Preface

During its 2.5 million years of evolution, the human species has evolved through major dramatic changes, mainly dictated by natural elements and, most importantly, by food availability. The diet of hunters and gatherers, hominids, was mainly based on fruit, vegetables, tubers, and occasionally meat and fish. Then, approximately 10,000 years ago, a drastic change in life style occurred, shifting from nomadic to settlers with domestication of animals and crops. A consequence of this change was the advent of wheat and other grains containing gluten-related proteins in human diet. This revolutionary transformation occurred at the Fertile Crescent, the modern-day Iraq, and spread from South to North and East to West at a speed of approximately 1 km/year. Ever since, the distribution of food goods became more and more uneven with wealthy countries getting more than necessary, while poor countries struggle with malnutrition and consequently this increased mortality. Unfortunately, the industrial revolution, rather than closing the gap, created even more inequalities that still exist today, leading to very different but equally worrisome pathologies, namely obesity in industrialized countries and famine in developing countries.

Beside nutritional problems secondary to quantitative imbalance, there are also nutritional pathologies triggered by specific dietary elements. Celiac disease (CD) is an autoimmune disorder occurring in genetically predisposed individuals, and triggered by the ingestion of dietary gluten, the major protein component in wheat, barley and rye. In many areas of the world, CD is one of the most common lifelong disorders affecting approximately 1% of the general population. Gluten is the typical example of a "friend" (food) becoming a foe (because it can cause an array of signs and symptoms in predisposed individuals). Gluten is a complex and ancient protein that represents the main component of wheat with a unique primary structure rich in proline and glutamine amino acid residues. For this reason, gluten is extremely difficult to digest. With more than 150,000 genes, wheat represents an extremely complicated component that evolved over the millennia to reach its present genetic and structural characteristics. The history of humans and the evolution of gluten related disorders are intertwined with the evolution of wheat and gluten: how they developed, how they continue to evolve, and how they affect humankind today around the world in a variety of gluten-related symptoms and disorders.

Almost 2,000 years ago, Aretaeus from Cappadocia reported what is believed to be the first description of a case of CD. It would take approximately another 1,800 years before CD resurfaced in medical literature. This time it was a British doctor, Samuel Gee, who officially placed celiac disease on the medical map in 1861 when he gave a famous lecture in London that provided the first modern description of CD:

*"There is a kind of chronic indigestion which is met with in persons of all ages, yet is especially apt to affect children between one and five years old. Signs of the disease are yielded by the fæces [sic]; being loose, not formed, but not watery; more bulky than the*  *food taken would seem to account for; pale in colour [sic], as if devoid of bile; yeasty, frothy, an appearance probably due to fermentation; stinking, stench often very great, the food having undergone putrefaction rather than concoction."*

Following his medical intuition, Gee described celiac disease as a malabsorption syndrome triggered by some unidentified foodstuff. He was right on target with his description, but not on target with the culprit of the disease. Gee's recommendation was to feed patients bread that was "cut thin and well toasted on both sides."

The real breakthrough that eventually led to the gluten-free diet as treatment came almost a century later thanks to the acumen of a Dutch physician, Willem-Karel Dicke. He noted that the mortality rate of children suffering from celiac disease before World War II decreased dramatically during the war from 30–35 percent to almost zero. Given the scarcity of wheat during the war, Dicke suspected that wheat flour was indeed responsible for the symptoms endured by the celiac children. He followed his intuition by performing a trial on a very limited number of children that proved him right. Since these pioneering studies and with the advent of specific and sensitive screening tools, we have appreciated that CD and other gluten related disorders are present worldwide and, like many other immune-mediated diseases, are increasing over time.

Gluten sensitivity (GS) was originally described in the 1980s and a recently "re-discovered" syndrome entity, characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected by either CD or a wheat allergy. Following the landmark work by Sapone and coworkers, describing the clinical and diagnostic features of GS in 2010, a rapidly increasing number of papers have been published by many independent groups, confirming that GS should definitely be included in the spectrum of glutenrelated disorders. However, many aspects of GS epidemiology, pathophysiology, clinical spectrum, and treatment are still unclear.

Treatment of CD and other gluten-relate disorders is based on the lifelong exclusion of glutencontaining cereals from the diet. The changes needed to begin and maintain a gluten-free diet (GFD) are substantial and have a major impact on daily life. Over the past 30 years, developments in the nutritional aspects of CD have been huge. Nutrient deficiencies have been described in celiac patients both before and after diagnosis, due to intestinal malabsorption and specific limitations of the GFD, respectively. The relationship between the level of gluten intake and intestinal damage has been analyzed leading to new Codex Alimentarius recommendations on the gluten threshold in gluten-free food. Contamination with gluten of the GFD is an important issue in CD management. The spectrum of cereal toxicity for CD patients has been investigated with practical implications on the GFD. The nutritional quality of gluten-free food is constantly improving thanks to the new scientific approach in the technology of gluten-free wheat substitutes.

In this *Nutrients* Special Issue, a summary of contemporary issues on the management of CD and other gluten-related disorders is provided. This book capitalizes on the contribution of opinion leaders concerning the multidisciplinary ramifications of these disorders. We want to take this opportunity to thank all contributors to this book. This project would not have been possible without the expertise and invaluable contribution and technical support of the *Nutrients* editorial team.

Carlo Catassi, Alessio Fasano *Guest Editors* 

Reprinted from *Nutrients*. Cite as: Catassi, C.; Bai, J.C.; Bonaz, B.; Bouma, G.; Calabrò, A.; Carroccio, A.; Castillejo, G.; Ciacci, C.; Cristofori, F.; Dolinsek, J. Non-Celiac Gluten Sensitivity: The New Frontier of Gluten Related Disorders. *Nutrients* **2013**, *5*, 3839-3853.
