If it's not celiac disease, what is it?

Irritable bowel syndrome (IBS) is one of the most common functional bowel disorders, affecting an estimated 15 to 25 percent of people worldwide. It has no established biomarkers and is diagnosed on the basis of symptoms such as abdominal pain, gas, bloating, and constipation or diarrhea. The etiology of IBS remains unclear, although many causative factors have been suggested, including gut dysmotility and hypersensitivity, genetic factors, infection, and changes in the gut microbiome.

More recently, research has focused on the role of dietary factors in IBS; in clinical practice, a majority of diagnosed patients report worsening symptoms within a few minutes to a few hours after eating. One of the foods commonly thought to trigger symptoms is wheat, but whether gluten or some other component of wheat is responsible continues to stir debate.

"The fact that gluten causes symptoms in the absence of celiac disease was described in a case series in the 1980s, but it wasn't until the 2000s that we had some data showing that excluding gluten could improve symptoms in a subset of patients without celiac disease," says Maria I. Vazquez Roque, M.D., a gastroenterologist specializing in functional bowel disorders at Mayo Clinic's campus in Jacksonville, Florida. "But dietary triggers in wheat other than gluten, such as short-chain carbohydrates (fermentable oligo-, di- and monosaccharides and polyols, or FODMAPs) have also been implicated."

She notes that Monash University researchers reached opposing conclusions on the subject. In 2011, they published a paper in The American Journal of Gastroenterology describing results of a double-blind, placebo-controlled re-challenge trial involving 34 patients with IBS. The participants, who did not have celiac disease but were symptomatically controlled on a gluten-free diet, were randomized to receive either gluten-containing foods or placebo. After six weeks, nearly 70 percent of those in the gluten group reported worsening symptoms of pain, bloating and tiredness compared with 40 percent of controls.

No difference in inflammatory markers or intestinal injury was seen in either group, and there was no difference in human leukocyte antigen (HLA)-DQ2 or HLA-DQ8 (HLA-DQ2/8) status. The investigators concluded that the evidence pointed to gluten as a trigger for GI symptoms, although the mechanism for this remained unknown.

Two years later, the same group published the results of a double-blind crossover trial in which 37 patients with IBS and non-celiac gluten sensitivity (NCGS) but not celiac disease improved markedly on a low FODMAP diet and worsened on diets containing gluten or whey. Only 8 percent of the patients had a gluten-specific response, leading to the conclusion that FODMAPs were responsible for gas, bloating and other symptoms. And indeed, FODMAPs are small molecules that are slowly absorbed, if at all, in the small intestine. They increase the intestinal luminal water content and ferment rapidly, releasing short-chain fatty acids and gases that can lead to abdominal pressure and distension.

In addition to FODMAPs, amylase trypsin inhibitors (ATIs) — naturally occurring pesticides in wheat — may trigger GI symptoms. A study published in The Journal of Experimental Medicine in 2012 found that ATIs were strong activators of innate immune responses, leading to the release of proinflammatory cytokines in both celiac and nonceliac patients.

Non-celiac gluten sensitivity

Evidence to support the role of NCGS also continues to accrue.

In 2013, Dr. Vazquez Roque and colleagues published the results of a controlled trial of patients with IBS with diarrhea (IBS-D). In that trial, 45 patients were randomized to a gluten-free or gluten-containing diet for 30 days. Patients in the gluten group were found to have increased stool frequency and small intestine permeability, an effect that was more pronounced in those who were HLA-DQ2 or HLA-DQ8 (HLA-DQ2/8) positive.

More recently, a British group performed a prospective study of 41 patients with IBS-D, half of whom were HLA-DQ2/8 positive. All were placed on a six-week gluten-free diet. At six weeks, 71 percent of patients had achieved a 50 percent or greater reduction in the IBS symptom severity score, the primary endpoint. Both groups had marked improvements in anxiety, depression and fatigue, although these were more pronounced in patients who were HLA-DQ2/8 positive. Most participants chose to stay on the gluten-free diet and maintained a reduction in symptoms 18 months after the study, which was published in Clinical Gastroenterology and Hepatology.

Who is right?

"The controversy surrounding non-celiac gluten sensitivity centers on whether it is truly a clinical entity separate from celiac disease and IBS and whether gluten or something else in wheat is the actual trigger for symptoms," Dr. Vazquez Roque says.

Although some experts think NCGS is a subgroup of IBS, Dr. Vazquez Roque argues that the underlying mechanism leading to symptoms is different in each disorder. She points to a study published in Gastroenterology in 2014 in which 22 of 36 IBS patients with suspected food intolerances showed, on laser confocal endomicroscopy, immediate changes in the structure and function of the intestinal mucosa after a food challenge. Thirteen of the patients responded to wheat and showed significant improvement in symptoms when it was excluded from their diets.

"This suggests there is stimulation of the innate immune system with food triggers, suggesting NCGS may be different from IBS," Dr. Vazquez Roque says. "But in 2016, we still don't know all the answers to these questions."

Dr. Vazquez Roque's critical review of the literature on NCGS was published in Mayo Clinic Proceedings in 2015.

For more information

Biesiekierski JR, et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: A double-blind, radomized placebo-controlled trial. The American Journal of Gastroenterology. 2011;106:508.

Biesiekierski JR, et al. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology. 2013;145:320.

Junker Y, et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. The Journal of Experimental Medicine. 2012;209:2395.

Vazquez-Roque M, et al. A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: Effects on bowel frequency and intestinal function. Gastroenterology. 2013;144:903.

Aziz I, et al. Efficacy of a gluten-free diet in subjects with irritable bowel syndrome-diarrhea unaware of their HLA DQ2/8 genotype. Clinical Gastroenterology and Hepatology. 2016;14:696e.

Fritscher-Ravens A, et al. Confocal endoscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology. 2014;147:1012.

Vazquez-Roque M, et al. Nonceliac gluten sensitivity. Mayo Clinic Proceedings. 2015;90:1272.