Abstract Non Celiac Gluten sensitivity (NCGS) was originally described in the 1980s and recently a "re-discovered" disorder characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected with either celiac disease (CD) or wheat allergy (WA). Although NCGS frequency is still unclear, epidemiological data have been generated that can help establishing the magnitude of the problem. Clinical studies further defined the identity of NCGS and its implications in human disease. An overlap between the irritable bowel syndrome (IBS) and NCGS has been detected, requiring even more stringent diagnostic criteria. Several studies suggested a relationship between NCGS and neuropsychiatric disorders, particularly autism and schizophrenia. The first case reports of NCGS in children have been described. Lack of biomarkers is still a major limitation of clinical studies, making it difficult to differentiate NCGS from other gluten related disorders. Recent studies raised the possibility that, beside gluten, wheat amylase-trypsin inhibitors and low-fermentable, poorly-absorbed, short-chain carbohydrates can contribute to symptoms (at least those related to IBS) experienced by NCGS patients. In this paper we report the major advances and current trends on NCGS. Keywords: gluten sensitivity, celiac disease, wheat allergy, gluten-related disorders, gluten-free diet

1. Introduction Gluten sensitivity (GS) was originally described in the 1980s [1] 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 with either celiac disease (CD) or wheat allergy (WA). Following the landmark work by Sapone and coworkers, describing the clinical and diagnostic features of GS in the year 2010 [2], a rapidly increasing number of papers have been published by many independent groups, confirming that GS should definitely be included in the spectrum of gluten-related disorders. However, many aspects of GS epidemiology, pathophysiology, clinical spectrum, and treatment are still unclear. Given the recent increase of the gluten-free market worldwide, partially sustained by individuals who claim a medical necessity to undertake a gluten-free diet (GFD), there is a need of "separating the wheat from the chaff" [3]. This goal will be achieved by (a) proper scientific information, (b) shared definitions, and (c) prospective, multi-center studies addressing the many unsolved issues on GS. In order to develop a consensus on new nomenclature and classification of gluten-related disorders, a panel of experts first met in London, in February 2011. The panel proposed a series of definitions and developed a diagnostic algorithm that has been recently published [4]. After the 2011 London Meeting, many new papers have been published on GS. Although its frequency in the general population is still unclear, epidemiological data have been generated that can help establish the magnitude of the problem. Clinical studies further defined the identity of GS and its possible implications in human disease. An overlap between the irritable bowel syndrome (IBS) and GS has been suspected, requiring even more stringent diagnostic criteria. The first case reports of GS in children have been described. Lack of biomarkers is still a major limitation of clinical studies, making the differential diagnosis with other gluten related disorders, as well conditions independent to gluten exposure, difficult. Evaluation and discussion of this new information was the aim of a Second Expert Meeting on GS that was held in Munich, November 30–December 2, 2012. In this paper we report the major advances and current trends on GS, as presented and debated at the Munich meeting.

2. Nomenclature At least three papers have recently addressed the issue of defining gluten-related disorders [4,5,6]. Interestingly, one of these [4] ranks among the most frequently downloaded paper of the publishing journal (BMC Medicine), particularly by physicians, internists or general pediatricians, and directors of diagnostic labs. There is a general agreement that the term "gluten-related disorders" is the umbrella-term to be used for describing all conditions related to ingestion of gluten-containing food. CD is a chronic small intestinal, immune-mediated, enteropathy precipitated by exposure to dietary gluten and related prolamines in genetically predisposed individuals, characterized by specific autoantibodies against tissue transglutaminase 2 (anti-TG2) and endomysium (EMA). WA is an adverse immunologic reaction to wheat proteins. In the pathogenesis of WA, wheat specific IgE antibodies play a central role, however non-IgE-mediated WA does exist [7], and this form may be difficult to distinguish from GS. GS, which this review will focus on primarily, is a condition in which symptoms are triggered by gluten ingestion, in the absence of celiac-specific antibodies and of classical celiac villous atrophy, with variable Human Leukocyte Antigen (HLA