Celiac disease is an inflammatory immune disorder that occurs in genetically susceptible individuals. In people with celiac disease, ingestion of gluten—the protein fraction of wheat, barley, and rye—provokes an immune attack that inflames and damages the lining of the small intestine. This typically results in nutrient malabsorption along with a wide variety of symptoms, ranging from diarrhea and constipation to skin rashes and depression (Brown 2012; Korponay-Szabo 2012; Lerner 2014; A.D.A.M. 2014). The reaction to gluten triggered by celiac disease is not an allergy, but rather an insidious inflammatory immune condition (FARE 2015a).

Untreated celiac disease can lead to the development of a host of other conditions including osteoporosis, infertility, neurological disorders, other autoimmune diseases, and in some cases, cancer (Ventura 1999; Fasano, Catassi 2012; Rashtak 2012; Kagnoff 2007; Sapone 2012; Bai 2013; UCMC 2014).

The prevalence of celiac disease has been rising sharply in recent decades. The reasons for the increase are not fully understood, but are thought to be due in part to better detection and diagnosis rates, as well as an actual increase in incidence, which may be a result of increasing dietary gluten content or changes in infant feeding patterns, among other possibilities (Sapone 2012). At least three million Americans, or approximately 1% of the US population, have celiac disease, making it more than four times as common today than just 30 years ago (Lundin 2012; Rubio-Tapia 2009; Lohi 2007).

Celiac disease is largely a hidden epidemic, since it is estimated that an alarming 85–90% of individuals in the United States who have celiac disease remain undiagnosed (Ferri 2015). In the United States, it takes an average of four years for a symptomatic person with celiac disease to be diagnosed, a delay that markedly increases the risk of developing autoimmune disorders, neurological problems, osteoporosis, and cancer (UCMC 2014).

In addition, emerging evidence suggests the existence of a clinically distinct sensitivity reaction to gluten-containing grains. This more recently characterized disorder has been referred to as both non-celiac wheat sensitivity and non-celiac gluten sensitivity (Carroccio 2012; Marchioni Beery 2015). This condition was described in the 1980s, and evidence for the existence of non-celiac gluten sensitivity has grown in recent years. Estimates suggest non-celiac gluten sensitivity is six times as common as celiac disease (Jackson 2012; Catassi 2013; Lundin 2012; Czaja-Bulsa 2014; Sapone 2012). Some recent research indicates that it may not be gluten or other proteins that cause people without celiac disease to react to these foods, but rather difficult-to-digest carbohydrates called FODMAPs (Biesiekierski 2013).

People with non-celiac gluten sensitivity can experience a spectrum of symptoms similar to those caused by celiac disease, such as abdominal pain, diarrhea, joint pain, and depression. Non-celiac gluten sensitivity does not appear to be an autoimmune condition, making it distinct from celiac disease; neither is non-celiac gluten sensitivity an allergic condition, which distinguishes it from classical wheat allergy (Sapone 2012). In fact, there are currently no universally recognized laboratory tests or biomarkers for non-celiac gluten sensitivity; the condition can be diagnosed by a double-blind challenge with gluten-containing food (Jackson 2012; Catassi 2013; Lundin 2012).

Currently, the only recognized treatment for celiac disease is strict, lifelong adherence to a gluten-free diet. This means avoiding all foods containing wheat, rye, barley, and their derivatives, as well as gluten-containing non-foods such as medicines and supplements. People with celiac disease must also be careful when selecting foods such as oats that may be contaminated with gluten-containing grains (Bai 2013; Sapone 2012; Fasano, Catassi 2012).

However, the gluten-free diet is nutritionally inadequate in some cases, whether as a result of poor food choices or inherent deficiencies in the diet due to lack of nutritional fortification of gluten-free foods (Shepherd 2013). While the gluten-free diet is also used to treat non-celiac gluten sensitivity, the need for strict adherence or permanency is not clear (Sapone 2012).

This protocol will give you a better understanding of celiac disease and non-celiac gluten sensitivity, and how they differ. The gluten-free diet will be reviewed and new treatment frontiers will be discussed. You will also learn about lifestyle changes and targeted nutritional support with several natural compounds that can complement the gluten-free diet by correcting nutritional deficiencies, promoting intestinal healing, balancing the immune system, and reducing chronic inflammation.

Gluten is not a single protein but rather a complex mixture of proteins, primarily gliadin and glutenin. Gluten forms when wheat flour is mixed with water to make dough. The combination of gliadin, a viscous (thick) protein, with glutenin, a long, elastic protein, yields gluten with its unique “visco-elastic” properties that are important in baking and food processing (Veraverbeke 2002; Allred 2010; Shewry 2002; Tatham 2000).

Thus, despite the common usage of the term “gluten-containing grains,” gluten itself is not actually present in the wheat seed; it is created during the formation of wheat flour dough (Hoseney 1990; Shewry 2002; Tilley 2001).

Rye and barley, the other “gluten” grains, do not actually form gluten (Tatham 2000). Instead, secalin proteins in rye and hordein proteins in barley contain toxic fragments that share properties with the wheat protein gliadin, most notably with regard to triggering celiac disease (Kagnoff 2007; Denham 2013). For convenience and simplicity, all three grains—wheat, rye, and barley—are considered “gluten-containing grains.”

Gliadin (wheat), secalin (rye), and hordein (barley) proteins are especially rich in two amino acid “building-blocks,” proline and glutamine, and thus are called “prolamins” (Stenman 2010; Hausch 2002; Denham 2013; Stern 2000). The bonds linking proline and glutamine on the gluten protein are resistant to digestion. This prevents complete breakdown of gluten into small, harmless molecules. Instead, large, undigested gluten fragments remain in the digestive tract (van den Broeck 2009; Kagnoff 2007; Denham 2013; Gass 2007).

In healthy people, these large, undigested fragments of gluten protein are eventually harmlessly excreted and do not provoke an immune response (Fasano 2009). For people with celiac disease, however, these glutamine- and proline-rich fragments, or peptides, are toxic (Sapone 2011; Holmes 2013; Volta 2013; Shan 2002).

Much has been learned about how environmental and genetic factors interact with the immune system to inflame and damage the lining of the small intestine in celiac disease. The most important and best-characterized genetic components involved in the development of celiac disease are known as human leukocyte antigens (HLAs). More than 98% of people with celiac disease have at least one of two variants of a gene called HLA DQ. The HLA DQ2 variant of this gene is found in approximately 95% of celiac patients, while the HLA DQ8 variant is carried by the remainder. These genes play an integral role in priming the autoimmune response to gluten that occurs in celiac disease (Denham 2013; Sapone 2012; Green 2003).

Celiac disease is characterized by increased intestinal permeability (“leaky gut”), which allows gluten to seep through the compromised gut barrier and provoke a dysfunctional immune response (Fasano 2009; Fasano 2008; Lionetti 2011).

During this inflammatory immune assault against gluten, collateral damage to intestinal epithelial cells causes leakage of their contents into the fluid surrounding the cells. Included in this cellular discharge is a critical enzyme called tissue transglutaminase (Dieterich 1997; Fasano 2009). Tissue transglutaminase modifies the composition of the gliadin peptide, enabling gluten to bond strongly to the HLA DQ2 and DQ8 proteins. This then provokes an immune response from the T and B cells of the immune system and the production of antibodies against tissue transglutaminase (Lionetti 2011; Denham 2013; Fasano 2009).

The helper T cells of the immune system trigger the release of cytokines (signaling molecules), particularly interferon-gamma, which promote inflammation that specifically targets the lining of the small intestine, resulting in the autoimmune damage and flattening of the intestinal villi that are characteristic of celiac disease (Lionetti 2011; Kagnoff 2007; Denham 2013).

Villous Atrophy

Nutrient absorption occurs in the small intestine, a tube roughly 20–22 feet long with an inner surface that, when magnified, appears wrinkled into hundreds of folds. Each fold is covered with thousands of fingerlike projections called villi (singular: villus). Each villus, in turn, is covered with thousands of tiny, tightly packed projections called microvilli. Together, the villi and microvilli increase the intestinal absorptive surface area 60–120 times (Helander 2014; CARTA 2015; CHP 2014). The villi also contain enzymes that help break down food particles to their smallest components: proteins into amino acids, and carbohydrates into simple sugars (Skovbjerg 1981; Nordström 1967).

