Gluten

Gluten is a complex protein found in grains such as wheat, barley, and rye, playing a vital role in the texture and structure of baked goods. Comprised mainly of gliadin and glutenin, gluten forms a sticky, elastic network when mixed with water, essential for dough's rise and elasticity.

While gluten is integral to many foods, some individuals experience sensitivities or severe allergic reactions to it.  

Gluten-related disorders including celiac disease, non-celiac gluten sensitivity, and wheat allergy can cause a range of symptoms, although they have different pathogeneses.  The primary treatment for those affected is adhering to a strict gluten-free diet to manage and alleviate symptoms.

What is Gluten?

Gluten is a complex protein found in various grains, primarily wheat, barley, and rye. It plays a crucial role in the structure and texture of baked goods, contributing to the elasticity and chewiness of dough. 

However, many individuals are born with, or develop, sensitivities to gluten ranging from mild symptoms to very severe allergies. 

Definition of Gluten

Gluten is a mixture of two main protein fractions: gliadin and glutenin.  These proteins are responsible for the unique properties of gluten, enabling it to form a sticky, elastic network when combined with water and kneaded.  

This network is essential for the rise and texture of bread and other baked goods.

Glutenin vs. Gliadin

Gluten proteins can be categorized into glutenin and gliadin based on their solubility. 

Glutenin is a fibrous protein with a higher molecular weight, composed of high and low molecular subunits.  Glutenin provides strength and elasticity to the dough through the particular chemical bonds it forms.  The quality of glutenin in a wheat flour determines the quality of bread.  [23., 27.]

Gliadin, a monomeric spherical protein with a lower molecular weight, offers viscosity and extensibility via non-covalent bonds within the glutenin network.  The ratio of glutenin to gliadin is considered important in breadmaking.  [1.] 

Gliadin contributes to the formation of the continuous protein network in dough that traps gas cells and allows dough to rise during proofing and baking.  [26.]  

Together, these interactions form a viscoelastic three-dimensional protein network, crucial for the unique rheological properties of dough that allow for the production of wheat-based products like bread.

Sources of Gluten  [6.] 

The primary sources of gluten are wheat, barley, and rye. 

Wheat, in particular, is a major contributor to gluten consumption due to its widespread use in various food products, including bread, pasta, cereals, and baked goods. 

Barley and rye are also significant sources of gluten and are commonly used in the production of certain types of bread, beer, and other fermented beverages.

Normal Gluten Digestion In the Body  [2., 3.] 

Normally, gluten digestion occurs in the following steps: 

In the mouth, salivary amylase starts breaking down the starch components of food, but the gluten proteins remain largely intact.

In the stomach, gluten proteins undergo partial digestion by the acidic environment (hydrochloric acid) and the enzyme pepsin.  Pepsin is a protease that can cleave some of the peptide bonds in gluten, breaking it down into smaller fragments like gliadin and glutenin.

The partially digested gluten proteins (high molecular weight oligopeptides) then move into the small intestine.

In the duodenum (upper part) of the small intestine, pancreatic proteases like trypsin, chymotrypsin, and elastase attempt to further break down the gluten fragments.  However, these enzymes have limited ability to completely digest proline and glutamine-rich sequences in gluten.

The intestinal brush border enzymes also act on the partially digested gluten, but they too cannot fully degrade the proline and glutamine-rich oligopeptides remaining from gluten.

Tissue trans-glutaminase enzymes are another type of enzyme in the small intestine that act on the partially-digestible gluten components, although they seem to be responsible for creating macromolecular complexes by crosslinking gluten proteins, which can become antigenic and participate in the pathogenesis of celiac disease.  [18., 24.] 

Tissue trans-glutaminase is expressed in the Paneth cells of the digestive tract, which are found in the crypts between villi.  [24.] 

Normally, tissue trans-glutaminase enhances tissue strength and resilience by crosslinking proteins, supports cellular stability, detoxifies ammonia through glutamine-glutamate interconversion, and plays a crucial role in wound healing and immune response. 

Additionally, it is utilized in the food industry for improving texture and quality of meat products.  [18.] 

As a result of the incomplete digestion of gluten along with the formation of macromolecular complexes, some high molecular weight gluten oligopeptides remain in the small intestine lumen and interact with the intestinal mucosa, potentially leading to issues in susceptible individuals.

So in summary, while gluten digestion is initiated by pepsin in the stomach, the human digestive enzymes (pancreatic proteases and brush border enzymes) are unable to fully break down the proline and glutamine-rich sequences in gluten proteins. 

This leads to the persistence of partially digested, high molecular weight gluten oligopeptides in the small intestine, which can trigger issues in those with gluten intolerances or sensitivities.

