Gluten-free diet beyond celiac disease: friend or foe?

The educational content in this post, elaborated in collaboration with Bromatech, was independently developed and approved by the GMFH publishing team and editorial board.

Celiac disease, gluten sensitivity, or wheat allergy?

The intake of gluten or wheat can induce organic diseases in genetically predisposed persons but has also been reported to cause functional bowel symptoms in others. An organic disease is a condition where objective damage to human tissues and organs can be observed. Conversely, in a functional disorder, the patient reports several symptoms, which can be mild or severe, but no alterations can be assessed at diagnostic tests.

The best well-known gluten-related condition is celiac disease¹. In this autoimmune-like disease, patients develop an inflammatory reaction when they consume gluten that causes damage to the small intestinal lining. This is called “enteropathy” which is characterized by villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes as observed in duodenal biopsies. The disease is diagnosed by a simple blood test measuring the tissue transglutaminase IgA antibody². Then, the mucosal damage is confirmed by a biopsy during an endoscopy.

Another organic condition linked to wheat intake is wheat allergy. This is an IgE-mediated systemic reaction to several wheat antigens. The specific components in wheat that trigger the allergic reaction are unclear and may include gluten or other non-gluten proteins. Specific serological tests (such as anti-gluten IgE) can also suggest the diagnosis³.

Many patients without celiac disease or wheat allergy report gastrointestinal or extraintestinal symptoms when consuming food that contains gluten. These include abdominal pain, bloating, bowel habit abnormalities (diarrhea, alternating bowel, and constipation), chronic tiredness, headache, joint and muscle pain, skin rash, and depression of variable severity⁴.

These symptoms are self-reported by the patient and occur within hours or a few days after ingesting gluten-containing foods. They improve by excluding these foods. This condition has been named “non-celiac gluten sensitivity” or “non-celiac wheat sensitivity”. It has been compared to a functional reaction due to the negativity of diagnostic tests and no apparent organic cause⁵. While some studies have reported mild intraepithelial lymphocytosis or changes in gut microbiome^6,7, concepts continue to evolve as significant nocebo effect, the belief that gluten will induce symptoms, exists.⁸

Other reasons a person’s symptoms might improve by avoiding a gluten-containing diet include intolerance to certain sugars called fructans and sensitivity to non-gluten proteins called a-amylase/trypsin inhibitors (ATIs)^9,10.

Removing gluten may alter the gut microbiome

Although not thoroughly evidence-based, individual patients not diagnosed with celiac disease or wheat allergy may still feel they benefit from a gluten-free diet. However, for the reasons described below, this diet must be followed up by a healthcare professional because a gluten-free diet that is not supervised can lead to nutritional deficiencies and other complications.

Removing wheat from the diet in healthy adults may starve beneficial gut bacteria, decrease beneficial bacteria such as Lactobacillus and Bifidobacterium, and increase potentially pathogenic bacteria like Escherichia coli and Bacteroides. These changes have been reported to be associated with increased intestinal permeability and reduced capacity of gut microbiota to stimulate immune system activity¹². Interestingly, several studies pointed out that an increased permeability of the gut lining is present even in patients with non-gluten sensitivity and not only in celiac disease, which leads to the translocation of microbial products that may contribute to the activation of the innate and adaptive immune responses^11-13.

A gluten-free diet may reduce gut microbiota richness in healthy individuals and those with celiac disease or non-celiac gluten/wheat sensitivity, which can be partly explained by the negative effect of emulsifiers and food additives found in gluten-free processed foods on gut barrier and gut microbiota¹⁴.

In addition, specific changes in the gut microbiome have been found depending on whether the individual is healthy or symptomatic. In healthy adults, the gluten-free diet may lead to a reduction of beneficial bacteria (e.g., Bifidobacterium species) in favor of opportunistic pathogens (e.g., Escherichia coli). In contrast, in individuals with celiac disease and non-celiac gluten/wheat sensitivity, the gluten-free diet positively affected gastrointestinal symptoms by restoring the beneficial gut bacteria and lowering pro-inflammatory bacteria¹³. The topic remains unclear because most studies use fecal sampling which does not reflect the site of inflammation in celiac disease, the upper small intestine, where a recent study has described that location is key to understand how celiac disease, or the gluten-free diet affects the microbiome¹⁵.