In celiac disease, intestinal damage induced by the autoimmune reaction to gluten ingestion manifests as a flattening of the villi (a hallmark of celiac disease), which reduces the surface area available for nutrient absorption. The resulting malabsorption leads to both intestinal consequences such as indigestion and diarrhea, and non-intestinal consequences such as anemia and osteoporosis (Kagnoff 2007; Guandalini 2014; Lionetti 2011).

Wheat Allergy vs. Celiac Disease vs. Non-celiac Gluten Sensitivity Wheat allergy, celiac disease, and gluten sensitivity are three separate conditions arising from distinct processes, though they may share certain signs and symptoms (UCLA Health 2015; ACDA 2015a). The conventional medical definition of wheat or gluten allergy refers to a less common condition that affects about 0.4–0.5% of the general population and which classically involves Immunoglobulin E (IgE) antibodies to wheat proteins, including gluten (Sapone 2012; Catassi 2013; Lundin 2012; Volta 2013). IgE antibodies play a central role in immediate food allergy reactions, the kind that usually occur within minutes to several hours after ingesting the allergenic food, though the reaction can occur up to two days later (Katta 2014). An allergy involves the release of histamine and other inflammatory substances and can cause serious symptoms such as skin eruptions, runny nose, itching, tearing, coughing, and in rare cases, anaphylaxis and even death (Matsumura 1994; Sapone 2012). IgE reactions to foods can be measured by blood or dermal testing (FARE 2015b; FARE 2015c). Celiac disease is an autoimmune disease, not an allergy. Whereas allergic reactions tend to be transitory, appearing and disappearing within minutes to hours after contact with an allergen such as wheat, the autoimmune reactions of celiac disease are enduring and highly destructive. Recovery of the normal structure of the intestinal lining takes 6–24 months of adherence to a strict gluten-free diet (Ferri 2015; Mayo Clinic 2014; UCLA Health 2015; ACDA 2015a). Non-celiac gluten sensitivity refers to a more recently-recognized condition characterized primarily by a beneficial response to dietary elimination of wheat-containing foods for people in whom celiac disease and classical IgE-mediated wheat allergy have been ruled out. Whereas wheat or gluten allergy and celiac disease are well-defined conditions, science still has much to learn about non-celiac gluten sensitivity, including the mechanisms underlying the condition and how best to diagnose it. Non-celiac gluten sensitivity is neither an autoimmune condition nor a classical allergic condition characterized by rapid IgE-mediated reactions (UCLA Health 2015; Sapone 2012). One study found that over half of non-celiac gluten sensitivity patients tested positive for antigliadin immunoglobulin G (IgG) antibodies, and some researchers consider IgG antigliadin antibody testing useful in identifying cases of non-celiac gluten sensitivity (Volta, Tovoli 2012; Mansueto 2014). A recent clinical study suggests gluten or other proteins in wheat and related grains may not be the sole cause of non-celiac reactivity to wheat. In some people, fermentable, oligo-, di-, monosaccharides, and polyols (FODMAPs), which are poorly absorbed carbohydrates, may contribute to sensitivity reactions to wheat among people without overt celiac disease or wheat allergy (Biesiekierski 2013). Table 1: Comparison of Wheat Allergy, Celiac Disease, and Non-celiac Gluten Sensitivity   Wheat or Gluten Allergy Celiac Disease Non-celiac Gluten Sensitivity Characteristics Misguided immune hypersensitivity to ingestion of wheat or gluten. Symptoms likely to occur within minutes to hours. Autoimmune reaction to gluten ingestion; strong genetic component. Symptoms often not perceived to be related to diet. Shares symptoms with wheat and gluten allergy and celiac disease, but unclear role for autoimmune and allergic mechanisms. Responds to gluten-free diet. Tests Classically, Immunoglobulin E blood or dermal testing. Gold standard test is small intestine biopsy demonstrating villous atrophy. Serum biomarkers can be strongly predictive. These tests must be performed while patient is consuming gluten-containing diet. Genetic HLA markers present in nearly all patients with celiac disease but also in significant portion of healthy populace. Some celiac serum and genetic biomarkers may be positive, but villous atrophy is never present. Immunoglobulin E negative; Immunoglobulin G antibodies to wheat, gluten, or gliadin may be present. Gold standard test is double-blind challenge with gluten-containing food. Digestive Symptoms Nausea, vomiting, diarrhea, constipation, bloating, and abdominal pain are all possible; Irritation of mouth and throat also possible Nausea, vomiting, diarrhea, constipation, bloating, and abdominal pain are all possible Nausea, vomiting, diarrhea, constipation, bloating, and abdominal pain are all possible Atypical (non-intestinal) presentation Varies widely. Hives, headaches, congestion, difficulty breathing can occur with classic IgE immediate hypersensitivity allergy. Can affect nearly any body system. Fatigue and mental cloudiness are most often described. Treatment Avoidance and elimination of allergen. Degree of adherence necessary depends on severity of reaction. Strict lifelong gluten-free diet is necessary. Gluten-free diet often resolves symptoms, though its necessity and the degree of adherence required remain unclear. Prognosis Very good with avoidance of wheat and gluten. Those with rare anaphylactic reactions will require greater vigilance. Good with strict adherence to gluten-free diet in most cases. Appears to respond to gluten-free diet as well as to FODMAP elimination (see Understanding Non-celiac Gluten Sensitivity). May be a transient disorder. (UCLA Health 2015; Ferri 2015; Sapone 2012; FARE 2015a) More general information about food allergies and food sensitivities is available in the Life Extension Magazine article titled What’s Really Making You Sick?

Some people who do not have celiac disease or a wheat or gluten allergy may still experience symptoms in response to gluten ingestion. These symptoms can resemble those associated with celiac disease and may include gastrointestinal symptoms and non-intestinal symptoms. This newly-recognized gluten-related syndrome has been named non-celiac wheat sensitivity or non-celiac gluten sensitivity. Current knowledge about non-celiac gluten sensitivity is limited, and many unresolved questions remain to be clarified (Volta 2013; Sapone 2012).

Non-celiac gluten sensitivity is not an autoimmune disease and does not result in the same damage to the lining of the small intestine that is characteristic of celiac disease. Overall, non-celiac gluten sensitivity is less severe than celiac disease. The mechanism underlying the development of non-celiac gluten sensitivity is not clear, though it is known to be different from that of celiac disease and wheat allergy. There are conflicting reports, for example, as to whether people with non-celiac gluten sensitivity have altered gut barrier function (Biesiekierski 2011; Sapone 2011; Vazquez-Roque 2013).

As in celiac disease, the fast-acting or “innate” immune system is activated in non-celiac gluten sensitivity, causing moderate inflammation of the intestinal lining. However, unlike celiac disease, most evidence indicates that the adaptive immune system (also called acquired or specific immunity) is not activated in non-celiac gluten sensitivity (Lundin 2012; Catassi 2013; Volta 2013; Sapone 2011; Goronzy 2012; Volta, Di Giorgio 2012).

Gluten proteins may not be the sole or main triggers of non-celiac gluten sensitivity; other non-gluten components in wheat may play a role as well (Bucci 2013; Biesiekierski 2013). For instance, amylase-trypsin inhibitors are non-gluten proteins in wheat that are resistant to digestion. They are the primary allergens in Baker’s asthma, an occupational asthma that afflicts bakers and others exposed to grain and wheat flour dust (Salcedo 2011; James 1997). They can provoke inflammation and immune reactions in the cells of celiac and non-celiac patients, though their potential role in non-celiac gluten sensitivity has yet to be explored (Junker 2012).

Other non-protein constituents of wheat could elicit gastrointestinal symptoms in people with non-celiac gluten sensitivity. FODMAPs—an acronym for fermentable oligo-, di-, and monosaccharides and polyols—are poorly digested and incompletely absorbed carbohydrates found in a wide range of foods including gluten-containing grains, fruits, foods made with high fructose corn syrup or sugar alcohols, and dairy (SHC 2014).

FODMAPs are easily fermented by gut bacteria, which can result in gas, bloating, and diarrhea, symptoms shared by both irritable bowel syndrome and non-celiac gluten sensitivity (Barrett 2012; Magge 2012).

A 2013 randomized controlled trial in 37 patients with non-celiac gluten sensitivity and irritable bowel syndrome found that gluten did not produce negative effects when FODMAPs were restricted in the diet. The study authors concluded that non-celiac gluten sensitivity may not be distinct from reactions to FODMAPs (Biesiekierski 2013).

