What’s really behind gluten sensitivity?

What’s really behind ‘gluten sensitivity’? | Science | AAAS – By Kelly Servick – May. 23, 2018

This article explains the phenomena I’ve noticed: even people who do not have celiac disease often feel better when they stop eating gluten.

The patients weren’t crazy—Knut Lundin was sure of that. But their ailment was a mystery. They were convinced gluten was making them sick. Yet they didn’t have celiac disease, an autoimmune reaction to that often-villainized tangle of proteins in wheat, barley, and rye. And they tested negative for a wheat allergy. They occupied a medical no man’s land.

About a decade ago, gastroenterologists like Lundin, based at the University of Oslo, came across more and more of those enigmatic cases. “I worked with celiac disease and gluten for so many years,” he says, “and then came this wave.”  

It was easy to assume that people claiming to be “gluten sensitive” had just been roped into a food fad.

But a small community of researchers started searching for a link between wheat components and patients’ symptoms—commonly abdominal pain, bloating, and diarrhea, and sometimes headaches, fatigue, rashes, and joint pain.

That wheat really can make nonceliac patients sick is now widely accepted. But that’s about as far as the agreement goes.

As data trickle in, entrenched camps have emerged.

Some researchers are convinced that many patients have an immune reaction to gluten or another substance in wheat—a nebulous illness sometimes called nonceliac gluten sensitivity (NCGS).

Others believe most patients are actually reacting to an excess of poorly absorbed carbohydrates present in wheat and many other foods.

Those carbohydrates—called FODMAPs, for fermentable oligosaccharides, disaccharides, monosaccharides, and polyols—can cause bloating when they ferment in the gut.

People with celiac disease are genetically predisposed to launch a self-destructive immune response when a component of gluten called gliadin penetrates their intestinal lining and sets off inflammatory cells in the tissue below.

Known wheat-related illnesses have clear mechanisms and markers.

People with a wheat allergy respond to wheat proteins by churning out a class of antibodies called immunoglobulin E that can set off vomiting, itching, and shortness of breath

The puzzle, for both doctors and researchers, is patients who lack both the telltale antibodies and the visible damage to their intestines but who feel real relief when they cut out gluten-containing food.

Like many doctors, Lundin believed that (fad dieters and superstitious eaters aside) some patients have a real wheat-related ailment. His group helped dispel the notion that NCGS was purely psychosomatic.

They surveyed patients for unusual levels of psychological distress that might express itself as physical symptoms. But the surveys showed no differences between those patients and people with celiac disease, the team reported in 2012. As Lundin bluntly puts it: “We know they are not crazy.”

Still, skeptics worried that the field had seized on gluten with shaky evidence that it was the culprit. After all, nobody eats gluten in isolation. “If we did not know about the specific role of gluten in celiac disease, we would never have thought gluten was responsible for [NCGS],” says Stefano Guandalini, a pediatric gastroenterologist at the University of Chicago Medical Center in Illinois. “Why blame gluten?”

Defenders of NCGS generally acknowledge that other components of wheat might contribute to symptoms.

In 2012, a group of proteins in wheat, rye, and barley called amylase trypsin inhibitors emerged as a potential offender, for example, after a team led by biochemist Detlef Schuppan of Johannes Gutenberg University Mainz in Germany (then at Harvard Medical School in Boston) reported that those proteins can provoke immune cells.

Against the grain

Data from the National Health and Nutrition Examination Survey show the rising tide of gluten avoidance by people without celiac disease. Celiac diagnoses also rose, but probably not its actual prevalence.

But without biological markers to identify people with NCGS, researchers have relied on self-reported symptoms measured through a “gluten challenge”:

Patients rate how they feel before and after cutting out gluten. Then doctors reintroduce gluten or a placebo—ideally disguised in indistinguishable pills or snacks—to see whether the symptoms tick back up.

Alaedini has recently hit on a more objective set of possible biological markers—much to his own surprise. “I entered this completely as a skeptic,” he says.

In NCGS, Alaedini saw another poorly defined spectrum disorder. He did accept that patients without celiac disease might somehow be sensitive to wheat, on the basis of several trials that measured symptoms after a blinded challenge. But he was not convinced by previous studies claiming that NCGS patients were more likely than other people to have certain antibodies to gliadin.

In 2012, he contacted researchers at the University of Bologna in Italy to obtain blood samples from 80 patients their team had identified as gluten sensitive on the basis of a gluten challenge.

He wanted to test the samples for signs of a unique immune response—a set of signaling molecules different from those in the blood of healthy volunteers and celiac patients.

The results shocked him. Compared with both healthy people and those with celiac, these patients had significantly higher levels of a certain class of antibodies against gluten that suggest a short-lived, systemic immune response.

the finding hinted that the barrier of those patients’ intestines might be defective, allowing partially digested gluten to get out of the gut and interact with immune cells in the blood.

Other elements—such as immune response–provoking bacteria—also might be escaping. Sure enough, the team found elevated levels of two proteins that indicate an inflammatory response to bacteria. And when 20 of the same patients spent 6 months on a gluten-free diet, their blood levels of those markers declined.

For Alaedini, the beginnings of a mechanism emerged: Some still-unidentified wheat component prompts the intestinal lining to become more permeable. (An imbalance in gut microbes might be a predisposing factor.)

Components of bacteria then seem to sneak past immune cells in the underlying intestinal tissue and make their way to the bloodstream and liver, prompting inflammation.

“This is a real condition, and there can be objective, biological markers for it,” Alaedini says. “That study changed a lot of minds, including my own.”

What a great scientist!

But others see the immune-response explanation as a red herring. To them, the primary villain is FODMAPs.

The term, coined by gastroenterologist Peter Gibson at Monash University in Melbourne, Australia, and his team, encompasses a smorgasbord of common foods.

Onions and garlic; legumes; milk and yogurt; and fruits including apples, cherries, and mangoes are all high in FODMAPs.

So is wheat: Carbs in wheat called fructans can account for as much as half of a person’s FODMAP intake, dietitians in Gibson’s group have estimated.

Gibson has long been skeptical of studies implicating gluten in such symptoms, arguing that those findings are hopelessly clouded by the nocebo effect, in which the mere expectation of swallowing the dreaded ingredient worsens symptoms.

His team found that most patients couldn’t reliably distinguish pure gluten from a placebo in a blinded test.

He believes that many people feel better after eliminating wheat not because they have calmed some intricate immune reaction, but because they’ve reduced their intake of FODMAPs.

Lundin, who was firmly in the immune-reaction camp, didn’t believe that FODMAPs could explain away all his patients.

His team recruited 59 people on self-instituted gluten-free diets and randomized them to receive one of three indistinguishable snack bars, containing isolated gluten, isolated FODMAP (fructan), or neither. After eating one type of bar daily for a week, they reported any symptoms. Then they waited for symptoms to resolve and started on a different bar until they had tested all three.

Lundin was confident that gluten would cause the worst symptoms. But when the study’s blind was lifted, only the FODMAP symptoms even cleared the bar for statistical significance

Twenty-four of the 59 patients had their highest symptom scores after a week of the fructan-laced bars. Twenty-two responded most to the placebo, and just 13 to gluten

Lundin now believes FODMAPs explain the symptoms in most wheat-avoiding patients

Alaedini agrees that FODMAPs explain some of the wheat-avoidance phenomenon. And Lundin acknowledges that some small population may really have an immune reaction to gluten or another component of wheat, though he sees no good way to find them.

Author: Kelly Servick is a staff writer at Science.