Finally, it is worth noting that the connection between dysbiosis, celiac disease and non-celiac gluten sensitivity symptoms extends beyond the gut. The topic and the mechanisms by which gut microbiome changes can impact these conditions has been extensively reviewed recently¹⁶. An altered gut microbiota can alter the production of short-chain fatty acids, impairing gut barrier function and promoting systemic inflammation, potentially contributing to the extra-intestinal symptoms observed in non-celiac gluten sensitivity, such as fatigue, headaches, and joint pain. Moreover, dysbiosis can impact the gut-brain axis, a bidirectional communication network between the gut and the brain, possibly explaining the neurological and psychological manifestations of non-celiac gluten sensitivity¹³.

Other dark sides of the gluten-free diet

Another important problem of a gluten-free diet is related to malnutrition, as this dietary management is often associated with macro and micronutrient imbalances. Patients following a gluten-free diet typically consume low amounts of complex carbohydrates and protein but high amounts of fat and simple carbohydrates. Complex carbohydrates in whole grains, fruits, and vegetables provide greater nutrient density than simple carbohydrates, promoting bowel motility and satiety and improving glucose and lipid levels. Conversely, several studies indicate that a gluten-free diet is characterized by high carbohydrate intake with low fiber and high sugar content due to the types of flour and starches used in gluten-free foods¹⁷.

Moreover, gluten-free products usually have a high saturated fat content. Therefore, the increase in dietary fat intake in a gluten-free diet can contribute to weight gain in patients following this dietary management¹⁷.

At the same time, many people struggle following a gluten-free diet, and micronutrient deficiencies -including vitamins and minerals- are often present in individuals adopting a gluten-free diet, suggesting that nutrient deficiencies are not solely due to malabsorption, which is a typical feature of patients with celiac disease. Micronutrient deficiencies associated with a gluten-free diet can be related to the limited selection of foods and to the lack of fortification in gluten-free products. Patients following a gluten-free diet frequently display low levels of zinc, iron, folate, calcium, vitamin B12, and vitamin D, especially if followed in the long term¹⁷. Some vitamin deficiencies may persist for ten years if proper dietary advice does not support the overall balance of the diet¹⁸. It is also associated with a high intake of sugar and unhealthy fats, particularly when gluten-free foods are consumed, leading to an increased risk of metabolic complications such as obesity and fatty liver¹⁹. Recent evidence shows that certain probiotic strains may be able to promote proper absorption of micronutrients by the gut, for example, by enhancing iron bioavailability²⁰.

Also, consuming gluten-free products may increase heavy metal intake, as rice, the main staple in a gluten-free diet, absorbs arsenic and mercury from the soil (seafood alone seems not to be the main contributor to heavy metal burden in people on a gluten-free diet)²¹.

Conclusions

The impact of a gluten-free diet on gut microbiota composition varies significantly among healthy individuals, patients with non-celiac gluten sensitivity, and patients with celiac disease. One of the most important limitations in the area is variation and lack of detail in sampling technique, which often uses fecal samples in conditions that involve the upper small intestine. Patients with celiac disease have been shown to have changes in microbiome in the small intestine that are location specific.¹⁵ Other studies have suggested persistent imbalances even after dietary intervention, but using fecal samples which may not reflect inflammation in celiac disease. Patients with non-celiac gluten sensitivity show a mix of improvements and persistent alterations, highlighting the need for additional therapeutic strategies that help restore their symptoms.

Ongoing research aims to develop targeted treatments that can modulate specific bacterial populations and their metabolic products. Future studies are needed to gain a deeper understanding of dysbiosis in non-celiac gluten sensitivity, to pave the way for more effective and personalized therapeutic strategies, ultimately improving the quality of life for individuals affected by this challenging condition.

Additionally, it is worth mentioning that the 20th International Coeliac Disease Symposium will take place in Sheffield (UK) from September 5th to 7th. This important international event will feature discussions on various topics, including non-celiac wheat reactions. This forum will be an excellent opportunity for both the general public and patients to learn about the latest advancements in this field.