Several risk factors for celiac disease are well established:

• Race. Caucasians are generally at higher risk (Murray 2013; Lidums 2015; A.D.A.M. 2014).
• Gender. Among women, the prevalence is 1.5–2.8 times higher than among men (Fasano, Catassi 2012; Gujral 2012).
• Family history. First- and second-degree relatives of celiac patients have a 10- to 15-fold and a 2.5-fold increased risk, respectively, compared to the general population (Bai 2013; Silvester 2013; Fasano, Catassi 2012).
• Genetics. Positive HLA DQ2 and DQ8 genes are almost always present in celiac disease patients. Approximately 95% of celiac patients carry the HLA DQ2 gene, while the remainder express the HLA DQ8 gene. Without one of these gene variants, celiac disease is extremely rare and unlikely (Sapone 2012; Denham 2013; Fasano 2009).
• Early gluten exposure. Early introduction of gluten into an infant’s diet increases risk. There is a 5-fold increased risk in children fed gluten during their first three months of life; introduction of gluten to the diet of genetically susceptible infants should be delayed until the 4th to 6th month of life, and the mother should continue to breastfeed (Ferri 2015).
• Breastfeeding status. Not breastfeeding increases the risk of celiac disease in childhood, and breastfeeding is protective. Gradually introducing gluten-containing foods while breastfeeding decreases the risk up to 48%. It is not known whether breastfeeding prevents adult onset of celiac disease (Lidums 2015).

The risk factors for non-celiac gluten sensitivity are not currently known, though the condition is believed to occur more commonly in females and in young and middle age adults (Catassi 2013).

Celiac Disease

Signs, symptoms, and possible manifestations. Symptoms of celiac disease are generally categorized as gastrointestinal (typical) or extraintestinal (atypical) (see Table 2). Other forms of celiac disease include silent, or symptomless celiac disease, as well as potential celiac disease in which autoantibodies are detected but the intestinal lining is undamaged (Sperandeo 2011; Fasano 2001; Di Sabatino 2009; Lionetti 2011). The absence of symptoms in silent celiac disease can be attributed to the ability of the small intestine to compensate for lost function in the damaged area, but only when the damage is minimal. As intestinal damage progresses, symptoms appear (Presutti 2007).

In recent years, more cases of atypical celiac disease and silent celiac disease have been recognized (Telega 2008; Roma 2009; Guandalini 2014; Fasano, Catassi 2012). Many of the signs and symptoms of typical and atypical celiac, as well as the diseases associated with celiac, can be at least partially attributed to the nutrient malabsorption that results from damage to the absorptive surface of the small intestine (Lidums 2015).

Table 2: Possible Presentations of Celiac Disease

Gastrointestinal Presentation (Typical)

Extraintestinal Presentation (Atypical)

Abdominal pain, bloating Anorexia Bulky stool Constipation Diarrhea Failure to thrive or weight loss Flatulence (gas) Nausea Steatorrhea (fatty stool) Vomiting

Asymptomatic Constitutional Fatigue Dermatologic (skin-related) Dermatitis herpetiformis Endocrinologic (related to hormonal system) Short stature Delayed puberty Unexplained infertility in women Miscarriage Hematologic (blood-related) Iron deficiency anemia Hepatic (liver-related) Mildly elevated ALT, AST levels Metabolic Nutritional deficiencies (iron, calcium, vitamin D, B vitamins, among others) Musculoskeletal Arthritis Arthralgia (joint pain) Osteopenia or osteoporosis Fractures Neurologic Cerebellar ataxia Recurring headaches Peripheral neuropathy Seizures Oral Dental enamel defects Aphthous ulcers (oral ulcers; canker sores) Psychiatric disorders Anxiety, panic attacks Depression

(Guandalini 2014; Ferri 2015; Kelly 2014; Nikpour 2012; Lawson 2005; Caruso 2013; Krzywicka 2014; Snyder 2015)

Associated conditions. Celiac disease has been associated with a number of other conditions, especially autoimmune-related conditions such as type 1 diabetes and autoimmune thyroid disease (Barker 2008; Kelly 2014). There is also some evidence that celiac disease may increase risk of certain cancers. A large population study in over 30 000 adult celiac patients corroborated earlier findings of increased risk of certain cancers in celiac patients. In this population, non-Hodgkin lymphoma occurred at a 1.94-fold increased incidence rate, and incidence of small intestinal cancer was increased 4.29-fold, compared with rates expected in the general population. The incidence of colon cancer and basal cell carcinoma were also modestly elevated, by 1.35-fold and 1.13-fold, respectively (Ilus 2014; Green 2003). Table 3 summarizes conditions that may be associated with celiac disease.

Table 3: Diseases and Conditions Associated with Celiac Disease

Strong Association

Weak Association

Autoimmune thyroid disease Immunoglobulin A (IgA) deficiency Indigestion Type 1 diabetes

Addison’s disease Alopecia (loss of hair) Angular cheilitis Asthma Atopic dermatitis (Eczema) Autoimmune liver disease Cataracts Dermatitis herpetiformis Dilated cardiomyopathy Down syndrome, Turner syndrome, Williams syndrome Early atherosclerosis among young adults Easy bruising Endometriosis Hallucinations in adolescents Heartburn/Gastroesophageal reflux disease IgA Nephropathy (Berger’s disease) Inflammatory bowel disease (Crohn’s and Ulcerative colitis) Ischemic heart disease Lack of muscle coordination and balance (gluten ataxia) Multiple sclerosis Myalgia (muscle pain) Nutrient deficiency, including vitamins B12 and folate, calcium, and iron Pancreatitis Primary hyperparathyroidism Poor or absent spleen function (hyposplenia or asplenia) Sjögren’s syndrome Suicidal behavior in adolescents Systemic lupus erythematosus Tooth discoloration or loss of enamel

(Guandalini 2014; Ferri 2015; Kelly 2014; Nikpour 2012; Lawson 2005; Caruso 2013; Krzywicka 2014; Snyder 2015; Elfström 2007)

Non-celiac Gluten Sensitivity

Many symptoms of non-celiac gluten sensitivity are similar to those of celiac disease. As in celiac disease, they include symptoms similar to irritable bowel syndrome such as abdominal pain, bloating, diarrhea, gas, and constipation; and atypical symptoms such as headache, fatigue, joint and muscle pain, dermatitis, depression, and anemia (Eswaran 2013; Sapone 2012; Volta 2013; Lundin 2012). The time interval between gluten exposure and onset of symptoms in celiac disease can be quite long—up to weeks and years—whereas it may be only a matter of a few hours to a few days in non-celiac gluten sensitivity (Catassi 2013; Sapone 2012; Volta, De Giorgio 2012).

There is no evidence that serious, long-term complications occur in non-celiac gluten sensitivity (Catassi 2013).

The Effects of Gluten on the Brain and Nervous System Among atypical or extraintestinal signs of celiac disease, brain and nervous system problems are prominent (Hu 2006; Bushara 2005; Cascella 2011; Jackson 2012; Briani 2008; Rodrigo 2011; Nikpour 2012). One mechanism for gluten’s effects on the brain may involve autoimmune antibodies against a subtype of tissue transglutaminase called transglutaminase 6. This enzyme is structurally similar to transglutaminase types involved in intestinal and skin damage in celiac disease, but transglutaminase 6 is found primarily in the brain and nervous system. Antibodies against this enzyme have been identified in patients with gluten ataxia and schizophrenia. Importantly, they do not appear to be present in healthy individuals (Hadjivassiliou 2008; Cascella 2013). Whether antibodies to transglutaminase 6 are involved in other neurological and psychiatric conditions associated with celiac disease is not known, and will require further research. However, there is evidence that transglutaminase 6, and the transglutaminase enzyme family in general, may be important in the development of degenerative diseases of the brain (Thomas 2013; Jeitner 2009; De Vivo 2009; Martin 2011). Multiple sclerosis is an inflammatory autoimmune disorder that damages the insulating covers of nerve cells in the brain and spinal cord (Compston 2002). Recently, the prevalence of celiac disease was reported to be 5–10 times higher in a study in patients with multiple sclerosis compared to the general population. All the patients in this study had an excellent response to the gluten-free diet in an average of three years, with regard to both digestive and neurological symptoms (Rodrigo 2011). A 2014 case report showed celiac disease can mimic multiple sclerosis. A 43-year-old male patient with a history of diarrhea and colic since youth and neurological symptoms since age 18 was diagnosed with multiple sclerosis at age 34. Seven years later, though his blood tests did not show any of the typical celiac-related antibodies, he was diagnosed with celiac disease based on neurologic signs and symptoms, positive tests for HLA DQ2 and DQ8, and improvement in both digestive and neurological symptoms on a gluten-free diet (Finsterer 2014).

