat fatigue in patients with quiescent IBD; in a randomized, double-blind, placebo-controlled crossover study, patients who were given supplementation with high-dose thiamine (600-1800 mg/d depending on sex and weight) had significant improvement in fatigue scores after 4 weeks compared with those who received the placebo.45 However, in a long-term maintenance study, these findings were not reproduced, as there was no clear effect of thiamine supplementation on fatigue at 12-week or 6-month follow-up.46 Nonetheless, the true prevalence and clinical impact of thiamine deficiency and supplementation in patients with IBD remains unclear and hopefully will be elucidated with future studies.1 Vitamin B2, also known as riboflavin, is a water-soluble vitamin that plays a crucial role in oxidative reduction reactions required for energy production and metabolism.44 Riboflavin is abundant in a variety of foods including fortified carbohydrates, eggs, milk, broccoli, and meats. This vitamin is mostly absorbed through active transport (sodium channels) in the jejunum. Isolated deficiency of vitamin B2 is almost never observed; however, it can occur in combination with other water-soluble vitamin deficiencies. Malabsorption of riboflavin has been associated with concurrent lactose intolerance, tropical sprue, CD, celiac disease, malignancy, and small bowel resection.44 Deficiency is often characterized by angular cheilitis and ocular changes, including photophobia.1 There are limited data to suggest that patients with IBD have lower levels of vitamin B2 compared with healthy control subjects.1,13 In vivo and in vitro models have shown that proinflammatory cytokines such as tumor necrosis factor α impair riboflavin absorption and that administration of riboflavin can intestinal in colitis Vitamin also known as or acid, is a water-soluble vitamin that plays a role in and energy is not a true vitamin by as it can be is absorbed by active and passive transport in the jejunum and is in red and A deficiency in in which is characterized by and In study vitamin levels in patients with CD, of patients in clinical remission were found to be deficient in by In there are of in patients with There are no studies to evaluating deficiency in patients with However, have these as may be with levels and not with this study suggests that deficiency in patients with both CD and is Vitamin or is a water-soluble vitamin that plays role in including metabolism, and the active of vitamin is in and such as and Vitamin is mostly absorbed through passive transport in the jejunum. the be in a known as to to the other vitamin deficiency occurs in the setting of other nutritional deficiencies and is seen in deficiency with neuropathy, and in studies estimated that the prevalence of vitamin deficiency to in patients with CD and was in those with Moreover, active inflammation was associated with higher rates of vitamin deficiency compared with those with quiescent disease however, it is unclear this is true deficiency or a of the that vitamin is a It is important to that such as and can with vitamin metabolism, and patients Vitamin or is a water-soluble vitamin that plays important role in metabolism, gene and of the inflammatory deficiency is quite rare, as is in a of including and cereals, and there is passive absorption in the jejunum. Although the data on deficiencies in patients with IBD are models have demonstrated that a diet can colitis that is by this study demonstrated that supplementation colitis in a for IBD by of factor inflammatory cytokines and to the of the Despite these human study did not a in levels in patients with CD as compared with healthy control The majority of the literature or however, it is unclear these are in levels have been proposed as however, it is unclear this is to or and levels are not in clinical Vitamin C, or acid, is that the all of the micronutrients, vitamin has the as vitamin was in the and has significant and over the and across the are to vitamin however, humans are not to and it the Vitamin plays a crucial role in and as oxidative this vitamin deficiency is known to cause poor loss, and a Vitamin is absorbed by active and passive transport in the jejunum and is found in many foods including and Vitamin as measured by has been reported in patients with CD and UC, and it not to be associated with disease Vitamin deficiency in IBD patients is to that are commonly in and the impact of long-term in this Vitamin or in is a vitamin that plays important role in and Vitamin A absorption and is more for the water-soluble vitamin A is to by and absorbed through active transport in the small bowel, it is to a to be to the and for There are of vitamin A that can be found in including in eggs, and as well as in broccoli, and other to other levels of vitamin A only are therefore, patients can have vitamin A with Although in countries, vitamin A deficiency has been in IBD and causes and poor et a response to identify of vitamin A and found that patients with CD were more likely to have a deficiency compared with control subjects In this study, vitamin A was associated with a body however, there was no deficiency and IBD disease or in a review with including patients with CD and patients with UC, the vitamin A was lower in those with IBD compared with the healthy control the of or supplementation in patients with IBD have had however, providers supplementation for a limited of in postoperative patients to especially in those with recent However, given that this vitamin is is and supplementation be limited to a of Malabsorption of such as vitamin also occurs in patients with bowel and in those with small intestinal and and supplementation be in these Vitamin A is also known to have important on the Vitamin is similarly a vitamin that is known for