Enteric infections, diarrhea, and their impact on function and development

Abstract

Enteric infections, with or without overt diarrhea, have profound effects on intestinal absorption, nutrition, and childhood development as well as on global mortality. Oral rehydration therapy has reduced the number of deaths from dehydration caused by infection with an enteric pathogen, but it has not changed the morbidity caused by such infections. This Review focuses on the interactions between enteric pathogens and human genetic determinants that alter intestinal function and inflammation and profoundly impair human health and development. We also discuss specific implications for novel approaches to interventions that are now opened by our rapidly growing molecular understanding.

Figure 1. Worldwide distribution of deaths caused by diarrhea in children under 5 years of age in 2000.

Although global mortality from diarrhea has declined in recent years, from approximately 4.6 million deaths during the mid-1980s to the current estimate of 1.6–2.1 million, most of these deaths occur in children in developing countries under the age of 5 years. Data are from the year 2000 (2).

Figure 2. Repeated bouts of diarrhea linearly ablate “catch-up growth.

The use of ORT has dramatically reduced acute mortality from dehydration caused by the diarrhea that often results from infection with an enteric pathogen. However, rates of morbidity as a result of enteric infections remain as high as ever. The morbidity impact of enteric pathogens is related to their ability to impair nutritional status, presumably by directly impairing intestinal absorption and by causing diarrhea. Therefore, repeated infection with enteric pathogens has a lasting impact on the growth and development of a child. Although malnourished children can catch up if given a chance, those with frequent bouts of diarrhea as a result of repeated infection with enteric pathogens have this catch-up growth linearly ablated. Weight-for-age Z score < –3, children with a Z score more than 3 SD below mean weight-for-age value, considered severely malnourished; weight-for-age Z score > –3, children with a Z score less than 3 SD below mean weight-for-age value, considered not severely malnourished. Figure reproduced with permission from Lancet (5).

Figure 3. Movement of Na⁺ and Cl^– in the small intestine.

(A) Movement in normal subjects. Na⁺ is absorbed by two different mechanisms in absorptive cells from villi: glucose-stimulated absorption and electroneutral absorption (which represents the coupling of Na/H and Cl/HCO₃ exchanges). (B) Movement during diarrhea caused by a toxin and inflammation. In toxigenic diarrhea (caused, for example, by the enterotoxin produced by V. cholerae), increased mucosal levels of cAMP inhibit electroneutral NaCl absorption but have no effect on glucose-stimulated Na⁺ absorption. In inflammatory diarrhea (e.g., following infection with Shigella spp. or Salmonella spp.) there is extensive histological damage, resulting in altered cell morphology and reduced glucose-stimulated Na⁺ and electroneutral NaCl absorption. The role of one or more cytokines in this inflammatory response is critical. In secretory cells from crypts, Cl^– secretion is minimal in normal subjects and is activated by cAMP in toxigenic and inflammatory diarrhea.