Celiac Disease

A blood test for immunoglobulin A (IgA) type autoimmune tissue transglutaminase antibodies is usually the first diagnostic step for celiac disease in most patients. Another test, IgA endomysial antibodies, may be used to confirm positive results. Deamidated gliadin peptide antibodies are tested for when serum IgA is low, a common occurrence in celiac disease (Ferri 2015; Rubio-Tapia 2013). Elevated antigliadin immunoglobulin G (IgG) antibody levels may also present in people with celiac disease who have recently consumed gluten. However, elevated IgG levels are not specific for celiac disease, and healthy people may sometimes have elevated IgG levels. Combined screening with IgG and IgA tests can be helpful in some cases, especially in people with IgA deficiency, which is thought to occur in about 2‒3% of individuals with celiac disease (ACDA 2015b).

A convenient screening panel, the Celiac Disease Antibody Screen, tests for immunoglobulin A antibodies to tissue transglutaminase, the most important blood test for celiac disease; serum immunoglobulin A levels, which can be low in celiac disease; and deamidated gliadin immunoglobulin A (Rubio-Tapia 2013).

Blood tests alone are often not considered adequate to confirm a diagnosis of celiac disease. The gold standard for a celiac diagnosis is a biopsy of the small intestine demonstrating flattened villi (Guandalini 2014; Gujral 2012; Rubio-Tapia 2013).

Genetic testing for HLA DQ2 and HLA DQ8 may be performed for three reasons: negative tests rule out almost all cases of celiac disease, including those already on a gluten-free diet; negative tests may help clarify the picture when the result of other testing is unclear; and these tests are used to screen close relatives of patients for genetic risk of celiac disease (those who are positive go on to receive conventional testing as listed previously) (Ferri 2015; Kelly 2014; Lidums 2015).

A simple “four-out-of-five” guideline has been proposed for the diagnosis of celiac disease, which would require that a minimum of four out of the five criteria below be met. Current practice guidelines, however, rely on more complex diagnostic algorithms. Generally, a biopsy demonstrating villous atrophy is still considered the “gold standard” for celiac diagnosis (Husby 2012; Rubio-Tapia 2013; Guandalini 2014; Ludvigsson 2014; Sapone 2012).

Four-Out-Of-Five Diagnosis Guideline (Sapone 2012)

1. Typical symptoms of celiac disease (See “Signs and Symptoms”).
2. Serum celiac disease immunoglobulin A antibodies are strongly positive.
3. HLA DQ2 and/or HLA DQ8 genes are present.
4. Characteristic changes, known as celiac enteropathy, are evident on small intestine biopsy.
5. Positive clinical response to a gluten-free diet.

Distinguishing Celiac Disease from Irritable Bowel Syndrome The misdiagnosis of celiac disease as irritable bowel syndrome (IBS) deserves special mention. Individuals diagnosed with IBS are considered to be at four- to seven-fold increased risk of celiac disease compared with the general population (Cristofori 2014; Sanders 2001). However, proper diagnosis of IBS necessarily includes ruling out conditions such as celiac disease (Moleski 2013). Typical gastrointestinal presentation of celiac disease may closely mimic the symptoms of IBS, including recurrent abdominal discomfort, bloating, constipation, and diarrhea (Lidums 2015; Verdu 2009). Patients who have received a diagnosis of IBS should confirm that celiac disease was adequately tested for and ruled out (Rodrigo 2013; Ford 2009; Zwolińska-Wcisło 2009; Spiegel 2004; Sanders 2001). More information on IBS can be found in Life Extension’s Irritable Bowel Syndrome protocol.

Non-celiac Gluten Sensitivity

While there are currently no universally recognized laboratory tests or biomarkers for non-celiac gluten sensitivity, wheat allergy and celiac disease must be ruled out in order to make a non-celiac gluten sensitivity diagnosis (Czaja-Bulsa 2014; Sapone 2012). The best available procedure to confirm non-celiac gluten sensitivity is a double-blind, placebo-controlled gluten challenge that demonstrates that gluten-related symptoms are relieved by a gluten-free diet (Volta 2013; Sapone 2012).

The only established treatment for celiac disease is strict, lifelong adherence to a gluten-free diet (Ferri 2015; Kelly 2014; Lidums 2015; Fasano, Catassi 2012). Absolute compliance to the gluten-free diet is vital, as even a tiny amount of gluten can lead to intestinal damage in those with celiac disease. In most cases, with strict adherence, symptoms are halted, existing intestinal damage is healed, and further damage is prevented (UCMC 2013).

The gluten-free diet excludes all foods that contain wheat (including spelt, triticale, and kamut), rye, and barley (Dirks 2004; Bai 2013). This means avoiding these grains, as well as pasta, cereals, and processed foods—unless they are labeled “gluten-free.” The status of oats in the gluten-free diet is less clear; it is thought that most celiac patients can eat modest amounts of pure oats, though some celiac patients do not tolerate oats (Fasano, Catassi 2012; Real 2012). Unless labeled “gluten-free,” oats should be avoided as they can be contaminated with gluten-containing grains (UCMC 2013; Kagnoff 2007).

There are many gluten-free alternatives to wheat: amaranth, buckwheat, corn, millet, rice (all varieties), quinoa, sorghum, teff, yucca, potato, nuts, flax, and all beans and legumes are naturally gluten-free (CDF 2015). There are also alternatives to gluten-containing flour, including potato, rice, soy, tapioca, carob, and bean flour (Zingone 2010; Eberman 2005).

The gluten-free diet is typically considered the primary treatment for non-celiac gluten sensitivity (though some researchers advocate avoidance of FODMAPs as opposed to gluten). While the level of gluten tolerance varies among individuals with non-celiac gluten sensitivity, with rare exceptions, most of these individuals can eat trace amounts of gluten without negative health consequences (Molina-Infante 2014; Sapone 2012; Volta 2013).

Unfortunately, lifelong strict adherence to a gluten-free diet is often difficult. Gluten is common in many types of food, and gluten-free products are often expensive and not widely available. Many people have difficulty maintaining the diet (Vahedi 2003; Abdulkarim 2002).

Gluten-Free Foods: Some Examples

Table 4 contains examples of foods that are allowed and those that are not allowed when eating gluten-free. This is not a complete list, however. It is important to read all ingredient labels carefully to make sure that a food does not contain gluten.

Table 4: Allowed and Disallowed Foods in the Gluten-Free Diet

Allowed Grains and Starches
amaranth arrowroot buckwheat cassava corn flax Job's tears (Coix lacryma-jobi)	legumes/beans millet nuts and seeds potatoes sweet potatoes/yams quinoa rice sago	sorghum soy tapioca teff squash yucca wild rice
Foods To Avoid
wheat including einkorn, emmer, spelt, kamut wheat starch, wheat bran, wheat germ, cracked wheat, hydrolyzed wheat protein		barley rye triticale (a cross between wheat and rye)
Other Wheat Products to Avoid
bromated flour durum flour enriched flour farina	graham flour phosphated flour plain flour	self-rising flour semolina white flour unbleached flour
Processed Foods that May Contain Wheat, Barley, or Rye*
bouillon cubes brown rice syrup candy chips/potato chips cold cuts, hot dogs, salami, sausage communion wafers	French fries gravy imitation fish matzo rice mixes sauces	seasoned tortilla chips self-basting turkey soup soy sauce vegetables in sauce

(NIDDK 2012)
* Most of these foods can be found gluten-free. When in doubt, carefully read food labels and check with the food manufacturer.

Avoiding FODMAPs: Potential Benefits for Those with Non-celiac Gluten Sensitivity? Although several studies have identified specific reactions to the protein components of wheat and related grains in some people with non-celiac gluten sensitivity, limited evidence suggests that poorly absorbed carbohydrates called fermentable, oligo-, di-, monosaccharides, and polyols (FODMAPs) may drive symptoms in some individuals (Biesiekierski 2013; El-Salhy 2015).  In one study of people with self-reported non-celiac gluten sensitivity, reducing FODMAP intake significantly reduced gastrointestinal symptoms (Biesiekierski 2013). Thus, avoiding dietary FODMAPs may be beneficial for gluten-sensitive individuals who fail to achieve relief by specifically avoiding gluten. Limiting FODMAP intake has also been shown to improve symptoms among individuals with irritable bowel syndrome (IBS), which has several similarities with non-celiac gluten sensitivity (Lowe 2014; Staudacher 2014). The low-FODMAP diet emphasizes avoidance of fructose, lactose, fructans, galactans, and polyols. Some examples of foods eliminated in a low-FODMAP diet are wheat, barley, and rye; high-lactose dairy; foods made with high-fructose corn syrup; certain fruits; soy protein; mushrooms; among others (SUMC 2014). Monash University in Australia has developed a comprehensive low-FODMAP diet program to assist individuals who wish to try this dietary approach. More information is available on Monash University’s website, here: http://www.med.monash.edu/cecs/gastro/fodmap/.