in the human The numerous of vitamin are found in and as well as in and of vitamin occurs in the bowel and and Vitamin is commonly absorbed with therefore, in patients with malabsorption, vitamin levels may similarly Vitamin to be in both the and in however, it can also be found in with higher vitamin deficiency in patients with IBD have had 1 study found that patients with CD had lower vitamin to a in vitamin levels IBD patients and healthy control the in the there is no for vitamin however, providers vitamin deficiency in patients with malabsorption, or with vitamin it is important to vitamin deficiency in patients with small bowel bowel and small intestinal Vitamin is a vitamin that plays a crucial role in the and in There are of vitamin vitamin and vitamin Vitamin is plentiful in the diet and is commonly found in and vitamin is by in sources and is found in such as and vitamin plays a role in the the vitamin is to have a role in and and numerous disease, malignancy, Vitamin has a and it is found the body not in the vitamins and and for absorption in the small These are for transport in the and in the or of vitamin deficiency in IBD is by significant and reduced of testing levels are commonly however, are by as well as and may be studies on vitamin deficiency in IBD as a of vitamin and found that of patients with gastrointestinal were studies have identified vitamin deficiencies in patients with CD but not in patients with There are no studies to vitamin and deficiencies in Although the of vitamin deficiency in IBD is not well deficiencies are associated with active small bowel and active ileal or is a mineral and that plays role in and is absorbed in the small bowel, and is through and intestinal Therefore, IBD patients with or malabsorption, or are at increased risk for zinc levels of zinc are found in red yogurt, and The prevalence of zinc in and is related to zinc levels in the which are by and the of other in the such as and The estimated prevalence of zinc deficiency in patients with IBD to deficiency can cause numerous and to and even and In a study of patients with both CD and UC, zinc deficiency in with was associated with increased for and IBD-related clinical or the of or in patients who were found to have a zinc deficiency and to zinc levels in this study, the risk of and poor outcomes to the risk associated with no zinc other studies have zinc deficiency in IBD, many identified in the of the zinc levels to limited zinc in the significant in zinc levels the and the impact of inflammation on zinc levels in more providers have testing other such as or for a of zinc this remains and is not in clinical is a and to it plays important role in and in of oxidative is to be absorbed in the and the is not well sources of fortified and such as deficiency has been identified in patients with IBD; study estimated the prevalence to be about in patients with CD and identified that levels were associated with increased disease body and small bowel Moreover, in models of deficiency is associated with of the intestinal inflammation and of inflammatory is a absorption is to zinc levels and other micronutrients such as and is commonly found in such as and and is the including in the and therefore, deficiency in the is quite both and levels are and are of in the setting of active Moreover, and zinc supplementation can a of However, studies in IBD have identified with a prevalence as as 80% in study of patients with quiescent studies have shown that levels in patients with IBD are to those of control It remains unclear deficiency is a in patients with IBD, and future to will to are other sources to for such as and to a more of systemic is a mineral that is required for energy and sources of and to levels in and are by levels in the In to be is a and in the of the in patients with or those on this is and will be is generally absorbed in the and jejunum and is in In patients with IBD, commonly occurs as a effect of supplementation with is often but can contribute to clinically significant and especially in patients supplementation with can be associated with clinically significant is important to to is a mineral that is in energy and is in both and as well as fortified and the other is to be absorbed in the and the deficiency is common in the it is estimated that 50% to of not the This is likely to increased consumption of reduced of in and of deficiency can be clinically and even can deficiency has been in patients with IBD with significant in the reported prevalence Deficiency is in patients with and small bowel In a recent study, levels were to about the impact of systemic inflammation on in this study, patients with IBD had lower levels of compared with healthy control and this was in those with there was no with disease and levels in this In all of these deficiency was commonly seen in patients with of and in those with malabsorption or poor oral The recent nutrition and IBD guidelines the for and with that all patients with IBD be for micronutrient deficiencies on a and be The also the specifically that those patients who are in remission and those who are well can have micronutrient deficiencies and be all patients for micronutrient deficiencies at the of and however, this is not Therefore, at a it is important to which patients micronutrient testing on medication or clinical disease These clinical and associated micronutrient deficiencies are in including supplementation in these IBD associated with micronutrient deficiencies and supplementation Abbreviations: IBD, inflammatory bowel disease; TPN, total parenteral the majority of the micronutrients deficiencies are with blood testing or The majority of the testing centers and those associated with centers have access to these will by the and However, or nutrient levels are less to a