It’s Not All in Their Heads: Non-Celiac Gluten Intolerance’s Immunologic Basis

By Leonard Calabrese, DO

It’s been argued, confirmed and debunked; parodied, ridiculed and exposed as a marketing ploy. But for millions of patients, going gluten-free relieves their symptoms of abdominal pain, bloating, diarrhea, fatigue, headache and even cognitive dysfunction.

These patients don’t have the genetic, environmental and immunologic signs of celiac disease. They don’t bear the HLA gene or show characteristic pathology in the small bowel or have characteristic abnormalities on a panel of autoantibodies. And so, lacking conclusive data for the presence of non-celiac gluten sensitivity (NCGS), many of us, physicians and otherwise, have dismissed this response to gluten as at best another bowel or autoimmune disorder, or at worst, transference of clever marketing to physical symptoms.

But recent research is providing provocative clarity to the possible etiology of NCGS. A group from Columbia University, led by Armin Alaedini, PhD, conducted a carefully controlled experiment, published in Gut, on patients with NCGS whose bowel biopsies were negative for both celiac disease and IgE food allergy. Researchers challenged the patients with gluten and assessed for markers of intestinal cell damage and immunologic activation. They were compared to two other groups, one with documented celiac disease and the other with healthy controls.

And they found multiple lines of scientific evidence for NCGS. The NCGS group had significant elevations of soluble CD14 and lipopolysaccharide-binding protein (both markers of translocation of microbial products from the bowel) in comparison to the healthy controls and to patients with classic celiac disease. The group also detected additional markers of systemic immune activation. Immune activation markers normalized when the individuals with gluten sensitivity excluded wheat from their diets.

These data provide evidence of systemic immune activation and gut epithelial damage in the absence of celiac disease. The findings are also provocative for the investigation of patients with other medically unexplained disorders, such as such as chronic fatigue syndrome. We don’t yet have biomarkers for NCGS, but I think we are ready for clinical discovery, based on searching for optimum biomarkers of immune activation and bowel injury.

For now, this is both a fascinating area of research as well as a strong reminder of how we must constantly reassess what we believe to be conventional wisdom about patients with medically unexplained disorders.

Dr. Calabrese is Director of the R.J. Fasenmyer Center for Clinical Immunology in Cleveland Clinic’s Department of Rheumatic and Immunologic Diseases.