In light of the limitations of the gluten-free diet, several new treatment strategies for celiac disease are currently under development. These novel and emerging therapies can be classified into four general categories: permeability inhibition, immunomodulation, grain modification, and gluten detoxification.

While ongoing research on novel therapies is targeting celiac disease, some of the dietary modification and gluten detoxification strategies described in this section may provide solutions for people with non-celiac gluten sensitivity.

Permeability Inhibition

Zonulin antagonism. Zonulin is a protein that regulates the tight junctions that “glue” intestinal cells together and control what passes through the gut wall. In celiac disease, overproduction of zonulin causes these tight junctions to come apart and remain open, increasing intestinal permeability (Tripathi 2009; Fasano 2012a). This “leaky gut” then allows large molecules, including gluten fragments, to enter the bloodstream, where they trigger an immune response and inflammation (Fasano 2012b; Fasano 2011; van Elburg 1993).

An investigational drug named larazotide acetate blocks zonulin from making the gut permeable, and appears to be effective in preventing gluten-related symptoms in celiac disease (Gopalakrishnan 2012). In a randomized controlled trial in patients with celiac disease, acute gluten exposure caused a 70% increase in intestinal permeability in the placebo group, while no change in permeability was seen in the larazotide group. The patients treated with larazotide tolerated the drug well and experienced fewer gastrointestinal symptoms. Moreover, larazotide-treated subjects exhibited a lessened inflammatory response to gluten in comparison with the placebo group, as determined by changes in levels of several inflammatory cytokines (Paterson 2007).

A more recent phase IIb trial evaluated larazotide in 342 celiac patients who did not respond to a gluten-free diet. Compared with controls, patients taking the zonulin-inhibitor at the lowest dose (0.5 mg daily) had significantly fewer gastrointestinal symptoms and headaches, as well as less fatigue. No changes in serum levels of anti-tissue transglutaminase or gliadin antibodies were seen (AGA 2014; Castillo 2014). The drug producer, Alba Therapeutics, is planning for phase III clinical trials of lazarotide’s efficacy and safety (AZO Network 2014). Larazotide acetate has been granted fast-track designation by the Food and Drug Administration (FDA), which is a process by which therapies that help address an unmet medical need may be approved and become available in the market more quickly (PR Newswire 2014).

Immunomodulation

Vaccination. A preventive vaccine may be one of the most attractive and exciting novel therapies for patients with celiac disease (Aziz 2011). The theory behind vaccination is that tolerance to gluten can be induced through repeated small exposures to strongly immunogenic fragments of gluten. The immune system becomes trained to not react to gluten, thus preventing an autoimmune attack in the small intestine (Bakshi 2012). Just this type of gluten vaccine (Nexvax2) is under development. Nexvax2 is a mixture of the three toxic peptides—gliadin (wheat), hordein (barley), and secalin (rye)—that provoke the immune system in individuals with HLA DQ2-positive genes. Nexvax2 was shown to be safe and well tolerated in a three-week phase I clinical trial in celiac patients (Castillo 2014; Rashtak 2012; Bakshi 2012). Phase II and III clinical trials will be necessary before FDA approval.

Inhibition of tissue transglutaminase 2. Tissue transglutaminase 2 (tTG2) is an enzyme that leaks out of damaged cells and modifies gluten. It is this modified gluten that is presented to immune cells, eventually leading to autoimmune and inflammatory responses in the intestine. As tTG2 is vital to the development of celiac disease, selective inhibition of tTG2 could be another potential therapeutic approach for celiac disease (Kupfer 2012; Esposito 2007; Siegel 2007).

However, tTG2 has many other diverse biological functions such as wound healing and assisting the ingestion of microbes or other foreign particles by immune cells (Siegel 2007). Therefore, inhibiting tTG2 may result in systemic side effects. Nevertheless, in animal studies a series of compounds called dihydroisoxazoles were shown to efficiently inhibit tTG2 with low systemic toxicity (Choi 2005; Watts 2006). Inhibition of tTG2 is still in the discovery phase with no clinical trials yet initiated.

Blocking HLA DQ2 and HLA DQ8. In celiac disease, the human leukocyte antigens HLA DQ2 and HLA DQ8 bind with gluten peptides and induce an immune reaction that leads to disease development. Blocking the binding sites of these HLA antigens may provide yet another treatment alternative. Various gluten analogues (structurally similar to gluten) have been developed that effectively bind and inhibit HLA DQ2, which is present in over 90% of cases of celiac disease (Juse 2010; Huan 2011; Kapoerchan 2008; Xia 2007). The primary concern with these HLA antagonists is the possibility of interfering with other similar HLAs that are involved in normal immune surveillance. This strategy is still in the discovery phase (Rashtak 2012).

Anti-interferon-gamma and anti-TNF-alpha therapies. Interferon-gamma and tumor necrosis factor-alpha (TNF-α) are cytokines (signaling molecules) that are activated by gluten’s interaction with T cells of the immune system. These cytokines contribute to the inflammatory cascade in celiac disease. Interventions that block these cytokines have been investigated in celiac disease. Infliximab (Remicade), an anti-TNF-α monoclonal antibody used in the treatment of inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, was beneficial in two case reports of unresponsive celiac disease (Guo 2013; Nilsen 1998; Pena 1998; Gillett 2002; Costantino 2008; Woodward 2013).

Anti-interleukin-15 therapy. Interleukin-15 (IL-15) is another cytokine that plays a significant role in the development of celiac disease. Genetically altered mice that produce excess IL-15 in intestinal cells develop inflammation along with flattening of the villi in the small intestine, much like the damage that occurs in celiac disease. One trial showed that in mice, blocking IL-15 with antibodies reversed this autoimmune damage (Yokoyama 2009). AMG 714, an anti-IL-15 antibody, is being evaluated in phase II clinical trials for the autoimmune diseases rheumatoid arthritis (Amgen 2007) and psoriasis (Amgen 2014). Targeting IL-15 is a plausible treatment strategy for celiac disease as well, though human trials are still lacking (Sollid 2011).

CCR9 antagonists. The chemokine receptor CCR9 acts as a trafficking or homing molecule that selectively causes T cells to move to the small intestine, where they promote persistent inflammation. This homing receptor has been associated with celiac disease (Olaussen 2007). An antagonist to CCR9 called CCX282-B induced a clinical response and maintenance of clinical remission in Crohn’s disease (Keshav 2013). A phase II trial of CCX282-B in celiac disease has been completed, but results are pending. Due to a lack of specificity, this drug may increase the risk of gastrointestinal infections (Stoven 2013; Sollid 2011).

Grain Modification

Wheat variants. The development and production of variant wheat strains that contain reduced levels of toxic gluten proteins is one novel approach currently under exploration. Success in this endeavor might allow people to consume wheat while reducing their exposure to gluten. Several studies have reported that various species of ancient wheat (einkorn) and some strains of pasta wheat (durum) contain little to no immunogenic gluten peptides. It appears that ancient forms of wheat contained less total gluten and toxic gluten fragments than modern bread wheat (Molberg 2005; Spaenij-Dekking 2005).

Research efforts are focused on breeding wheat strains similar to ancient wheat that lack harmful gluten peptides. Identification and breeding of grain varieties with less immunotoxic profiles is in development (Molberg 2005). 

Gluten Detoxification

Enzyme therapy. Enzyme therapy is a promising new intervention designed to detoxify gluten. Certain protein-digesting enzymes (proteases) derived from plants and microorganisms can completely break down gluten peptides into harmless fragments. One such enzyme preparation, AN-PEP, is a proline-specific protease extracted from the common fungus Aspergillus niger. This enzyme specifically cleaves the proline-rich gliadin peptides, making them less immunogenic. Experiments with cell cultures demonstrated that AN-PEP can withstand the strongly acidic environment of the stomach, and fully digest gluten and immunogenic peptides (Stepniak 2006). Human clinical trials are underway to confirm this.