Understanding Celiac Disease: What Does Gluten Do to Your Body?

Pathogenesis of Celiac Disease  [21.] 

The digestion of gluten is a complex process that involves various enzymes and gut microbiota. 

Some individuals develop a complex autoimmune response triggered by gluten-containing macromolecule complexes, which is considered the cause of celiac disease.  

Innate Immune Response:  [7., 18.] 

Gluten proteins, particularly the gliadin fraction, are partially digested in the intestine, resulting in large peptide fragments.

These peptides interact with the enzyme tissue transglutaminase (tTG), which deamidates them, increasing their immunogenicity.  Specifically, this deamidation enhances the binding of these peptides to HLA-DQ2/DQ8 molecules and triggers an immune response in celiac disease patients.

The deamidated gluten peptides activate the innate immune system, leading to the release of inflammatory cytokines and intraepithelial lymphocytosis.

Adaptive Immune Response:  [7.] 

In individuals with HLA-DQ2 or HLA-DQ8 genes, the deamidated gluten peptides are presented to CD4+ T cells, triggering an adaptive immune response.

This leads to the activation of both T cells and B cells, resulting in the production of antibodies against gluten (anti-gliadin) and tTG (anti-tTG).

The activated T cells release pro-inflammatory cytokines such as interferon-gamma (IFN-γ), which contribute to intestinal damage and villous atrophy.

‍Intestinal Damage:  [17.] 

The inflammatory response and cytokine release lead to the destruction of intestinal epithelial cells and villous atrophy, resulting in nutrient malabsorption.

Intraepithelial lymphocytosis and crypt hyperplasia are also observed.

Genetic Factors:  [17.] 

Celiac disease is strongly associated with the presence of HLA-DQ2 and HLA-DQ8 genes, which are involved in presenting gluten peptides to T cells.

It's important to note that while the production of anti-gliadin and anti-tTG antibodies is a characteristic feature of celiac disease, their direct pathogenic role is not well-established. However, they serve as useful diagnostic markers.

Symptoms of Celiac Disease [5., 15.]

For individuals with celiac disease, an autoimmune disorder triggered by gluten ingestion, the consumption of gluten can lead to severe consequences. 

Gluten exposure in these individuals can cause gut inflammation, nutrient malabsorption, and damage to the small intestine's lining.  This can result in a range of symptoms, including: 

Digestive Symptoms:

• Chronic diarrhea 

• Abdominal pain or cramping 

• Bloating and gas

• Constipation 

• Nausea and vomiting 

• Pale, foul-smelling, fatty stools (steatorrhea) 

Other Symptoms:

• Weight loss 

• Fatigue 

• Anemia (iron deficiency) 

• Bone/joint pain 

• Osteoporosis or osteomalacia (bone loss) 

• Itchy skin rash (dermatitis herpetiformis) 

• Mouth ulcers 

• Headaches 

• Tingling/numbness in hands and feet (neuropathy) 

• Missed menstrual periods 

• Infertility 

• Tooth enamel defects 

Symptoms in Children:

• Failure to thrive/growth issues 

• Irritability

• Delayed puberty 

• ADHD/learning disabilities 

• Lack of muscle coordination

• Seizures 

Gluten Sensitivity Disorders

Gluten sensitivity disorders refer to a group of conditions triggered by the ingestion of gluten, a protein found in wheat, barley, and rye. 

The main gluten sensitivity disorders include:

Celiac Disease

An autoimmune disorder where gluten ingestion causes damage to the small intestine, leading to malabsorption of nutrients. It is a lifelong condition requiring strict adherence to a gluten-free diet.

Non-Celiac Gluten Sensitivity (NCGS)  [4.] 

 A condition characterized by intestinal and extra-intestinal symptoms related to gluten ingestion, without the autoimmune response or intestinal damage seen in celiac disease. 

Individuals with NCGS may experience symptoms such as abdominal pain, bloating, brain fog, and headaches after consuming gluten-containing foods. 

The exact mechanisms underlying NCGS are not fully understood, but it is believed to involve an innate immune response or a sensitivity to other components in gluten-containing grains.

Symptoms improve with a gluten-free diet.

Wheat Allergy 

Wheat allergy is an immune response to various wheat proteins, which can be IgE-mediated or non-IgE-mediated, and may cause severe reactions, including anaphylaxis. 

Unlike celiac disease and NCGS, which are primarily triggered by gluten, wheat allergy can be caused by various wheat proteins, including gluten and other components. 

Symptoms of wheat allergy can range from mild to severe and may include skin rashes, digestive issues, and, in severe cases, anaphylaxis.

IgE-mediated reactions involve specific antibodies and can result from ingestion or inhalation of wheat, leading to symptoms like hives, swelling, and respiratory issues. 

