I have to admit: I’ve had trepidations about writing on this subject. First, because I have long held “opinions” that were based more on my gut than my brain. Why the sudden explosion of gluten sensitivity? It’s reminiscent of other popular diagnoses of the past: hypothyroidism, B12 deficiency, and low blood glucose.

All made epidemic appearances but eventually vanished from the popular consciousness. The fact that the array of symptoms of so-called “non-celiac gluten sensitivity” (NCGS) are almost identical to the real syndrome of celiac disease, but without any of the objective evidence, aroused the skeptic in me. But most of all, I was leery of taking on a highly technical subject without dumbing it down.

So what made me change my mind? Last month, we were in Australia and New Zealand. And on our several visits to food stores there, I was astonished to find whole shelves dedicated to gluten-free products….even the straight-thinking Kiwis and Aussies have bought into the gluten fad? This was enough for me to reconsider and finally take on the task of writing about the gluten issue.


Gluten and celiac disease

There are two actors in the celiac disease story: gluten and surface molecules on the white blood cells, called HLA, for Human Leukocyte Antigens.

Gluten is a group of proteins found in cereals, primarily in wheat, rye, and barley. One of the constituent proteins in gluten is called gliadin.

HLA is a group of molecules that make up the fingerprint of our uniqueness. They serve the immune response to recognize self from non-self. HLA is also called MHC which stands for Major Histocompatibility Complex. Which tells us that 1) it’s a complex of molecules, and 2) they are responsible for compatibility of “self” cells and for rejection of transplantations that are non-self.

DQ molecule binding an antigen (yellow) such as gliadin.
DQ molecule binding an antigen (yellow) such as gliadin. | via Wikipedia

There are several molecules that make up HLA. One of these molecules is called HLA-DQ. There are seven isoforms (variants) of HLA-DQ: DQ2 and DQ4–DQ9. Over 95% of people with celiac disease have isoforms DQ2 or DQ8. These isoforms are inherited in families.

A part of the HLA-DQ molecule is an antigen-presenting receptor that binds to “non-self” peptides and activates T lymphocytes, an important player in the immune response to foreign proteins.

The reason the DQ2 or DQ8 isoforms produce an increase in risk of celiac disease is that their receptors bind to gliadin peptides of gluten more tightly than other forms. Therefore, they are more likely to activate T lymphocytes and initiate an immune process. This is the crux of the problem. The inflammation accompanying the immune response to gliadin destroys small projections, called microvilli, on the surface of the small intestine. Microvilli greatly increase the overall surface area of the small intestine available for absorption of nutrients; their destruction reduces the surface area and leads to less absorption (known as malabsorption) of nutrients.

microvilli on the surface of the small intestine. In celiac disease these are destoyed.
Microvilli on the surface of the small intestine. In celiac disease, these are destroyed by an immune process

As if that’s not enough, on the surfaces of those microvilli sit sugar-digesting enzymes, specifically the di-, tri-, and larger saccharides. Since these enzymes are not around to perform their digestive task, the bacteria in the gut are happy to oblige. They break down the sugars by a process of fermentation. And this, in turn, causes the all too familiar sensations of bloating, flatulence, and terribly smelly stools (because of fat malabsorption). Abdominal pain and bloating are the most common signs of celiac disease.

According to a recent review of celiac disease in JAMA Pediatrics, symptoms of the disorder include chronic or intermittent constipation; vomiting; loss of appetite; weight loss (or, in children, growth failure); fatigue; iron deficiency anemia; abnormal dental enamel; mouth ulcers; arthritis and joint pain; bone loss and fractures; short stature; delayed puberty; unexplained infertility and miscarriage; recurring headaches; loss of feeling in hands and feet; poor coordination and unsteadiness; seizures; depression; hallucinations; anxiety and panic attacks. Oy vey!

If you stuck with me to this point, you understand why the definitive diagnosis of celiac disease requires biopsies of the small intestine (a minimum of six) demonstrating destruction of the microvilli. And, as you can guess, the treatment of celiac disease is avoidance of all gluten-containing foods.


So, what is non-celiac gluten sensitivity (NCGS)?

It will be easier to say what it is not. It has none of the immune mechanisms of celiac disease. It has none of the histopathology features of celiac disease. But it has an astonishing array of symptoms that overlap those of celiac disease. So is it real?

In 2011, Peter Gibson, a gastroenterologist at Monash University in Victoria, Australia, and his colleagues studied 34 people with irritable bowel syndrome who did not have celiac disease but reacted badly to wheat, a gluten-rich grain. The researchers concluded that non-celiac gluten sensitivity “may exist”.

Many of their subjects still had symptoms on a gluten-free diet, however, which prompted a second study of 37 patients with irritable bowel syndrome and non-celiac gluten sensitivity who were randomly assigned to a two-week diet low in certain carbohydrates, collectively called FODMAPS.

All patients on the special diet improved but got significantly worse when fed gluten or whey protein. Only 8% of the participants reacted specifically to gluten, prompting the researchers to conclude that FODMAPS, not gluten, accounted for most of the distress.


What are FODMAPS?

FODMAPS is an acronym for Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols—sugars that draw water into the intestinal tract. They may be poorly digested or absorbed, and become fodder for colonic bacteria that produce gas and can cause abdominal distress. An example of a disaccharide that causes such symptoms is lactose, the sugar in milk and dairy products. A deficiency of the enzyme that digests it (lactase) causes the familiar condition of lactose intolerance.

A list of foods that contain FODMAPS can be found here: https://stanfordhealthcare.org/content/dam/SHC/for-patients-component/programs-services/clinical-nutrition-services/docs/pdf-lowfodmapdiet.pdf.

The list is long, but that doesn’t mean that you should forever avoid them all. First, eliminate all the foods on the list for a couple of weeks and see if your symptoms disappear. If they do, start introducing one food at a time to see if symptoms return. It’s an arduous process, but, unfortunately, there are no shortcuts.

So no, gluten sensitivity doesn’t rise (or sink) to the level of popular craze. But apparently, it isn’t gluten sensitivity either, but a general deficiency in enzymes that digest short-chain sugars. And, by the way, that doesn’t mean that you have to forswear the sweet taste. Glucose is a monosaccharide, and it doesn’t require enzymatic digestion in the small intestine for its absorption. Just don’t overdo it.

Featured Photo Credit: Michael Mandiberg

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.



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