Non-Celiac Gluten Sensitivity Research

New Research Explains How Gluten Sensitivity Differs From Celiac Disease

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Research into non-celiac gluten sensitivity — also known as gluten intolerance — increasingly is proving that you can get serious symptoms from gluten ingestion without having celiac disease.

In a landmark study on gluten sensitivity released in early 2011, prominent celiac researcher Dr. Alessio Fasano concluded that "gluten sensitivity" represents a completely different condition from celiac disease, and most of the people who suffer from gluten sensitivity will never develop celiac.

While his research is certainly of interest to the medical community, it's important to note that his research has not yet been replicated and so the medical community at large still considers this a theory in development.

Dr. Fasano and a group made up of prominent celiac disease researchers, including Drs. Peter Green (head of the Columbia University Celiac Disease Center) and Dr Marios Hadjivassiliou (a consultant neurologist and expert in gluten ataxia), followed up the initial study with a consensus statement released in February 2012 proposing ways to differentiate between celiac disease, gluten sensitivity and gluten ataxia.

Additional researchers also have chimed in with findings. Some studies show that some gluten-sensitive people have similar metabolic profiles to diagnosed celiacs, indicating that there might be a pre-celiac condition. Other studies back Dr. Fasano's findings that gluten can trigger symptoms in people who don't have classic celiac disease.

Research into gluten sensitivity is evolving rapidly. In addition, more and more frequently, people who have positive celiac disease blood tests but a negative biopsy are being handed diagnoses of gluten sensitivity.

In some cases, their physician says they can eat gluten in moderation, or they are told to follow the gluten-free diet but that they don't need to be as careful as celiac patients.

Others are told they're "potential" celiac disease patients, and to check back in a year or so for more testing to see if they've developed the condition.

More research will be needed to determine if people with gluten sensitivity really can ingest small amounts of gluten without damage, or if a specific sub-group of gluten-sensitives will eventually go on to develop celiac disease.

Read more on possible health risks in gluten sensitivity: Gluten Sensitivity Health Risks

U. of Maryland Pegs 'Gluten Sensitivity' As Real Condition

In Dr. Fasano's initial gluten sensitivity research, published online in March 2011 in BMC Medicine, the researchers found distinctive differences between celiac disease and gluten sensitivity on the molecular level, even though symptoms of the two conditions overlapped considerably.

Dr. Fasano and other University of Maryland researchers compared 42 diagnosed celiacs who had Marsh 3 or Marsh 4 intestinal damage with 26 people whose intestines showed little or no damage, but who still clearly reacted to gluten.

For each participant, the researchers determined the level of intestinal permeability (in celiac disease, your intestines become more permeable, which can allow proteins to escape into the blood stream). They also looked at genetics, along with the expression of genes in the small intestines.

The study found differences in intestinal permeability between the groups of people, along with differences in the expression of the genes that regulate the immune response. That indicates gluten sensitivity is a different condition than celiac disease, according to Dr. Fasano.

Differences in Celiac, Gluten Sensitivity Stem From Immune System Responses

The differences between the two conditions stem from differing immune system responses, Dr. Fasano says.

In gluten sensitivity, the innate immune system -- an older part of the immune system and the body's first line of defense against invaders -- responds to gluten ingestion by fighting the gluten directly. That creates inflammation both inside and outside the digestive system, according to Dr. Fasano.

Meanwhile, celiac disease involves both the innate immune system and the adaptive immune system, he says. The adaptive immune system is a more advanced, sophisticated part of the immune system, and miscommunications between adaptive immune system cells lead those cells to fight your body's own tissues, creating the villous atrophy seen in celiac disease.

People with gluten sensitivity do not get villous atrophy, even though they can still experience near-identical symptoms to celiac, including diarrhea, bloating, abdominal pain, joint pain, depression, brain fog and migraines, according to Dr. Fasano. (Read more on potential symptoms here: Gluten Sensitivity Symptoms.)

However, only those people with the adaptive immune system response unique to celiac disease are at risk for developing intestinal lymphoma and other conditions associated with celiac, such as osteoporosis, Dr. Fasano says.

Some of the gluten-sensitive people included in Dr. Fasano's study had minor intestinal damage (classified as Marsh 1 or 2), but that damage had different biomarkers than those seen in celiac disease.

'Potential' Celiac Patients Share Distinctive Metabolic Fingerprint with Celiacs

There's other research indicating some people labeled "gluten-sensitive" may in fact have early-stage celiac disease.

