Digestion of proteins commences in the stomach with partial denaturation (unfolding) of the large protein polypeptide chains by hydrochloric acid, which enhances their breakdown into smaller polypeptide chains by the proteolytic enzyme pepsin. In the highly acidic conditions of the stomach, pepsin is very active, cleaving a number of different peptide bonds. Breakdown of food proteins in the stomach is incomplete (Gray 1991), and relatively large peptides pass from the stomach into the duodenal part of the small intestine. Enzymes secreted by the pancreas - trypsin and carboxypeptidases - enter the interior (lumen) of the small intestine to continue digestion of proteins until they are broken down into amino acids or small peptides. Peptides this small are unlikely to be active in celiac disease.
Breakdown of proteins to amino acids or short peptides, both of which can be absorbed, is probably complete in the distal small bowel, even in celiac patients, as evidenced by a gradient of intestinal damage from the duodenum through the jejunum in active celiac disease. The ileum may remain free of tissue damage (Rubin et al. 1962). Instillation of wheat proteins into the ileum (Rubin et al. 1962) or the rectum (Dobbins and Rubin 1964; Loft, Marsh, and Crowe 1990) produces similar damage to that seen in the small intestine, indicating that the entire epithelial surface is susceptible to the damaging effects of wheat proteins or peptides. The final breakdown of food particles to relatively small molecules, and their active or passive absorption for use by the body, takes place at the membranes of cells lining the surface of the small intestine.
Almost all nutrients, ranging through amino acids, sugars, fatty acids, vitamins, and minerals are absorbed from the small intestine so that damage to this absorptive surface may have many manifestations in celiac disease. Obviously, a deficiency of calories from carbohydrates and fats and a deficiency of amino acids needed for protein synthesis can be responsible for a loss of weight or a failure to thrive, but the effects of malabsorption are often more diverse, ranging from osteoporosis in later life as a consequence of a failure to absorb calcium adequately to nerve degeneration as a consequence of a failure to absorb vitamins. The large intestine, or colon, extracts water and electrolytes from the food residues while bacterial action on these residues reduces the bulk of indigestible materials, such as cellulose. Relatively little absorption of nutrients occurs in the colon.
When intestinal biopsy was introduced in the 1950s, it was demonstrated that the surface of the intestinal mucosa in patients with active celiac disease appeared flattened as a consequence of the loss of villous structure and enhanced proliferation of immature cells in the crypts. Subsequently it was recognized that the microvilli of mature enterocytes were often damaged as well. Together, these losses significantly diminish the absorptive surface area and give rise to an increased crypt layer with an immature population of enterocytes having incompletely developed enzyme and transport activities. The net result is a diminished capability to absorb nutrients, although it should be noted that malabsorption may occur even in patients with little or no obvious damage to the epithelium.
It has been noted that initial responses to gluten challenge included infiltration by lymphocytes of the epithelium and lamina propria and thickening of the basement membrane and that these changes preceded major changes in mucosal structure (Shmerling and Shiner 1970; Marsh 1992a), providing strong support for the involvement of immunological processes in the destruction of the absorptive epithelium. A highly significant association of celiac disease with certain proteins of the major histocompatibility complex (histocompatibility antigens) also provides evidence for involvement of the immune system and a genetic predisposition to the disease. The inheritance of celiac disease appears to be complex, however, involving two or more genes (Strober 1992), and an environmental contribution, such as a viral infection or stress, may be necessary before the genetic predisposition comes into play (Kagnoff et al. 1984). What remains to be clarified is how these immune processes are triggered by gliadin peptides and how they ultimately result in the loss of epithelial absorptive cells.
World History
