No abstract

Coeliac disease is a chronic inflammatory disorder of the small bowel induced in genetically susceptible people by the irritant gluten and possibly other environmental cofactors. The disorder is characterised by a diverse clinical heterogeneity that ranges from asymptomatic to severely symptomatic, and it manifests with frank malabsorption, an increased morbidity attributable to the frequent association with autoimmune disorders and increased mortality resulting from the emergence of T-cell clonal proliferations that predispose the patient to enteropathy-type T-cell lymphoma. Our understanding of the molecular basis for this disorder has improved and enabled the identification of targets for new therapies, although a strict gluten-free diet remains the mainstay of safe and effective treatment. In this Seminar we critically reassess the clinical and diagnostic aspects of this disease and new perspectives in its pathogenesis and treatment.

In healthy individuals, the intestinal microbiota cannot access the liver, spleen, or other peripheral tissues. Some pathogenic bacteria can reach these sites, however, and can induce a systemic immune response. How such compartmentalization is achieved is unknown. We identify a gut-vascular barrier (GVB) in mice and humans that controls the translocation of antigens into the blood stream and prohibits entry of the microbiota. Salmonella typhimurium can penetrate the GVB in a manner dependent on its pathogenicity island (Spi) 2-encoded type III secretion system and on decreased β-catenin-dependent signaling in gut endothelial cells. The GVB is modified in celiac disease patients with elevated serum transaminases, which indicates that GVB dismantling may be responsible for liver damage in these patients. Understanding the GVB may provide new insights into the regulation of the gut-liver axis.