Another protease, ALV003, is further along in development and appears to have greater therapeutic potential. Composed of a proline-specific protease and a glutamine-specific protease called EP-B2, this two-enzyme combination was shown to be superior to either enzyme alone (Siegel 2006; Siegel 2012). According to a phase II trial, ALV003 appeared to reduce gluten-induced small intestinal damage in patients with celiac disease who were challenged with up to 2 g gluten per day while following a gluten-free diet (Lähdeaho 2014). A 500-person multi-center trial is currently ongoing (Adelman 2014).

Iron

Iron-deficiency anemia is one of the most common extraintestinal signs of celiac disease (Horowitz 2011; Caruso 2013); iron deficiency without anemia may also occur. Although iron deficiency is usually corrected by a gluten-free diet, restoration of iron levels can require 6–12 months after the lining of the small intestine has healed (Caruso 2013). Blood tests for iron deficiency, including a complete blood count and ferritin level, are important in diagnosis (Ferri 2015) and iron supplementation is considered part of necessary care for celiac patients, in part due to the nutritional insufficiency possible with a gluten-free diet (Thompson 2000; Kupper 2005; Lidums 2015; Kelly 2014).

Calcium

In celiac disease, damage to the intestinal lining often leads to calcium malabsorption and decreased serum levels of calcium (Rastogi 2012; Pantaleoni 2014; Babar 2011; Szymczak 2012), which then lead to bone loss, osteopenia, osteoporosis, and increased fracture risk (AGA 2001; Pantaleoni 2014). Calcium levels and bone mineral density improve on a gluten-free diet, but only after one to two years (Caruso 2013; Molteni 1995). However, a gluten-free diet can be low in calcium, and can lead to calcium deficiency (Kupper 2005; UCMC 2013; Blazina 2010) and subsequent low bone mineral density (Blazina 2010). Thus, supplementation with calcium is important for patients with celiac disease (Rastogi 2012; Mancini 2011; Szymczak 2012; Blazina 2010; Lucendo 2013; Caruso 2013; Bianchi 2008).

Vitamin D

Vitamin D deficiency is a common problem in celiac disease and is associated with a range of musculoskeletal disorders including bone pain, muscle disorders (myopathy), loss of bone mineral density, osteopenia, and osteoporosis (Mulder 2011; Rastogi 2012; Rabelink 2011; Karaahmet 2014; Caruso 2013). One study found low vitamin D levels in 64% of men and 71% of women with celiac disease (Kemppainen 1999). Importantly, however, this study defined vitamin D “deficiency” as below 10 ng/mL 25-hydroxyvitamin D, which is far below levels considered optimal. Also, evidence suggests serum vitamin D levels decrease with age in individuals with celiac disease, and low levels occur even in sunny climates (Lerner 2012). A case report described a celiac patient with myopathy and a vitamin D level below 4 ng/dL. The patient was started on a gluten-free diet and initiated vitamin D supplementation at a dose of 300 000 IU once every two weeks, while under physician supervision. The patient’s symptoms resolved within a week (Karaahmet 2014).

Supplementation with vitamin D and calcium, along with a gluten-free diet, has been shown to markedly improve bone status in celiac patients (Duerksen 2012; Bianchi 2008; Rastogi 2012), and supplementation with vitamin D and calcium is widely recommended for celiac patients (Szymczak 2012; Lucendo 2013; Rastogi 2012). Vitamin D has many additional functions beyond its role in the musculoskeletal system, particularly modulation of the immune system and anti-inflammatory effects. Data from laboratory studies provide evidence for vitamin D’s potential to decrease systemic inflammation and prevent autoimmune disease in humans (Richards 2007; Kriegel 2011; Agmon-Levin 2013; Antico 2012). Specifically, vitamin D inhibits secretion of pro-inflammatory cytokines such as interferon-gamma and TNF-α, while promoting the production of anti-inflammatory cytokines including IL-4, IL-5, and IL-10 (Prietl 2013).

Blood tests for 25-hydroxyvitamin D can determine baseline levels and monitor changes in levels resulting from vitamin D supplementation and a gluten-free diet.

B Vitamins

Deficiencies of folate and vitamins B12 and B6 are common in celiac disease (Dickey 2002; Haapalahti 2005; Tikkakoski 2007; Dahele 2001; Reinken 1978; Caruso 2013), and supplementation with these B vitamins, and also niacin (vitamin B3) and riboflavin (vitamin B2), is considered an important part of conventional care for celiac patients (Hadithi 2009; Caruso 2013; Wierdsma 2013; Halfdanarson 2007; Lidums 2015). In one study, folate and pyridoxal 5’-phosphate, the active form of vitamin B6, were deficient in 37% and 20% of adult celiac patients, respectively, who had been on a gluten-free diet for 10 years and who exhibited biopsy-proven recovery. Among the participants in this study, mean daily folate and vitamin B12 intake were significantly lower in those with celiac than in controls (Hallert 2002).

Homocysteine is an amino acid derivative that can damage the lining of blood vessels and promote atherosclerotic disease (Eren 2014; Pushpakumar 2014). Elevated homocysteine is often attributable to a lack of vitamins B12, B6, and folate, which are necessary for the metabolism of homocysteine (Higdon 2014a; Higdon 2014b). Several studies have demonstrated elevated blood levels of homocysteine in celiac patients (Hallert 2002; Dickey 2008; Saibeni 2005). One study showed celiac patients who took vitamin supplements had higher blood levels of folate and vitamins B6 and B12, and lower levels of homocysteine, compared with those who did not use supplements (Hadithi 2009).  Deficiency in folate and vitamin B12 can cause B-deficiency anemia, which is common in celiac disease, occurring in up to 34% of untreated patients (Wierdsma 2013; Halfdanarson 2007).

Magnesium

Magnesium is an essential mineral involved in hundreds of enzymatic reactions in the body (Higdon 2013a). Magnesium is also required for proper metabolism of vitamin D and calcium, and thus for bone health (Zofkova 1995; Hardwick 1991).

The importance of magnesium deficiency in celiac disease was first recognized over fifty years ago, when a detailed case report showed a dramatic improvement in magnesium absorption and status in a young adult celiac patient after she commenced a gluten-free diet (Goldman 1962). Another study investigated magnesium status in children and adolescents with celiac disease. While all of the patients with classical celiac disease (with malabsorption) were magnesium deficient, only 1 in 5 patients on a gluten-free diet (no malabsorption) and 1 in 5 patients with silent celiac disease (no malabsorption) were low in magnesium (Rujner 2001). A later study examined magnesium in 41 children and adolescents with celiac disease or normal intestinal villi who had been on a gluten-free diet for an average of 11 years; 28 patients with untreated atypical celiac disease and eight controls were also included in the study. The researchers found magnesium deficiency, as assessed by red blood cell magnesium levels, in 14.6% of those on the gluten-free diet and 25% of untreated patients (Rujner 2004).

An earlier study in 23 adult celiac patients found that all of them had depleted intracellular magnesium levels despite being asymptomatic (no malabsorption) and on a gluten-free diet. Magnesium therapy in these individuals resulted in increases in both red blood cell magnesium and bone mineral density, suggesting magnesium deficiency may play a role in the development of osteoporosis in people with celiac disease (Rude 1996). Screening for magnesium status and deficiency, and magnesium supplementation and dietary enrichment, are considered essential aspects of care for celiac patients (Ferri 2015; Lidums 2015; Caruso 2013).

Zinc

Zinc is an essential nutrient mineral that acts as a catalytic agent for over 300 separate enzymatic reactions in the body (Higdon 2013b). Zinc deficiency is common in untreated celiac disease, and this deficiency is not always corrected by a gluten-free diet; zinc supplementation is considered a necessary part of celiac treatment by some sources (Caruso 2013; Lidums 2015; Kupper 2005). Zinc deficiency may be a culprit in poor growth, immune function, and wound healing, and skin problems in celiac disease.

A review of studies of both untreated and treated celiac patients found a remarkable prevalence of zinc deficiency, as measured by either plasma or serum zinc. Eleven separate studies of untreated adults and children with celiac disease found zinc deficiency in up to 100% of patients. Three of nine studies of celiac patients on a gluten-free diet for as little as three months to as long as 10 years found zinc deficiency persisted in 20–40% of patients. On a gluten-free diet alone, zinc deficiency usually takes a full year to resolve, and monitoring of serum zinc levels in celiac patients has been suggested (Caruso 2013; Wierdsma 2013; Guevara Pacheco 2014).

