Gluten-free diet: A promising plan for several health problems.

The popularity of gluten as an ingredient of food grew due to the Chinese Buddhist cuisine, which used gluten as a substitute for meat in the 6th century. A Chinese agricultural encyclopedia written in 544 CE, known as "Jia Sixie’s Qimin Yaoshu," mentions "bótuō," which represents the use of gluten in noodles. In Western literature, "De Frumento" is an Italian article about wheat that documented the extraction of gluten from wheat flour and was written by Bartolomeo Beccari in 1745. "Gluten" was defined in the English language in "Elements of Science and Art" by John Imson in 1803. Moreover, the Industrial Revolution, the Great Depression, and World War II raised the popularity of wheat in the Western diet, as the wheat-containing products (e.g., bread and pasta) were cheaper and acted as substitutes for meat and dairy products. The use of wheat and gluten is increasing rapidly worldwide; therefore, the concerns about the health effects of gluten are also increasing. 

Wheat, which can be involved in various products including bread and pasta, is one of the most important crops, representing about 20% of global calorie consumption. Gluten is formed of water-insoluble prolamin proteins (a group of alcohol-soluble lectins representing major seed proteins in cereals). The most common prolamins are gliadin and glutenin, which are present mainly in wheat. Celiac disease is a chronic autoimmune disorder affecting about 1% of the population (1 in every 100 individuals in western countries), attacking the gut mucosa through antibodies against tissue transglutaminase 2 (anti-TG2), endomysium, and deamidated gliadin peptide, leading to a reversible inflammatory reaction with gastrointestinal symptoms such as bloating, diarrhea, nausea, and vomiting. Mucosal damage due to inflammation leads to malabsorption and deficiency of vitamin B12, folic acid, calcium, vitamin D, iron, and zinc. Therefore, several health problems arise, including anemia, lymphoma, and osteoporosis. In children, the classic presentation is distension, abdominal pain, malnutrition, and stunted growth (delayed growth) with risk of short stature and constitutional delay of puberty. While in adults the symptoms are mainly gastrointestinal and less severe compared to children, except some cases may present with severe diarrhea. The first line of treatment for celiac disease is a lifelong gluten-free diet. Several factors that affect the adherence to a gluten-free diet will be discussed later.

A complex mechanism involving genetics and environment leads to abnormal immune reactions affecting the intestinal mucosa, leading to cell destruction and villous atrophy. Both innate and adaptive immune responses are involved in the mechanism of celiac disease. Interleukin (IL)-15 is released as part of the innate response triggered by the antigen-presenting cells (e.g., dendritic cells) that present peptides to gluten-specific T-cells, leading to destruction of gut epithelial cells by CD8+ (cytotoxic) T-lymphocytes. The mucosal barrier is negatively affected. Inflammatory cytokines are released as part of the adaptive response, activating interferon-gamma (IFN-γ) T helper cells that promote B-lymphocyte maturation into plasma cells that, in turn, produce anti-gliadin and anti-tissue-transglutaminase antibodies. The gastrointestinal mucosa undergoes inflammation, crypt hyperplasia, villous atrophy, and invasion of intraepithelial tissue by CD4+ and CD8+ T-cell lymphocytes. There is also increased risk of esophageal cancer, small intestinal adenocarcinoma, non-Hodgkin’s lymphoma, and melanoma due to repeated exposure to the stimulus and the corresponding damage.

The treatment of individuals with celiac disease is a lifelong gluten-free diet. That means avoiding any source of gluten proteins, such as wheat, oats, barley, and rye. The diet will be based on fish, meat, legumes, fruits, vegetables, and other nutrients. A gluten-free diet is any product with <20 ppm of gluten according to the Food and Drug Administration (FDA), with possible contamination during production. A strict gluten-free diet can restore about 95% of the histology of the small bowel within 2 years, about 34% after 2 years in adults, and 66% in adults within 5 years of a strict gluten-free diet. The recovery decreases in older age (30-60 years and older than 60 years). The recovery includes improvement of symptoms, including weight loss, diarrhea, and steatorrhea. Improvement of bone mineral density and growth rate of children was also observed, according to the research. 

A gluten-free diet recently is widely used for other health problems, including inflammatory bowel disease and irritable bowel syndrome, gluten ataxia, cognitive impairment, and neurological and mental illnesses.

• Inflammatory Bowel Disease (IBD) and Irritable Bowel Syndrome (IBS):

Patients with diarrhea-dominant irritable bowel syndrome (d-IBS) usually experience a relief of symptoms by being adherent to a gluten-free diet. A study demonstrating the effect of a 6-week gluten-free diet on patients with d-IBS showed that 71% of patients had a relief of symptoms following the gluten-free diet. A study involved 1647 patients with IBD; 65.6% of IBD patients had a relief of gastrointestinal symptoms following a gluten-free diet. IBD patients who were strictly adherent to a gluten-free diet reported less fatigue. Therefore, a gluten-free diet may be effective in the management of IBS and IBD. 

