Despite downward trends in diarrhoeal mortality, there are still an unacceptably high number of child deaths annually. The principles of acute treatment are continued feeding, increased fluids (including oral rehydration solution), zinc supplementation and rational use of antibiotics. However, in a study from Dhaka, only 6% of caregivers of children with diarrhoea sought help from a qualified healthcare provider . Even when caregivers do seek appropriate help, healthworkers may have inadequate knowledge  and incorrect practices are common . In a survey of 264 healthcare workers in Indian slums , overuse of antibiotics and intravenous rehydration was widespread; practitioner knowledge strongly predicted correct practice, suggesting the need for ongoing caregiver and healthworker education.
Stunting is driven by complex interactions between genetics, epigenetics, environmental influences, recurrent infections and inadequate diet. A condition called environmental enteric dysfunction (EED), which is almost universal in impoverished settings, is also associated with stunting. EED is characterized by small intestinal inflammation and abnormal villous architecture, modest malabsorption and gut permeability; however, there is no case definition or gold standard biomarker and its cause remains unclear . A recent murine model [18▪▪] provides insights into the interactions between microbial exposure, enteropathy and malnutrition. Mice fed a suboptimal diet developed shifts in the small intestinal microbiota but retained normal intestinal histopathology; if they also received a bacterial cocktail they developed villous blunting and inflammation characteristic of EED. This supports the hypothesis in humans that EED arises from exposure to environmental microbes in conditions of poor sanitation and hygiene, particularly in the context of inadequate diet. Frequent enteropathogen carriage indicates that environmental contamination begins early in life. Exposure to faecal bacteria through geophagia  and contact with animal faeces  may be particularly important. The hypothesized causal pathway from EED to stunting is through malabsorption and chronic inflammation (arising from microbial translocation across an impaired gut barrier); however, this is difficult to confirm with current biomarkers . Recent studies using anti-endotoxin antibodies (EndoCAb) as markers of microbial translocation showed no relationships with growth in Malawi  or Zimbabwe , and plasma concentrations of intestinal fatty acid binding protein (indicative of villous damage) were elevated in Zimbabwean infants but not associated with stunting ; however, the role of chronic inflammation in stunting has been confirmed in several recent studies [22,23]. Dissecting the interactions between recurrent infections, impaired gut integrity, chronic inflammation and stunting will require more longitudinal studies, using panels of emerging biomarkers together with gut biopsy samples where feasible.
There are intriguing interrelationships between enteric and respiratory infections. For example, diarrhoea appears to increase the risk of subsequent pneumonia, possibly because of hypochlorhydria . Higher gastric pH may predispose to enteric infections through loss of the protective gastric acid barrier, and increase the risk of pneumonia via reflux of heavily colonized gastric contents. An elegant murine study [34▪] dissected a complex mechanism through which lung infections unexpectedly cause intestinal damage. Following intranasal infection with influenza, mice developed small intestinal damage, which was not caused by viral dissemination to the gut. Instead, lung-derived CCR9+CD4+ T cells homed to the small intestine and disrupted the microbiota through interferon-gamma secretion. In response to dysbiosis, the intestinal epithelium secreted IL-15, causing Th17 polarization of mucosal CD4+ T cells and IL-17-mediated gut damage. Thus, infections at distant sites may disrupt intestinal homeostasis through immune-mediated effects on the microbiota; further studies in humans are needed to explore these mechanisms further.
There is an urgent need for new approaches and scale-up of existing interventions to reduce morbidity and mortality from diarrhoea, enteropathy and malnutrition. In a systematic review  of nonmedical interventions, such as infrastructure investments and behaviour change communication, most showed benefits ranging from 18 to 61% reduction in diarrhoeal incidence. The Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea outlines priority, low-cost, effective interventions to end preventable pneumonia and diarrhoea deaths by 2025 . A modelling exercise in South Africa showed that even 10% scale-up of 13 existing interventions for diarrhoea by 2030 would reduce under-5 diarrhoeal deaths by 48%; water, sanitation and hygiene (WASH), oral rehydration solution and exclusive breastfeeding would avert the majority of deaths .
Oral vaccines are the cornerstone of enteric infection prevention, but are least effective where they are most needed, possibly because of EED, enteric coinfections, malnutrition and interference from breast milk antibodies. Several strategies aimed at overcoming the oral vaccine effectiveness gap have recently been reported. In Pakistan , injectable poliovirus vaccine given with oral poliovirus vaccine (OPV) induced superior immune responses than OPV alone in well-nourished and malnourished infants. Withholding breastfeeding for 1 h prior to oral rotavirus vaccination paradoxically showed higher IgA seroconversion in the immediate feeding arm (37.8 vs. 28.2%; P = 0.07), although breast milk interference occurred in a subset of infants . A trial in Karachi  showed no improvement in serconversion with later or additional rotavirus vaccine doses. Further studies of alternative strategies are, therefore, needed to improve oral vaccine performance in settings with the highest enteric disease burdens.
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