Vitamin E

Vitamin E is an important fat-soluble vitamin and free radical scavenger that plays a major role in protecting cell membranes from oxidative damage (Higdon 2008). Several studies have reported low levels of vitamin E in individuals with celiac disease (Odetti 1998; Guevara Pacheco 2014; Henri-Bhargava 2008). Vitamin E deficiency has also been implicated in the development of neurological symptoms in celiac disease (Kleopa 2005; Mauro 1991; Battisti 1996; Henri-Bhargava 2008). Vitamin E supplementation, together with a gluten-free diet, has been shown to improve neurological impairment caused by vitamin E deficiency in celiac disease (Kleopa 2005; Henri-Bhargava 2008; Mauro 1991).

Vitamin A

Vitamin A is a fat-soluble nutrient that can become deficient in celiac disease patients as a result of malabsorption. Vitamin A is important for normal immune function, vision, and gene expression (Higdon 2007a). The treatment for vitamin A deficiency in celiac disease is both a gluten-free diet and supplementation (Lidums 2015). One study of newly diagnosed celiac patients found that 7.5% of them were deficient in vitamin A versus none in a healthy control group (Wierdsma 2013). A case study reaffirmed the importance of vitamin A, even in controlled celiac cases. A 64-year-old man, with biopsy-proven celiac disease controlled on a gluten-free diet, presented with recent onset of diarrhea as well as redness and blurring in one eye. During three weeks of treatment of his eye symptoms with medication, his condition deteriorated. Testing of vitamin A revealed a stark deficiency. The patient received an intramuscular injection containing 100 000 IU vitamin A, and dramatic improvement in vision and the condition of his eye was noted within a week. This patient’s follow-up included regular vitamin A treatment (Alwitry 2000).

Vitamin K

Vitamin K is another fat soluble vitamin that can become deficient in celiac disease as a result of malabsorption (Lidums 2015; Mager 2012; Kelly 2014; Lidums 2015). Vitamin K deficiency can contribute to easy bruising, an atypical sign of celiac disease; vitamin K deficiency has also been shown to increase risk of blood clots and bleeding events in individuals with celiac disease (Berthoux 2011; Chen 2007; Vaynshtein 2004; Lerner 2014; Lerner 2014; Chen 2007; Vaynshtein 2004). In a 2012 study in children and adolescents with celiac disease, dietary intake of vitamin K was assessed. At diagnosis, 41% of patients had intakes less than half of the recommended amount, while intake remained deficient in 31% of patients after one year on a gluten-free diet (Mager 2012).

Children with both symptomatic and asymptomatic celiac disease have been found to have reduced bone mass at diagnosis (Mager 2012; Turner 2009; Rajani 2010). Vitamin K enhances calcium metabolism and therefore plays an important role in bone health (Zittermann 2001; Booth 2009). Because dietary intake of calcium and vitamins K and D is often inadequate, including for patients on a gluten-free diet, routine supplementation with vitamin K at the time of diagnosis of celiac disease has been suggested (Mager 2012). 

Selenium

Selenium is an integral part of the enzyme glutathione peroxidase, which plays a major role in cellular antioxidant defense (Higdon 2007b). In a study of 30 children with celiac disease, 80% had serum selenium levels below the normal range (Yuce 2004). Selenium is essential for thyroid hormone regulation, and selenium deficiency in celiac disease has been linked to an increased risk of autoimmune thyroid disease (Stazi 2008; Stazi 2010).

Probiotics

Probiotics are beneficial microorganisms that colonize the intestine and play an important role in intestinal health; the balance of these organisms appears to be deranged in patients with celiac disease (Pozo-Rubio 2012; Round 2009). In a three-week randomized controlled trial, supplementation with Bifidobacterium infantis NLS super strainin untreated celiac disease patients resulted in improvements in indigestion, constipation, and acid reflux (Smecuol 2013).

Various strains of probiotics are being developed to specifically target mechanisms of immune and intestinal damage in celiac disease. The probiotic strain Bifidobacterium lactis has been shown to protect cultured gut epithelial cells from damage induced by gluten, possibly by blocking gluten-induced increases in intestinal permeability (Lindfors 2008). Also, in a lab experiment, a blend of eight different strains of probiotic bacteria, including several Lactobacillus and Bifidobacterium species, was demonstrated to extensively pre-digest gluten proteins in wheat flour. When intestinal biopsy samples from celiac patients were exposed to these pre-digested gluten proteins, recruitment of immune cells was reduced. Researchers concluded that the probiotic formulation reduced or eliminated the toxicity of wheat gluten (De Angelis 2006).

L-Carnitine

L-carnitine is a compound made in the human body from the amino acids lysine and methionine and also obtained in our diet primarily from animal foods such as meat, fish, and dairy (Higdon 2012a). 

In a randomized controlled trial, supplementation with 2 g L-carnitine daily for six months resulted in significant improvement in reported fatigue in adults with celiac disease. The L-carnitine dosage was safe and well tolerated (Ciacci 2007).

L-carnitine is required to shuttle long chain fatty acids into the mitochondria (power plants of the cell) for muscle energy production. The intestinal damage in celiac disease results in a decrease in absorptive surface area, increasing risk of L-carnitine deficiency. In one study, untreated celiac patients were found to have low serum L-carnitine concentrations, which returned to normal with a gluten-free diet (Lerner 1993). Another study found low serum carnitine levels in children with celiac disease (Yuce 2004). L-carnitine deficiency may produce fatigue, weakness, and difficulty gaining weight, all common symptoms in celiac disease (Lerner 1993; Guandalini 2014).

Omega-3 Fatty Acids

Omega-3 fatty acids have important biological anti-inflammatory effects (Skulas-Ray 2015; Yan 2013; Calder 2015). When ingested through food or supplements, omega-3 fatty acids compete with the more pro-inflammatory omega-6 fatty acid arachidonic acid for incorporation into lipid-rich cell membranes (Westphal 2011; Calder 2007; Pischon 2003; Surette 2008).

A study of serum fatty acid composition in adults with newly diagnosed celiac disease found that concentrations of omega-3 fatty acids were significantly lower than those of a control group. After one year on a gluten-free diet and having achieved clinical remission, levels of omega-3 fatty acids increased but still remained well below control values (Solakivi 2009). A study in children with celiac disease and type 1 diabetes mellitus found their omega-3 fatty acid levels—including docosapentaenoic and docosahexaenoic acid (DHA)—were significantly lower than those in a control group (Tarnok 2015). 

A study that used cultures of intestinal epithelial cells (enterocytes) supports the potential benefit of oral supplementation with DHA in reducing intestinal inflammation in celiac disease. In response to inflammation triggered by gluten, enterocytes release arachidonic acid. DHA was shown to block this release of arachidonic acid and the resulting inflammatory cascade that furthers disease development (Vincentini 2011; Ferretti 2012). Another mechanism by which omega-3 fatty acids reduce inflammation is through inhibition of nuclear factor-kappaB (NF-ĸB), a pro-inflammatory mediator (Lee 2009). DHA also stimulates a cellular receptor called PPAR-gamma, which activates genes that lessen the production of pro-inflammatory cytokines (Zapata-Gonzalez 2008).

Vitamin C

Vitamin C is a water-soluble free radical scavenger that is also essential to the structural integrity of tissues throughout the body (Higdon 2013c). In one experiment, cultured intestinal biopsies from celiac patients were challenged with the gliadin component of gluten with and without the addition of vitamin C. The addition of vitamin C to the cultured cells decreased the secretion of pro-inflammatory cytokines TNF-α, IL-6, and interferon-gamma. Vitamin C also completely inhibited the secretion of the pro-inflammatory cytokine IL-15, which is strongly implicated in the damage that occurs in celiac disease (Bernardo 2012; Gujral 2012).

Glutathione

Glutathione is one of the body’s most powerful defenses against destructive free radicals, and is essential to the liver’s detoxification functions (NLM 2015; Kidd 1997). Several studies have reported significant reductions in glutathione concentrations in the intestinal lining (Stojiljkovic 2009; Stojiljkovic 2012) and peripheral blood (Stojiljkovic 2007; Stojiljkovic 2012) of celiac patients compared with controls. As a result, concentrations of lipid peroxides, or rancid fat, in the intestinal lining increased. Lipid peroxides can promote a cascade of oxidative damage in tissues, contributing to the tissue damage in the intestine that is characteristic of celiac disease, and to the increased risk of cancer in celiac patients (Stojiljkovic 2007; Stojiljkovic 2009; Stojiljkovic 2012).