• Gluten Ataxia:

Gluten ataxia is an immune-mediated disease, as the immune system of the body initiates a reaction against the nervous system, specifically the cerebellum, following ingestion of gluten. A marker that can be used in patients with gluten ataxia is transglutaminase 6 (TG6) autoantibody. A study showed that in gluten ataxia patients who followed a gluten-free diet, their serum showed a decrease in TG6 autoantibodies. 

• Cognitive Impairment and Neurological and Mental Illnesses: 

*Autism:

One of the neurological illnesses that may be related to gluten is autism. A high prevalence of IgG antibodies to gliadin that are the same antibodies found in celiac disease and gluten ataxia patients is found related to autism. Therefore, there is a link between gluten sensitivity and autism. Most studies showed that children with autism that were adherent to a gluten-free diet had a relief of gastrointestinal symptoms associated with the disease, with a decrease in the levels of IgG antibodies to gliadin. 

*Depression:

Some studies showed potential benefits of a gluten-free diet for individuals with depressive disorders. A study involved 22,274 participants of the 2009–2014 National Health and Nutrition Examination Survey and compared quality of life, insomnia, depression, and the use of psychotropic medication in patients with celiac disease and people adherent to a gluten-free diet to a control group. Individuals adherent to a gluten-free diet had lower levels of depression compared to the control group. Further research is required to prove the relation between gluten exposure and depression. 

*Schizophrenia:

Some studies showed that patients with schizophrenia have elevated anti-gliadin antibodies and transglutaminase 6 antibodies. Another study showed a relief of schizophrenia symptoms after following a gluten-free diet.

*Risk of contamination:

There is a risk of contamination during preparation and storage of gluten-free food, so the product may still have gluten, and a threshold of gluten exposure should be established. This threshold may differ among individuals. Some studies have shown that individuals may have symptoms with an average of 36 mg of gluten per day, while others develop mucosal changes with 10 mg of gluten per day. Studies concluded that exposure to less than 10 mg of gluten per day is unlikely to produce mucosal changes and symptoms, and this level is considered the safest threshold. Gluten may be used as a flavor enhancer, emulsifier, thickener, and filler of some products and might be hidden under some terms such as "hydrolyzed vegetable proteins" or "flavorings." Some mucosal changes may persist even with a strict gluten-free diet, and not all reactions are reversible. 

*A dramatic lifestyle change:

The need to follow a specific diet while sharing life with other individuals, including family and friends, and eating at restaurants must be challenging. The risk of diet contamination increases, leading to impairment of its effectiveness. The ingredients of processed food, certain soups, seasonings, and French fries may also contain gluten and become a possible source of contamination. Strict adherence to a gluten-free diet may cause social isolation, as individuals will not be able to enjoy different occasions such as birthdays, weddings, work events, and religious rituals. A study based on a questionnaire involving 5240 members of the Canadian Celiac Association and 2681 adults with biopsy-proven celiac disease evaluated the quality of patients' lives. According to the study, 44% of participants had difficulty adhering to the gluten-free diet, including 38% avoiding travel, 79% avoiding restaurants, 83% making an effort to find gluten-free foods in stores, and 85% making an effort to ensure the food is gluten-free. However, many restaurants nowadays include gluten-free labels on the menu. A close follow-up of the level of adherence to a gluten-free diet, quality of everyday life, and patient education is crucial.

*High cost:

Grains are usually cheaper, as they grow in large quantities and in different climates. Following a strict gluten-free diet can be costly. Further processing is required to remove the naturally existing gluten in food, making it more expensive. High cost may also be due to overpricing. Limited availability of gluten-free products is another cause of their high cost. A study showed that gluten-free products were 242% more expensive compared to the ordinary gluten-containing products. High cost may be distressing for most individuals.

*Risk of coronary heart disease:

Lack of whole grain benefits may be a risk factor of coronary heart disease. A study by Lebwohl et al. included 64,714 women in the Nurses’ Health Study and 45,303 men in the Health Professionals Follow-up Study and assessed the development of coronary heart disease in these individuals. From 1986 to 2010, food diaries were used to assess the amount of gluten consumed and were updated every 4 years. The study concluded an inverse relation between gluten intake and the risk of coronary heart disease. However, another study that analyzed 27 articles on patients adherent to a gluten-free diet and conducted by Potter and colleagues demonstrated an increase in high-density lipoproteins, total cholesterol, and body mass index without an increase in low-density lipoprotein, triglycerides, and blood pressure, with the conclusion that a gluten-free diet is not associated with coronary heart disease. Further research is needed, and no conclusive findings can be made. 

