Celiac disease (CD) is a chronic inflammatory condition that results in immune-mediated damage to the mucosal lining of the small intestine. It occurs in genetically predisposed people who consume gluten — a protein in foods such as wheat, rye and barley — and usually responds to a gluten-free diet. Less than a decade ago, CD was less often recognized by clinicians. Today, thanks to epidemiological research done at Mayo and other centers, that is no longer the case.
The same is not true of non-celiac gluten sensitivity (NCGS) — a poorly understood disorder with intestinal symptoms similar to those associated with CD, but without the presence of transglutaminase autoantibodies or small bowel damage.
Diagnosis of NCGS is by exclusion. It requires eliminating gluten in the diet and an open challenge — an approach that runs the risk of a placebo effect when gluten is withdrawn. Thus, as with other heterogeneous, symptom-based disorders, NCGS invites skepticism.
"There is controversy among experts and in the literature as to whether non-celiac gluten sensitivity actually exists," notes Maria I. Vazquez Roque, M.D., a gastroenterologist at Mayo Clinic's campus in Jacksonville, Florida. "Currently, we don't have biomarkers or small bowel biopsy findings for diagnosis. So the best explanation that is generally accepted in the medical community is that patients with NCGS have a gluten reaction in which allergic and autoimmune mechanisms have been ruled out, there is normal duodenal histopathology, and symptoms resolve on a gluten-free diet but return after a gluten challenge."
Lesley A. Houghton, Ph.D., a researcher specializing in functional gastrointestinal disorders at Mayo Clinic's campus in Florida, says efforts to understand the biological mechanisms of action in NCGS are complicated by similarities with irritable bowel syndrome (IBS).
"The overlap of associated symptoms — bloating, diarrhea, constipation, headache, neurological disturbances, bone or joint pain — makes it challenging," she says. "We have honed in on gluten as a factor in IBS, but we need more studies to determine the exact mechanisms for symptom development."
Dr. Vazquez Roque was lead author of one such study. Published in Gastroenterology in 2013, it compared the effects of gluten-free and gluten-containing diets in patients with diarrhea-predominant IBS (IBS-D). Results of the four-week, randomized controlled trial showed that gluten was associated with an increase in bowel movements and small bowel permeability in IBS-D patients, especially those with HLA-DQ2 and HLA-DQ8 genotypes, which are present in almost all CD patients and about half of those with NGCS. Conversely, bowel function improved in most patients eating a gluten-free diet.
To further explore the relationship between gluten, IBS and alterations in gut barrier function, Dr. Vazquez Roque and Dr. Houghton are currently recruiting patients for two clinical trials.
Two hypothesis-generating studies
The aim of Dr. Vazquez Roque's pilot study is to compare the effects of a four-week gluten-containing diet versus a gluten-free diet in IBS patients with NCGS. It will evaluate small bowel permeability using two-sugar differential excretion, probe-based confocal laser endomicroscopy (pCLE) and tight junction messenger RNA expression.
Dr. Vazquez Roque also intends to evaluate relationships among the gut microbiome, intestinal permeability and endoscopic findings. Previous in vitro and in vivo studies have shown that intestinal bacteria change the expression and distribution of tight junction proteins, thereby regulating intestinal barrier function.
"Many studies have identified signs and symptoms of IBS and gluten sensitivity, including psychological disturbances, increased visceral sensitivity, gut permeability and alterations in gut microflora," Dr. Houghton notes. "What we have to remember is that these things are all interconnected. Alterations in the gut microflora will affect the nervous system and other body functions and vice versa. We can't think of them as separate, stand-alone factors."
Her own objective is to determine whether findings of pCLE correlate with those of established gut permeability studies and to see how those measures relate to the IBS phenotype and its pathophysiology.
Unlike conventional endomicroscopy, where scattered fluorescent light reflecting back from tissues can blur or obscure images, pCLE blocks any light outside the focal plane. This allows high-resolution imaging of tissue in vivo. Originally used to detect colon polyps and Barrett's esophagus, pCLE has recently also been used to assess the gut barrier.
"We need to show that we can use this new technique, which may be more sensitive in looking at barrier function, to identify an exacerbation of symptoms among IBS patients after a gluten-containing meal. If we can, then gut permeability may well be a target for medications," Dr. Houghton says.
For more information
Vazquez Roque MI, 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.
Mayo Clinic. Change in permeability of the small intestine after treatment. ClinicalTrials.gov.