The body’s glutathione reserves can be increased by means of direct supplementation with glutathione (Richie 2014) or with the use of physiologic precursors such as cysteine (Lee 2013; Sekhar 2011) and N-acetyl cysteine (NLM 2015; Kidd 1997), as well as with alpha-lipoic acid, selenium, and whey protein (Chen 2011; Zavorsky 2007; Jiang 2012).

Pancreatic Enzymes

Exocrine pancreatic insufficiency, a condition in which not enough digestive enzymes are secreted into the small intestine (Toouli 2010), is relatively common in celiac disease patients who do not respond to a gluten-free diet (Ferri 2015). Damage to the small intestine may inhibit the ability of the pancreas to secrete digestive enzymes. One study found that in cases in which diarrhea persisted even after a gluten-free diet, there was a significantly higher prevalence of laboratory signs of pancreatic insufficiency. Patients treated with pancreatic enzymes experienced a 75% reduction in symptoms. Another study found that the severity of villous atrophy in the small intestine was significantly associated with laboratory signs of pancreatic exocrine insufficiency. Pancreatic enzyme insufficiency was found to occur in over half of celiac patients in one study, and to return to normal after one year on a gluten-free diet (Malterre 2009; Evans 2010; Weizman 1987; Regan 1980).

Additional Support

The following interventions have not been thoroughly studied in the context of celiac disease, but may nonetheless be of benefit by helping support intestinal health or combatting inflammatory responses or cellular metabolic derangements, which are thought to underlie several manifestations of celiac disease.

Curcumin. Curcumin is the principal polyphenolic compound in turmeric, a plant used in Indian Ayurvedic medicine for centuries (Higdon 2009). Curcumin has powerful anti-inflammatory and antioxidant properties and has demonstrated in laboratory, animal, and human models an ability to protect against a wide range of conditions including autoimmune disease and IBD (Gupta 2013; Aggarwal 2009; Brumatti 2014; Bright 2007). 

Like Crohn’s disease and ulcerative colitis, celiac disease is an inflammatory autoimmune disorder (Ferri 2015). In celiac disease, the inflammatory mediator interferon-gamma promotes enhanced permeability and damage in the small intestine (DiRaimondo 2012; Nilsen 1998). Curcumin has been shown to suppress interferon-gamma, suggesting that curcumin may be beneficial in celiac disease (Fahey 2007).

Interestingly, curcumin may be able to ameliorate psychological manifestations of celiac disease and non-celiac gluten sensitivity as well. In a randomized controlled trial, a highly bioavailable form of curcumin was found to be as effective as the standard antidepressant medication fluoxetine (Prozac) in the treatment of major depressive disorder (Sanmukhani 2014; Antony 2008). Since depression and other psychological manifestations of celiac disease and non-celiac gluten sensitivity are being recognized with increasing frequency (Peters 2014; Smith 2012; Bushara 2005; Carta 2002; Corvaglia 1999; Addolorato 1996), this is another of curcumin’s benefits that may be valuable in these gluten-related disorders.

Alpha-lipoic acid. Alpha-lipoic acid is a naturally occurring compound centrally involved in energy production within the mitochondria of the cell. It is also a powerful free radical scavenger (Higdon 2012b). In addition, alpha-lipoic acid regenerates other free radical scavengers such as glutathione, vitamin C, vitamin E, and coenzyme Q10 (Chen 2011; Packer 2011; Jones 2002).

Alpha-lipoic acid’s ability to increase levels of glutathione is important in celiac disease, in which low glutathione levels are common (Stojiljkovic 2007; Stojiljkovic 2009; Stojiljkovic 2012). In an animal model, dietary supplementation with alpha-lipoic acid significantly increased both cellular glutathione concentrations and the activity of glutathione peroxidase, a key glutathione-dependent antioxidant enzyme. Compared with controls, levels of oxidized lipids (peroxidation) were significantly lower as well (Chen 2011). Other studies support alpha-lipoic acid’s potential to accelerate glutathione synthesis (Packer 2011; Kolgazi 2007; Suh 2004). In a rodent model of gut inflammation, a feature of celiac disease, treatment of rats with alpha-lipoic acid markedly reduced several measures of damage to the gut lining (Kolgazi 2007).

Boswellia serrata. In recent years, preparations from the gummy resin of Boswellia serrata and other boswellia species have become popular in parts of Europe for the treatment of various chronic inflammatory conditions including chronic bowel diseases. Clinical studies suggest boswellia is safe and effective in the treatment of autoimmune bowel diseases (Crohn’s disease and ulcerative colitis). Boswellic acids, which are active constituents of boswellia, exert anti-inflammatory effects through inhibition of proinflammatory pathways involving 5-lipoxygenase, leukotrienes, and TNF-α (Ammon 2006). In a similar manner, boswellia may help reduce the intestinal inflammation of celiac disease.

Green tea extract (EGCG). Animal studies have indicated that green tea extract and its chief constituent, epigallocatechin-3-gallate (EGCG), are capable of interrupting inflammatory tissue damage that contributes to the symptoms of celiac and other autoimmune disease. Helper T cells are key drivers in many autoimmune diseases including celiac disease (Monteleone 2001). One mechanism for the protective effect of EGCG is suppression of autoreactive T cells and reduced production of pro-inflammatory cytokines. EGCG was also shown to inhibit interferon-gamma, a dominant inflammatory mediator in celiac disease (Wu 2012).

In a human cell-line study, EGCG prevented interferon-gamma from increasing intestinal permeability (Watson 2004). In an animal model of colitis, green tea extract significantly diminished damage to the colon, as evidenced by reduced amounts of inflammatory markers, less diarrhea, and slowing of weight loss (Mazzon 2005).

Glutamine. Glutamine, an amino acid, is especially important for the lining of the gastrointestinal tract, particularly during stress and illness. Glutamine is the most abundant amino acid in the body, and a critical fuel for the cells lining the intestine. In fact, oral glutamine supplementation is capable of increasing the height of intestinal villi, helping the cells of the gut lining to proliferate, and maintaining integrity of the gut lining and preventing excessive permeability (de Vasconcelos 1998; Miller 1999). As a regulator of tight junction proteins that “glue” intestinal cells together (Li 2004), glutamine has been shown to exert a positive effect on gut barrier function (permeability) in a variety of clinical conditions (Beutheu 2013; Sevastiadou 2011; Choi 2007). In a 2012 randomized controlled trial in patients with Crohn’s disease in remission phase, oral glutamine administered at 0.23 g per pound body weight for two months significantly improved intestinal permeability and mucosal integrity (Benjamin 2012).

Glutamine supplementation has yet to be studied in celiac disease. However, since supplementation with glutamine has been demonstrated to safely enhance and maintain gut barrier function, its application in the increased permeability caused by celiac disease is an area of great scientific interest (Kuhn 2010; Beutheu 2013; Choi 2007; Benjamin 2012; Fasano 2011; Clemente 2003; Fasano 2005; Arrieta 2006).

Whey protein. Glutathione forms an integral part of the defense mechanisms that protect the intestinal mucosa (gut lining) from oxidative damage (Stojiljkovic 2009). Whey protein is a rich source of cysteine that is needed for the synthesis of glutathione (Alt Med Rev 2008). Several studies have shown that whey protein is highly effective for increasing glutathione levels in various types of cells (Zavorsky 2007; Vilela 2006; Kent 2003; Grey 2003; Middleton 2004). Additionally, in a 2012 study in patients with Crohn’s disease, whey protein significantly reduced intestinal permeability (Benjamin 2012). This benefit of whey on gut integrity may be useful in celiac disease, and whey protein can easily be incorporated into a gluten-free diet as a source of high-quality protein and glutathione precursors. 

Zinc-carnosine. Zinc-carnosine, a free radical scavenger and anti-glycation agent, is composed of zinc and carnosine (Alhamdani 2007). In a randomized crossover trial, healthy participants were given either zinc-carnosine or placebo after five days of indomethacin (Indocin) treatment. The indomethacin caused a 3-fold increase in gut permeability in the placebo group, while zinc-carnosine prevented this rise in permeability in the treatment group. Although more studies are needed, zinc-carnosine appears to help maintain the integrity of the gut barrier (Mahmood 2007).