limited of the nutrient in the in the blood levels of the nutrient related to in the the and the impact of as many micronutrients are In these deficiency is supplementation may be zinc levels the of a and can also and zinc levels are to the limited of zinc in after Therefore, in patients with many providers zinc supplementation without this needs to be for a to associated and deficiencies.1 many providers studies have shown that levels not body and many deficiencies are The of is a however, this is mostly in nutrition and has not been well by Micronutrient testing the of of Abbreviations: blood micronutrient such as vitamin and are by systemic inflammation and less measured in patients with active IBD However, this is often the that are about malabsorption, reduced intake, and nutritional deficiencies. Therefore, have proposed to nutrient levels that are not by systemic such as testing minerals and in There are studies specifically and mineral levels in patients with IBD, both of which that mineral levels iron, selenium, and were less by inflammation and were more of This can be to other human such as however, it is specifically to identify and be to vitamin are to to both vitamins and minerals or especially in patients in there is for nutritional deficiencies in the setting of active inflammation the of micronutrient in the setting of a deficiency or in patients at risk for a deficiency is of the or of the micronutrient may especially in patients with deficiencies. there is as to oral vitamin be or all supplementation be given In the is to treat vitamin deficiency with however, are more for patients and reduce Although there is in the studies have demonstrated not with oral vitamin supplementation as compared with Therefore, in patients with IBD who not have oral supplementation be and the vitamin to that in patients with symptoms to a vitamin be such as vitamin or have been Although the of these remains studies have reported significant in vitamin levels with compared with In patients with malabsorption and deficiencies in such as vitamins D, or supplementation can be In response to a of vitamin supplementation was in which the vitamin is in a water-soluble to the water-soluble these vitamins no or for Although for patients with with disease, or after these vitamins can be in patients with IBD who have that a significant of vitamin is absorbed through the have studied the of vitamin Although there are limited data on this early studies have as a to especially in patients with reduced this has not been well studied in patients with IBD can to that of and can the production of vitamin in the In patients with bowel and have who have vitamin has been as with This has also been proposed for in the during the is of for micronutrient have been including oral and 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supplementation has also been shown to be for patients with IBD, including disease and quality of Although there is a recent in the of disease in patients with IBD, studies in the literature have vitamin D, selenium, and zinc deficiency in the of These micronutrients are to blood and Micronutrients play important role in oxidative as well as the both and in the In healthy vitamins and inflammatory as and the production of over the more inflammatory to absorption and active inflammation in patients with IBD, micronutrient levels often to more inflammation and oxidative a vitamin A and active play a role in both the and In these have been shown to proinflammatory In a vitamin A were also shown to play a role in by and A Moreover, studies models and the other in patients with have that has and plays important role in as well as In IBD a diet deficient in in increased intestinal a of and in a vitamin is known for role in and it is also in In active of vitamin can in the proinflammatory 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malnutrition therefore, it is unclear energy had on this of vitamin deficiencies and vitamins have been studied as a therapeutic intervention to However, in a patients with who received vitamin B12, folic acid, and vitamin had no in or compared with those who received the (vitamin oxidative is to play a role in the of and deficiencies in vitamins or minerals that may in patients with in the and have demonstrated that selenium, vitamin C, and vitamin deficiencies are all associated with reduced Moreover, as of the et the impact of micronutrients on and found that higher of and was associated with increased These have not been reproduced, that are to the impact of antioxidants on especially in patients with Micronutrient deficiencies are common in patients with IBD and can have a significant impact on systemic inflammation and clinical Despite there are important in of to and treat these deficiencies. evaluating levels of that are also to for vitamin and mineral deficiencies in patients with IBD, in which systemic inflammation is quite studies levels of vitamins and minerals with testing such as or are to which levels are least by systemic inflammation and associated with poor clinical have a of to vitamin and mineral levels in patients with IBD, future studies on the for supplementation is and all impact therefore, oral supplementation may not be the for supplementation. many studies have identified clinical symptomatology associated with micronutrient long-term studies evaluating the impact of these deficiencies on IBD-related clinical such as for response to and of disease be this knowledge be a clinical in to micronutrient deficiency and clinical quality of and long-term outcomes in patients with has received and has received and and in and has as or for and has received and and is by a of to and is a and of the of for and have no of and to

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