Non-IgE-mediated reactions, such as celiac disease, cause chronic inflammation in the gastrointestinal tract. 

Diagnosis involves evaluating symptoms and confirming with skin prick tests or serum IgE levels, while management focuses on strict avoidance of wheat and emergency preparedness with epinephrine for severe reactions.

Gluten Ataxia  [12.]

Ataxia is a neurological condition involving loss of muscle coordination or control, resulting in impaired movements, balance, speech, and other voluntary functions. 

Gluten ataxia is a condition where gluten sensitivity leads to ataxia, often seen in patients with sporadic idiopathic ataxia. It is thought to be caused by an autoimmune response to gluten in susceptible individuals.  

In a study, 41% of sporadic idiopathic ataxia patients had antigliadin antibodies, compared to 12% in the general population, indicating a significant association.  [12.]

Clinical features of gluten ataxia include gait ataxia, upper and lower limb ataxia, dysarthria, and ocular signs, with cerebellar atrophy evident in MRI scans. 

The presence of HLA DQ2 was noted in 72% of patients, and antigliadin antibody testing is recommended for early diagnosis and management, as a gluten-free diet may benefit these patients.

Dermatitis Herpetiformis  [8.]

Dermatitis herpetiformis (DH) is a chronic, intensely itchy, blistering skin rash associated with gluten sensitivity, particularly celiac disease. 

It is considered the skin manifestation of celiac disease and affects 80-90% of people with underlying celiac disease or gluten-sensitive enteropathy, even if they don't have gastrointestinal symptoms.  [8.]

Ingesting gluten triggers an autoimmune response in DH, leading to IgA antibodies attacking epidermal transglutaminase, resulting in the rash. 

The rash appears as clusters of small, itchy blisters or papules, commonly on the elbows, knees, buttocks, back, and scalp. 

Treatment includes a strict, lifelong gluten-free diet, which helps control the rash, and medications like dapsone for symptom management.

How to Test for Gluten Intolerance

Accurate diagnosis of gluten-related disorders is crucial for proper management and treatment. 

Biomarkers for Celiac Disease

The diagnosis of celiac disease typically involves a combination of serological tests, intestinal biopsy, and genetic testing. 

Serological tests measure the following:

IgA and IgG Antibodies against Deamidated Gliadin Peptides: these antibodies against partially broken-down gliadin molecules that stimulate a T cell antibody response in susceptible individuals.

• Anti-DGP IgA

• Anti-DGP IgG

IgA and IgG Anti-Tissue Transglutaminase Antibodies: antibodies against the anti-tissue transglutaminase enzyme which is released as part of the inflammatory process.

• Anti-tTG IgA

• Anti-tTG IgG

Total IgA

Anti-EMA IgA (IgA Anti-Endomysial Antibodies)

Biomarkers for Non-Celiac Gluten Sensitivity

Currently, there are no definitive tests available for diagnosing NCGS. However, researchers are investigating potential biomarkers that may aid in the diagnosis and monitoring of this condition. 

Increasingly, testing for immune markers such as IgG and C3b/d is performed.  Additional testing may include markers for leaky gut such as zonulin.  

What is the Clinical Significance of IgG Antibody Testing for Food Sensitivities?

Food sensitivity testing using IgG antibodies is employed due to its potential clinical relevance in identifying delayed immune responses to specific food antigens. 

While IgE-mediated food allergies typically provoke immediate hypersensitivity reactions, IgG-mediated responses are associated with delayed onset reactions, making them challenging to diagnose clinically. 

However, accumulating evidence suggests that IgG antibody testing for food sensitivities may shed light for clinicians. [11., 20., 25.]  Some studies indicate that IgG-mediated immune responses might contribute to the pathogenesis of gastrointestinal inflammation.  [22.]  

Increasingly, IgG subtype testing is performed in the context of food sensitivities.  

IgG4, a subtype of immunoglobulin G antibodies, plays a crucial role in modulating immune responses, particularly in the context of allergies. 

Research indicates that IgG4 antibodies can help neutralize allergic reactions orchestrated by IgE, thereby mitigating histamine responses and promoting immune tolerance to foods.  

However, it's essential to maintain a balanced level of IgG4, as excessive amounts can paradoxically lead to increased inflammation and immune sensitization; increased IgG4 levels have been associated with allergies and with autoimmune conditions.  

For instance, elevated IgG4 levels have been implicated in conditions such as rheumatoid arthritis, myasthenia gravis, pemphigus vulgaris and thrombotic thrombocytopenic purpura.  [13., 14., 19.]

What is the Clinical Significance of C3b/d Testing for Food Sensitivities? 

