Protein-energy malnutrition may produce major structural and functional changes in the gastrointestinal tract and pancreas, which, in turn, may aggravate the underlying poor nutritional condition. In severe protein-energy malnutrition, for example, acinar cell atrophy occurs and exocrine cells have decreased numbers of zymogen granules. Pancreatic secretion may be reduced following stimulation with cholecystokinin and/or secretin. With malnutrition, the activities of enzymes contained in pancreatic juice (i.e., trypsin, chymotrypsin, lipase, amylase) are reduced. With reversal of malnutrition these can return to normal levels, but this may require several weeks.

In addition to pancreatic exocrine changes, the entire wall and mucosal lining of the stomach and intestine may be reduced in thickness. This change appears to be reversible, as a more normal macroscopic appearance can follow nutritional repletion. Microscopically, marked changes may develop, including severe "flattening" of the small intestinal mucosa, similar to celiac disease. In contrast to celiac disease, however, reduced numbers of crypt mitoses are seen; the mucosa is hypoplastic rather than hyperplastic. In this setting, correction of the nutritional state per se can produce a complete reversion to normal. Nonspecific ultrastructural changes also occur, including epithelial cell lipid droplets. Changes may be present throughout the small intestine in an irregular patchy distribution, although the jejunum appears to be most severely affected. Qualitative and quantitative changes in the intestinal microflora, particularly anaerobes, also occur in protein-energy malnutrition. However, their role in altering mucosal structure and function requires definition. Some brush-border enzymes (i.e., disaccharidases) may be reduced; as a result, malabsorption of a variety of substances (e.g., lactose) may be observed. Altered uptake of glucose and D-xylose has also been reported, and steatorrhea may be present with impaired absorption of fat and some fat-soluble vitamins. In addition, there may be increased protein loss from the gut, leading to increased fecal nitrogen loss. Finally, specific nutrients may be deficient and cause alterations in certain tissues. For example, folic acid and vitamin B₁₂ deficiencies have well-recognized effects on rapidly dividing hematopoietic precursor cells in the bone marrow; for similar reasons, as shown in Table 5, analogous changes may be anticipated in the small intestinal epithelium.

There is increasing evidence that the colonic mucosa uses short-chain fatty acids (especially butyrate) as an energy source. In patients who undergo a colostomy, the bowel that is left distally does not have a fecal stream. The mucosa of this bowel may develop inflammation, called "diversion colitis." This condition can be corrected by administering short-chain fatty acid enemas. A major source of the short-chain fatty acids in the colon is fermented dietary fiber, and thus fiber may be considered a "nutrient."