Gluten may not be the only wheat protein that makes people sick
Two years ago, on the recommendation of a nutritionist, I stopped eating wheat and some other grains. Within days, the crippling headaches and fatigue I had been suffering from for months were completely gone. At first, my gastroenterologist interpreted the disappearance of the symptoms as a sign that I may have suffered from celiac disease, a strange disease in which the immune system attacks a group of proteins found in wheat, barley and rye known as gluten clusters. The misguided attack causes inflammation and damage to the small intestine, impairs the absorption of essential nutrients and therefore causes abdominal swelling, diarrhea, headaches, fatigue and in rare cases even death. But some tests I did ruled out this diagnosis. My doctor therefore concluded that I have "gluten sensitivity", a relatively new diagnosis. The prevalence of gluten sensitivity is not yet clear, but there are data indicating that it characterizes up to 6% of US residents, six times the number of celiac patients.
Although there are many common symptoms of gluten sensitivity and celiac disease, gluten sensitivity is usually less severe. Compared to celiac patients, people who are sensitive to gluten are more likely to report non-gastrointestinal symptoms, such as headaches, and usually do not suffer from acute intestinal damage or inflammation. But recently, some researchers have begun to wonder if all these problems are indeed related to gluten. A handful of new studies indicate that in many cases the phenomenon called "gluten sensitivity" is not related to gluten at all. In fact, the researchers believe, it is a cluster of diseases caused by different molecules in wheat and other grains.
"Do you know the story about the blind man and the elephant? Well, that's where the research on gluten sensitivity is now," says Sheila Crowe, director of research in the Division of Gastroenterology at the University of California, San Diego School of Medicine. The attempt to understand all the ways in which the human body reacts to all the other proteins and molecules found in grains besides gluten, will allow doctors to develop more accurate tests for the various sensitivities to these compounds. Ultimately, clinicians hope the tests will help people with true disease avoid the components of grains that cause the disease and allow others to continue consuming nutritious whole grains.
the seeds of disease
Among the most common grains, wheat is the main seed of calamity. Man first domesticated wheat 10,000 years ago in the Fertile Crescent region of the Middle East. Since then, the amount of wheat in our diet, for all the molecules it contains, has increased considerably. Of all these molecules, it can be argued that gluten is the most important for the quality of bread, because it gives bakery products their structure, texture and flexibility. When bakers add water to wheat flour and begin kneading it into dough, two smaller proteins, gliadin and glutenin, change shape, bind together and form long, flexible loops of what is known as gluten. The more gluten there is in the flour, the more stretchy and spongy the dough will be after baking.
Until the Middle Ages, the types of grains that people grew contained much smaller amounts of gluten than today's grains. In the following centuries, even before they understood what gluten was, breeders selected wheat varieties that produced lighter, more bite-sized bread, and protein consumption increased considerably. As wheat breeding and farming methods improved, humans began to produce and eat more wheat in general. Today, the average person in the US eats about 60 kg of wheat per year, mostly in the form of bread, cereal, crackers, pasta, cookies and cakes. This means about 23 grams of gluten daily.
Although historical records from the first century AD mention a disease very similar to celiac disease, it was not until the middle of the 20th century that doctors realized that the blame lay in the gluten in wheat. During the Second World War, the Dutch doctor Willem-Carl Dick documented a sharp decrease in the number of deaths in children with the most severe version of celiac disease at the same time as the lack of bread. In a follow-up study, researchers removed various wheat components from the diets of ten children who suffered from intestinal disease. When gluten was reintroduced to the diet, symptoms such as diarrhea returned, while reintroducing another complex molecule found in wheat, namely starch, did not. This is how it turned out that gluten is responsible for celiac disease.
Additional experiments conducted by other researchers discovered what is the ingredient in gluten that stimulates the immune system. During digestion, gluten breaks down back into gliadin and glutenin. For reasons not yet clear, the immune system of people with celiac disease sees gliadin as a dangerous invader.
For years, doctors used nutrition to diagnose celiac disease: if the patient's symptoms disappeared following a gluten-free diet, then they were suffering from the disease. But over time, clinicians have developed more sophisticated ways to detect the disease, such as tests that look for molecules of the immune system, called antibodies, that recognize gliadin and stick to it. When these tests came into use, doctors soon discovered that some of the people with mild symptoms after eating bread or pasta did not actually have celiac disease: biopsies of the intestine showed that there was at most little damage to the intestine, and blood tests did not detect the antibodies associated with the disease. Over time, the new condition was called non-celiac gluten sensitivity.