C3b/d (Complement Component 3) is a protein of the innate immune system that is activated by microorganisms in the absence of an antibody.  The inclusion of complement proteins C3d and C3b in the food sensitivity testing may provide a more comprehensive assessment of the immune response to dietary antigens. 

Complement proteins play a crucial role in the immune cascade triggered by IgG-mediated reactions. 

Specifically, C3d and C3b are involved in the opsonization of immune complexes, facilitating their recognition and clearance by phagocytic cells; their role can increase the actions of IgG antibodies many times over. 

By measuring levels of C3d and C3b alongside IgG antibodies against common foods, this test may offer valuable insights into the inflammatory response associated with food sensitivities.

Complement activation, particularly through the C3d/C3b pathway, may contribute to the pathogenesis of various immune-mediated disorders, including food sensitivities and allergic reactions. [28.]

What is the Clinical Significance of Zonulin Testing?  [9., 10.]

Assessing zonulin levels through a stool test holds significant clinical relevance, particularly in the context of gastrointestinal health and body-wide conditions related to intestinal permeability. 

Zonulin is a protein that reinforces the tight junctions between intestinal epithelial cells.  Elevated levels of zonulin indicate increased intestinal permeability, often referred to as "leaky gut syndrome." 

This happens when intestinal inflammation, commonly caused by intestinal dysbiosis and gluten sensitivity, causes the enterocytes to swell: this weakens tight junctions and allows zonulin to spill into the intestinal lumen. 

Research suggests that elevated zonulin levels may be associated with various gastrointestinal disorders, autoimmune diseases, and metabolic conditions. 

By measuring zonulin levels in stool, healthcare providers can gain valuable insights into the integrity of the intestinal barrier and identify potential underlying factors contributing to gastrointestinal dysfunction and systemic inflammation.

Frequently Asked Questions (FAQs) on Gluten

The FAQ section addresses common questions and concerns about gluten, providing clear and concise answers for better understanding.  Whether you're curious about gluten's role in food, its health impacts, or dietary considerations, this section covers essential information you need to know.

What Is Gluten?

Gluten is a group of proteins found in wheat and related grains, including barley, rye, and oats.  It gives dough its elastic texture and helps baked goods maintain their shape.

What Does Gluten Free Mean?

"Gluten free" means that a product does not contain gluten, a group of proteins found in wheat, barley, rye, and triticale.  This label is essential for individuals with celiac disease or gluten sensitivity, as consuming gluten can cause adverse health effects in these individuals.

What Foods Have Gluten?

Foods that commonly contain gluten include bread, pasta, cereals, baked goods, pizza, beer, and processed foods that use wheat, barley, or rye as ingredients.  Gluten is also present in sauces, dressings, and soups where flour is used as a thickener.

How to Reverse Gluten Intolerance?

Currently, there is no known way to reverse gluten intolerance or celiac disease.  The primary treatment is to follow a strict gluten-free diet, which helps manage symptoms and prevent damage to the intestines. 

Ongoing research is exploring potential therapies, but adherence to a gluten-free diet remains the most effective approach.

How Do I Know If I Have Gluten Intolerance?

Symptoms of gluten intolerance can include bloating, diarrhea, constipation, abdominal pain, headache, fatigue, skin rashes, and joint pain.

If you suspect gluten intolerance, consult a healthcare provider for proper testing and diagnosis, which may include blood tests and a biopsy of the small intestine.

What Is Celiac Disease?

Celiac disease is an autoimmune disorder where the ingestion of gluten leads to damage in the small intestine. 

It affects the absorption of nutrients and can cause a range of symptoms, including gastrointestinal issues, anemia, and fatigue. Diagnosis is typically made through blood tests and an intestinal biopsy.

Can I Eat Oats on a Gluten-Free Diet?

Pure oats are naturally gluten-free, but they are often contaminated with gluten during processing. 

Look for oats labeled as gluten-free, which have been processed to avoid contamination with gluten-containing grains.

What Are the Health Benefits of a Gluten-Free Diet?

For individuals with celiac disease or gluten sensitivity, a gluten-free diet is essential for managing symptoms and preventing complications. 

Some people without these conditions report feeling better on a gluten-free diet, but there is no evidence that it offers health benefits for the general population.

Are There Any Risks Associated with a Gluten-Free Diet?

A gluten-free diet can be healthy if well-planned, but it can also lead to nutritional deficiencies if not managed properly. 

Foods with gluten often contain important nutrients like fiber, iron, and B vitamins.  It's important to ensure you're getting these nutrients from other sources or supplements.

What Are Some Gluten-Free Grains?

Gluten-free grains include rice, corn, quinoa, millet, buckwheat, amaranth, and sorghum. These grains can be used as alternatives to wheat, barley, and rye in various recipes.

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