Research could take the biscuit

Tue, Oct 28, 2008, 00:00

New research means that coeliacs could soon be enjoying the taste of real bread and biscuits, writes Alex Gazzola

TO DATE, the only treatment for the Republic's estimated 20,000 people diagnosed with coeliac disease has been very strict adherence to a gluten-free diet. However, that may be about to change, as new research is just emerging which may go some distance towards tackling the problem.

The gluten protein - found in wheat, rye, barley, oats, and products based on them, such as breads, pastas and an array of processed foods - triggers an abnormal immunological reaction in the intestines of coeliacs, leading to tissue damage in the gut, affecting food absorption, and symptoms which can include diarrhoea, weight loss, lethargy and anaemia, among others.

Finding a drug or vaccine remains the medical Holy Grail of scientists working towards an alternative. Last month, leading experts attending the annual International Coeliac Disease Meeting in Genoa, Italy, unveiled several avenues of promising new research concerning the management, prevention and cure of the disease.

Although the news was largely overlooked by mainstream media throughout Europe, the Italians showed no such reservations, with a headline in La Repubblica reading "Goodbye gluten-free diet - the anti-coeliac pill has arrived" being merely one example of the excitement generated.

The pill - or rather drug - in question is larazotide acetate (AT-1001), and it has not quite "arrived" yet. Discovered by Alessio Fasano, medical director of the University of Maryland Center for Coeliac Research, Baltimore, the drug inhibits a human protein called zonulin, which regulates the permeability of the intestine.

Results on phase II trials on 110 coeliac patients announced at the meeting found a dramatic reduction in symptoms associated with gluten among those who had taken the pill.

Just 14 per cent (still about one in six) of those given the drug and then exposed to gluten experienced symptoms normally associated with gluten consumption. This compared with 75 per cent of those exposed to gluten after taking a placebo (dummy) pill.

"Zonulin is a type of 'key' which opens doors from one cell to another in the intestinal wall," explains Fasano.

"The intestine is covered by a single layer of cells which forms a considerable barrier against outside attack, but coeliacs lose this because they produce too much zonulin."

Too much zonulin means too much permeability, he adds, allowing incompletely digested, toxic fragments of gluten to enter the body, which in turn gives way to the immune response that triggers typical symptoms.

The drug works by temporarily "shoring up" the cell wall, effectively blocking gluten from entering the bloodstream. Larger clinical trials are now being planned, and confident researchers have predicted a revolution for patients within five years.

"It would be a remarkable transformation to lives," says Richelle Flanagan, consultant dietitian from NutritionWise in Dublin who has a special interest in coeliac nutrition.

"A huge problem is ensuring patients obtain adequate iron and B vitamins, with which standard, gluten-containing bread is fortified.

"A big plus of a pill allowing the consumption of gluten might be a reduction in the vitamin and mineral deficiencies we see in coeliac disease - calcium included, given that osteoporosis remains a long-term risk."

Health benefits aside, there are potential financial ones too, as gluten-free rendered staples such as breads and pastas are more expensive, with prescription items available only to those with medical cards or high monthly prescription costs - although others can claim some tax reliefs.

Palatability is another, long-standing complaint; although specialist "free-from" manufacturers are constantly widening and improving their products, gluten-free bread doesn't come close to the real thing in taste terms. Then there are issues concerning socialising and eating out - the constant threat of contaminated food, embarrassing requests for dishes to be made in a particular way, and so on.

Clearly, any benefits are only speculative at this stage, and can only be theoretically applied to those diagnosed with coeliac disease.

According to the Coeliac Society of Ireland (CSI), non-diagnosis in the Republic is widespread. It is estimated that there could be about 20,000 living with it unawares, increasing their risk of long-term complications, such as gastro-intestinal cancers.

"Often, GPs don't consider coeliac disease as quickly as they should," says CSI spokeswoman Emma Clarke Conway. "Other conditions such as IBS are explored first, and it may be the last in a long list of considerations, making it a struggle for many to get diagnosed."

Complicating matters are poorly individuals, perhaps disillusioned with conventional medicine, seeking out complementary practitioners who then advise them to avoid wheat and dairy.

Clarke Conway adds: "From a coeliac point of view, people must go through the orthodox route, and excluding wheat before testing can make an accurate diagnosis more difficult."

Further buzz was created in Italy by an announcement regarding the development of a coeliac vaccine for which initial trials will begin shortly, co-ordinated by a team led by Dr Robert Anderson of the Walter Eliza Hall Institute of Medical Research in Melbourne, Australia.

The vaccine has been synthesised to work by "introducing" fragments of gluten to the immune system of coeliacs in a particular way, "re-educating" them to tolerate the protein, and not react inappropriately.

Some experts, though, have expressed reservations. Prof Fergus Shanahan of University College Cork, a consultant gastroenterologist at Cork University Hospital, says any vaccine would have to be "highly effective and very safe, given that the current management of coeliac disease - avoidance of gluten - is straightforward and safe.

"What is needed is research into the development of a greater variety of gluten-free foods, rather than drugs and vaccines."

Others, such as Dr Ross McManus, a geneticist from Trinity College Dublin who specialises in coeliac research, are more upbeat - not only about AT-1001 and the vaccine, but also about ongoing work on proteases, which are enzymes capable of chemically dismantling gluten, effectively "digesting" it and rendering it non-toxic.

"It may be that these treatments won't be a total panacea, and that people will still have to manage their diets to some extent, but they could serve as extra tools to allow them to be less rigorous about eliminating gluten," says McManus.

"We have different avenues to explore," he says. "This gives us more than one option, should some fail, and the possibility that they may work together in a complementary way if they succeed."

Although quality-of-life issues for coeliacs are at stake as research rolls forward, McManus stresses that safety issues will remain paramount.

Large-scale tests still need to be carried out, and any emerging long-term side effects must be weighed against benefits.

How to most effectively use treatments also needs to be established.

For instance, will proteases be employed in manufacturing to "pre-digest" gluten in order to formulate more palatable gluten-free products?

Or might they be given to patients in pill form prior to a gluten meal?

"Resolving all this will take a lot of time," he says. "While we're not there yet, and although we have to be cautious about the future prospect of treatments and cures - I do think it's all exciting."