Now some studies suggest that this phenomenon, known as gluten sensitivity, is not always caused by gluten. In some cases, the problem lies in completely different proteins, or even in carbohydrates. "We are so used to seeing gluten as the enemy, but it could 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, Minnesota, agrees: "I'm less and less comfortable using the term non-celiac gluten sensitivity. I think it's better to call it non-celiac wheat sensitivity.”
A gardener grew grain in the garden
If the culprits in some cases of gluten sensitivity are actually other components of the wheat, then finding them will be complex. Wheat has six sets of chromosomes and an impressive number of genes, about 95,000. By comparison, humans have only two sets of chromosomes and about 20,000 genes. Genes encode the instructions for building proteins, so more genes mean more proteins to scan. However, preliminary experiments are already focusing on some possible offenders.
In laboratory experiments, wheat proteins known as amylase-trypsin inhibitors stimulate immune system cells grown in culture and cause them to release cytokines, molecules that produce inflammation, which can cause the immune system to become overactive. Further tests revealed that these wheat proteins cause the same inflammatory response in mice. Similarly, an Italian study showed that low concentrations of a protein known as wheat germ agglutinin (WGA), which is distinct from gluten, activates cytokines in human intestinal cells growing in culture.
Preliminary studies suggest that in other cases, byproducts of gluten digestion may trigger 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 narcotic opiates. It is possible that these molecules explain to some extent the fatigue felt by people who do not have celiac disease but who nevertheless have a sensitivity to wheat, suggests Aristotle Vojdani, CEO of Immunosciences Lab in Los Angeles. In a small study conducted by Vojdani and his colleagues, it was found that the blood of people diagnosed with gluten sensitivity contained higher levels of antibodies that recognize these gluten byproducts than the blood of healthy volunteers.
Another group of potential culprits belong to a diverse family of carbohydrates, such as fructans, which are notorious for being difficult to digest. The inability to absorb these compounds into the bloodstream can cause water to accumulate in the digestive system and interfere with the intestinal bacteria. Since these resistant carbohydrates are found in a variety of food types, and not only in grains, a gluten-free or wheat-free diet will not necessarily solve the problem if it actually originates from these molecules.
Eat the cake and leave it whole
Despite the recently accumulated evidence that wheat sensitivities are many and varied than we thought, studies also show that many people who think they have such reactions to wheat are actually wrong. In a 2010 study, only 12 of 32 people who said they felt better after switching to a diet free of gluten or other wheat proteins actually had a negative reaction to these molecules. "In other words, about 60% of the patients removed components from the diet for no real reason," notes the author of the article, Antonio Crucio from the University of Palermo in Italy.
However, identifying disease triggers other than gluten will provide doctors with a more accurate way to diagnose grain sensitivity and help people avoid certain foods. Researchers could, for example, develop blood tests that detect antibodies that bind to short chains of amino acids or proteins such as WGA, says Umberto Volta, a gastroenterologist at the University of Bologna in Italy. And some scientists believe that the research will eventually lead to new drugs. "If we know what activates the immune system, we hope to be able to silence the system and cure the disease," says Roberto Ciniola from the University of Verona in Italy.
I myself suspect that something other than gluten caused my symptoms. I have occasionally tasted gluten-free products made from grains, such as gluten-free barley beer. Each time my headaches came back with intensity (long before a migraine attack could develop), and reinforced the feeling that gluten was not the root of my troubles.
If this is true, and there is even a faint possibility of reintroducing gluten to my menu, I would definitely like to know. As a New Yorker, it's hard for me to give up pizza. If gluten is proven in my case, maybe I can add it to a non-grain based flour or bake another experimental pizza at home and extract the gooey, stretchy triangles straight from my dreams onto the plate.
______________________________________________________________________________________________________________________________________________________________________________________
on the notebook
Roxanne Khamsi is a senior news editor at Nature Medicine. She wrote in New Scientist, Economist and Wired News. Follow her on Twitter at: @rkhamsi
The article was published with the permission of Scientific American Israel
