Enteric and diarrheal diseases are a major worldwide cause of death among children under the age of 5. In this age group, diarrhea occurs 2.5 billion times per year  and causes 15% of childhood deaths. Diarrheal diseases claim 59 million disability-adjusted life years (DALYs), nearly all from children in low- and middle-income countries. Despite this enormous burden, these numbers fail to capture the full impact of enteric and diarrheal diseases. Early and frequent exposure to intestinal pathogens begins a cycle (Figure 1A) that affects digestion, nutrient absorption, growth, and immunity. Repeated infections, with either overt diarrhea or subclinical enteropathy, produce acute and chronic undernutrition, which leads to more frequent and severe infections. Undernutrition contributes to 53% of childhood deaths  and is the leading risk factor for poor health outcomes in childhood; survivors are at risk for developmental deficits in growth, fitness, and cognition that persist into adulthood with devastating consequences. These consequences have a multiplicative effect on calculations of DALYs from diarrheal disease.
Fortunately, there are strategies to break this cycle, although each approach has limitations. Sustainable access to potable water and improved sanitation reduces pathogen exposure; a $70 billion annual investment would only begin to reduce the number of people without these necessities (2.5 billion) by 2015. Antimicrobial agents are effective against specific pathogens but are expensive and can exacerbate toxin-mediated diseases, disrupt the human microbiome, and induce antibiotic-associated diarrhea as well as drug resistance. Immunization with enteric vaccines can reduce the burden of severe diarrhea, but vaccines must be kept in the cold, only protect against specific pathogens, and are less effective in regions of high mortality. For example, the efficacy of the live, attenuated rotavirus vaccine against severe disease is only 48.3% in southeast Asia  and 39.3% in sub-Saharan Africa. Zinc reduces the propensity to develop recurrent diarrhea and oral rehydration solution (ORS) attenuates overt symptoms of diarrhea and dehydration. However, these approaches do not adequately address broader growth and developmental processes that could yield long-term benefits. Likewise, trials of therapeutics to reduce diarrhea severity, unplanned intravenous fluid administration, or duration of hospitalization fail to address longer-term, initially subclinical, consequences of recurrent infections. Complementary outcome measures, including measures of growth and biomarkers of acute intestinal inflammation, barrier disruption, and impaired immunity, would provide greater insight into underlying pathology and therapeutic efficacy. Use of these measures could reduce acute, overt, as well as chronic, often unrecognized, intestinal diseases (Figure 1B).
No single intervention is sufficient to eliminate the global burden of enteric and diarrheal diseases. Vaccines, for example, can protect against limited infectious agents but immunization can be overwhelmed by heavily contaminated water. Multiple interventions could work synergistically, such as the combination of improved water and sanitation, vaccines, micro- and macronutrient provision, and selectively-targeted antimicrobial therapy (e.g. single-dose albendazole for intestinal helminths). Do current global health strategies use the best available interventions?
One underexplored approach, probiotics, could combine favorable safety profiles with improved nutrition and microbiome function. Probiotics are live microorganisms that confer a health benefit on the host, and have been used to treat multiple gastrointestinal (GI) diseases. Microbes are inexpensive to grow, and have the potential for rapid global scale-up. Is there compelling evidence to recommend developing probiotics-based strategies to complement current approaches against enteric and diarrheal diseases for children in developing countries? If so, what steps must be taken before these therapies are ready for clinical impact in the global health arena?