Celiac disease (CD) is an immune-mediated disease characterized by small intestinal
inflammation from gluten ingestion, a group of proteins present in various cereals,
including wheat, rye, barley, spelt, and kamut. CD is the most common chronic
gastrointestinal disease and one of the most common autoimmune disorders, estimated to
affect 0.4-1.7% of the general population. Currently, a strict lifelong gluten-free diet
(GFD) is the only available treatment to avoid the inappropriate inflammatory response
and prevent the shortening of the villi lining the small intestine (villous atrophy).
However, a significant proportion of CD patients, ranging from 4% to 79%, show persistent
villous atrophy despite following an intentional GFD. The causative factors and the
clinical consequences of persistent villous atrophy in CD patients are not well known yet
but might resemble untreated CD long-term complications.
Interestingly, in the precedent study (CADER) persistent villous atrophy was found to be
more present in patients diagnosed at an older age (65% of CD patients diagnosed after 30
years of age) than in younger patients. Moreover, unintentional exposure to gluten was
found in 70% of the cases. The causative factors of this hypersensitivity to small
amounts of gluten present in older patients are unknown. The intestinal microbiota and
age-related epigenetic changes may help maintaining the dysregulation of the immune
response, causing older patients to be hypersensitive to small amounts of gluten.
The aim of this study (CADER2) is to identify the immunological and clinical consequences
of persistent villous atrophy in CD and study whether changes in the intestinal
microbiome and age-related epigenetic modifications may contribute to it. Last, the
investigators want to assess if an ultra-strict GFD can be a viable and effective
alternative to treat this subset of CD patients. In order to achieve these objectives,
the study includes 2 phases: 1) Cross-sectional study to assess the causes and the
clinical consequences of persistent villous atrophy in CD patients; and 2) Longitudinal
study to evaluate the potential therapeutic effect of an ultra-strict GFD on persistent
villous atrophy and its subtle clinical manifestations.
The investigators hypothesize that persistent villous atrophy in CD patients despite an
intentional GFD is associated with chronic low-grade inflammation and increased
circulating cytokines in blood, potentially leading to cognitive deficits, fatigue,
anxiety, depression, malnutrition, sarcopenia and osteoporosis. The intestinal microbiota
and age-related epigenetic changes may help to maintain the dysregulation of the immune
response, causing patients to be hypersensitive to small amounts of gluten. This subset
of CD patient could highly benefit from an ultra-strict GFD.
To date, six centers have been recruited: Hospital Universitari Mutua Terrassa
(Barcelona), Hospital Clínico San Carlos (Madrid), Hospital Fundación Jiménez Díaz
(Madrid), Hospital Universitario de La Princesa (Madrid), Hospital Universitario Ramón y
Cajal (Madrid) and Hospital Universitario Virgen Macarena (Sevilla). Digestive,
endocrine, nutritional and clinical psychology experts will be involved in the monitoring
of the patients. Microbiome analysis will be performed at the Genomics Unit, Microbiota
Laboratory (LABMIC) of the IdISSC (Madrid). The methylation studies (age-related
epigenetic modifications) will be hired externally.
Overall, the results of this study (CADER2) may help identify new therapeutic strategies
as well as improve the management of chronicity and care of CD patients who do not
respond to the current treatment. Furthermore, it will contribute to a deeper
understanding of the pathophysiological relationships between diet, microbiome, genetics
and immunology in CD.