A study published in the December 2010 Journal of Proteome Research finds that "potential" celiac patients with positive blood tests but negative biopsies actually have the same distinctive metabolic fingerprint as diagnosed celiacs.

These "gluten-sensitive" people may simply represent an earlier stage of the condition, before it causes major damage to the intestines, the researchers said.

The study used magnetic resonance metabolic profiling to analyze biochemical markers in the urine and blood of 141 patients: 61 with diagnosed celiac disease, 29 with positive blood tests but negative biopsies, and 51 healthy controls.

They found that those with so-called "potential" celiac disease shared the same biochemical profile as diagnosed celiacs, while the biochemical profiles of the healthy controls differed markedly.

"Our results demonstrate that metabolic alterations may precede the development of small intestinal villous atrophy and provide a further rationale for early institution of GFD [gluten-free diet] in patients with potential CD [celiac disease]," the study concluded.

Gluten Sensitivity Probable in Patients with Borderline Biopsies

Another study looked at patients with celiac disease symptoms whose intestinal biopsies revealed only minor abnormalities, such as Marsh I or II lesions.

Many physicians will not diagnose celiac disease unless intestinal damage reaches Marsh III or Marsh IV levels.

In this study, 35 patients had low-level damage and were advised to follow a gluten-free diet anyway. Only 23 patients adhered to the diet, and the researchers took follow-up biopsies from everyone following the diet after eight to 12 months.

All 23 patients who followed the diet had a "dramatic clinical improvement in symptoms," and most saw complete or partial healing of their intestinal villi.

Seven of the 11 patients who refused to follow the gluten-free diet were evaluated eight to 12 months later, as well. Of these, six had unchanged symptoms and intestinal damage, and again declined to start a gluten-free diet. One saw increased damage in his intestinal villi (from Marsh I to Marsh IIIa), and opted to start the diet.

The study's authors concluded that the patients who didn't meet the criteria for celiac disease nonetheless were clearly gluten sensitive and benefited from the gluten-free diet.

"Although Marsh I-II lesions cannot be classified as celiac lesions, the patients' symptoms at presentation and the clear improvement of symptoms when on GFD [gluten-free diet], with or without improvement of histologic lesions, supports the assumption that these patients are sensitive to gluten and may justify treatment with a GFD," the researchers concluded.

Gluten Sensitivity May Affect One in 14 People

Gluten sensitivity (or intolerance) may affect about 6% to 7% of the population, according to Dr. Fasano. Others in the medical community have placed the percentage of gluten-intolerant people higher — I've seen estimates ranging from 10% to a mammoth 50% of the population.

Read more on these numbers: How Many People Have Gluten Sensitivity?

It's impossible to tell how many people actually have gluten sensitivity without more research and accepted gluten sensitivity tests. But clearly, even if the numbers are on the low side, they'll dwarf the number of celiacs, who make up about 1% of the population.

Many in the celiac/gluten-sensitive community believe that diseases caused by gluten array themselves on a "spectrum" of gluten-related conditions, with celiac disease, gluten ataxia (neurological damage from gluten) and gluten sensitivity all falling somewhere on that spectrum.

Dr. Fasano says the next step is the identification of a biological marker, or "biomarker," for gluten sensitivity. The clinical trial to do just that is underway right now, and Dr. Fasano says he's "confident" researchers will pinpoint that biomarker. From there, researchers can develop a test to detect gluten sensitivity — that could be available commercially within the next several years.

Sources:

Bernini P. et al. Are Patients with Potential Celiac Disease Really Potential? The Answer of Metabonomics. Journal of Proteome Research. Published online Nov. 19, 2010. DOI: 10.1021/pr100896s.

J. Biesiekierski et al. Gluten Causes Gastrointestinal Symptoms in Subjects Without Celiac Disease: A Double-Blind Randomized Placebo-Controlled Trial. American Journal of Gastroenterology advance online publication, Jan. 11, 2011; doi:10.1038/ajg.2010.487.

A. Fasano et al. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Medicine 2011, 9:23. doi:10.1186/1741-7015-9-23.

Fasano A. et. al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Medicine. BMC Medicine 2012, 10:13 doi:10.1186/1741-7015-10-13. Published: 7 February 2012

Tursi A. et al. The symptomatic and histologic response to a gluten-free diet in patients with borderline enteropathy. Journal of Clinical Gastroenterology. 2003 Jan; 36(1):6-7.

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