Although historical records dating from the first century a.d. mention a disorder that sounds a lot like celiac disease, it was not until the mid-1900s that doctors realized the gluten in wheat was to blame. During World War II, Dutch physician Willem-Karel Dicke documented a sharp drop in the number of deaths among children with the severest forms of celiac disease in parallel with a bread shortage. In a follow-up study, researchers removed different components of wheat from the diet of 10 children with the intestinal illness. Adding back gluten caused symptoms such as diarrhea to resurface, but reintroducing a different complex molecule found in wheat, namely starch, did not. Thus, gluten was shown to be responsible for celiac disease.
Later experiments by other researchers revealed which component of gluten provokes the immune system. When digested, gluten splits back into gliadin and glutenin. For reasons that remain unclear, the immune system of people with celiac disease treats gliadin in particular as though it were a dangerous invader.
For years doctors used diet to diagnose the gut disorder: if someone's symptoms disappeared on a gluten-free diet, then that person had celiac disease. Over time, however, clinicians developed more sophisticated ways to identify celiac disease, such as tests that look for immune system molecules known as antibodies that recognize and cling to gliadin. With the advent of such tests, clinicians soon discovered that some people who became mildly ill after eating bread and pasta did not in fact have celiac disease: biopsies revealed little or no intestinal damage, and blood tests failed to find the same antibodies associated with the disorder. In the process, the new condition became known as nonceliac gluten sensitivity.
Now several studies hint that so-called gluten sensitivity might not always be caused by gluten. In some cases, the problem may be entirely different proteins—or even some carbohydrates. “We're so used to dealing with gluten as the enemy, but it might actually be something else,” says David Sanders, who teaches gastroenterology at the University of Sheffield in England. Joseph Murray, a gastroenterologist at the Mayo Clinic in Rochester, Minn., agrees: “I'm starting to feel more uncomfortable calling it nonceliac gluten sensitivity. I think it might be better to call it nonceliac wheat sensitivity.”
Against the Grain
If the culprits behind certain instances of gluten sensitivity are, in fact, wheat constituents other than gluten, finding the right ones will be difficult. Wheat has six sets of chromosomes and a whopping 95,000 or so genes. In comparison, we humans have just two sets of chromosomes and about 20,000 genes. Genes code the instructions to build proteins, so more genes mean more proteins to sift through. Some initial experiments have spotlighted a few potential offenders, however.
In laboratory tests, wheat proteins known as amylase-trypsin inhibitors have stimulated immune cells in plastic wells to release inflammatory molecules called cytokines that can overexcite the immune system. Further tests showed that these wheat proteins provoked the same inflammatory response in mice. Likewise, in an Italian study, small concentrations of wheat germ agglutinin, a protein distinct from gluten, roused cytokines from human intestinal cells growing in a plastic well.
Preliminary research suggests that, in other cases, by-products of gluten digestion may be the problem. Breaking down gliadin and glutenin produces even shorter chains of amino acids—the building blocks of proteins—some of which may behave like morphine and other soporific opiates. Perhaps these molecules explain some of the lethargy exhibited by people who do not have celiac disease but are nonetheless sensitive to wheat, suggests Aristo Vojdani, chief executive officer of Immunosciences Lab in Los Angeles. In a small study by Vojdani and his colleagues, the blood of people classified as gluten-sensitive had higher levels of antibodies that recognize these gluten by-products than blood taken from healthy volunteers.