*Nutritional Deficiencies:

Many individuals have been adherent to a gluten-free diet without being diagnosed with celiac disease. This is due to the rising popularity and promotion of gluten-free diets. This may cause these individuals to have nutritional deficiencies, including vitamin D, iron, calcium, zinc, and magnesium deficiency. An additional negative side of a gluten-free diet is increased consumption of lipids and proteins, as a study involving 47 adolescents with celiac disease adherent to a gluten-free diet had a higher prevalence of obesity (72%). Not only the quantity but also the quality of the consumed lipids and proteins matters. Eating the naturally occurring gluten-free foods, including fish, meat, and green vegetables, may solve this problem.

*Constipation:

A study in 2021 showed that people following a gluten-free diet are more likely to have constipation. A gluten-free diet restricts many sources of fiber, such as bread and bran, which explains the constipation experienced by those individuals.

*The effect on the microbiome of the gut:

The role of the gut flora (bacteria that normally exist in the gut) is diverse and includes drug metabolism, metabolism of some nutrients, maintaining the integrity of the gut mucosal barrier structure, immunomodulation, and protection against some organisms. Several factors may affect the viability of the gut flora, including the prolonged use of antibiotics, diet, and birth method (vaginal delivery or cesarean section). Therefore, a change in diet, including gluten restriction, may influence the gut bacteria. A study involved 42 healthy subjects and 14 patients with celiac disease, analyzed their gut bacteria, and concluded that despite adherence to a gluten-free diet, patients with celiac disease had an imbalance in their intestinal flora. This imbalance of gut flora may also cause the gastrointestinal symptoms of individuals with celiac disease in addition to the mechanism of the disease itself. Using probiotic supplements can provide the balance and the nutrients required to maintain the gut functioning properly.

*Frequent assessment is required:

A frequent assessment is required to evaluate the improvement of the gut mucosa and the clinical symptoms. Routine assessments include a complete blood count, ferritin, serum calcium, vitamin B12, and alkaline phosphate. Screening of other autoimmune diseases that may be associated with celiac disease is also required, including thyroid function tests (thyroid-stimulating hormone and thyroid hormone) and liver function tests (alanine aminotransferase and aspartate aminotransferase) to exclude thyroid and liver diseases. Other tests include stool analysis, urine analysis, serology, and small bowel biopsy. Assessment requires commitment, which may be challenging for some individuals. 

To conclude, a gluten-free diet is primarily used for celiac disease. However, it may be beneficial for other health problems. But it is not suitable for everyone. Careful assessment of an individual is required before deciding whether to follow a gluten-free diet or not. A gluten-free diet may be challenging and have negative sides, but these problems can be addressed with further research, patient education, public awareness, and organizational and teamwork.  

To summarize, here are quick tips for individuals following a gluten-free diet: 

-Tell your family, friends, and close people that you are on a gluten-free diet. This may help to choose proper restaurants when deciding to go out. 

-Read food labels before buying any product. Ensure that products are gluten-free. Do not underestimate the amount of gluten that may be present in any product. Even a small amount may cause you to suffer from distressing symptoms. 

-Try to prepare your own meals. This may be safer for you. You may also enjoy the experience of cooking and preparing different dishes. If you are travelling, set a plan to help you find supermarkets and restaurants providing gluten-free diets. 

-Avoid contamination. If you share a kitchen with family, roommates, or other people, use separate cooking utensils. Do not underestimate the possibility and the effect of gluten contamination.

(1) Aljada B, Zohni A, El-Matary W. The Gluten-Free Diet for Celiac Disease and Beyond. Nutrients. 2021 Nov 9;13(11):3993. 

(2) Melini V, Melini F. Gluten-Free Diet: Gaps and Needs for a Healthier Diet. Nutrients. 2019 Jan 15;11(1):170. 

(3) Itzlinger A, Branchi F, Elli L, Schumann M. Gluten-Free Diet in Celiac Disease-Forever and for All? Nutrients. 2018 Nov 18;10(11):1796. 

(4) Mazzola AM, Zammarchi I, Valerii MC, Spisni E, Saracino IM, Lanzarotto F, Ricci C. Gluten-Free Diet and Other Celiac Disease Therapies: Current Understanding and Emerging Strategies. Nutrients. 2024 Mar 29;16(7):1006. 

(5) Gentry J, Sherwood L, Haynes J. Gluten-Free Diet for Irritable Bowel Syndrome. Am Fam Physician. 2017 Jul 1;96(1):52. 

(6) Rej A, Sanders DS. Gluten-Free Diet and Its 'Cousins' in Irritable Bowel Syndrome. Nutrients. 2018 Nov 11;10(11):1727. 

(7) Usai-Satta P, Lai M. New Perspectives on Gluten-Free Diet. Nutrients. 2020 Nov 18;12(11):3540. 

(8) Gluten-Free Foods. Celiac Disease Foundation.

(9) Gluten-Free Diet. NHS.

(10) Gluten-free diet. MayoClinic. 

(11) The Gluten-Free Diet: A Beginner’s Guide with Meal Plan. HealthLine.