Malnutrition and the Immune Response: Understanding the Biology of Nutrition-Related Immune Dysfunction

Malnutrition affects 20% of the world’s children. As a result of malnutrition children experience reduced congition, motor and development skills and reduced productivity and economic growth as adults. They are also at increased risk for morbidity and mortalitiy due to infectious disease: a malnourished child can be up to 9 times more likely to die from a diarrheal infection. Susceptibility to disease is a result of malnutrition-induced immunosuppression. High burdens of infections tax the already weak immune system and result in increased inflammation when young. Investigating the effect of immune dysfuncition in malnutrition is an active area of research, but currently there is a gap in knowledge as to the biological mechanism for immune cell dysfunction, and an unclear understanding of the relationship between immune inflammation and nutrition.
Leptin is a hormone intimately connected with nutrition. Leptin signals adequate energy from food intake; malnourished children have significantly reduced circulating leptin levels. Leptin is a hormone with pleiotropic effects, including regulation of the immune system. Leptin is thought to signal energy availability and could play a critical role in controlling the functional capabilities of immune cells. A mutation in the leptin receptor, Q223R, was found to increase susceptibility to Entamoeba histolytica in a cohort of children in Dhaka, Bangladesh. Using a murine model expressing either wild-type Q223 receptor or mutant R223 receptor, we investigated the effect of this mutation on the host’s ability to respond to an E. histolytica infection. We found that neutrophil influx to the site of the infection was reduced early after infection in R223 mice, and that neutrophil influx was important for amebic clearance. Leptin expression was increased in the cecum after infection, and we further observed that R223 neutrophils did not chemotax towards leptin to the same extant as wild-type neutrophils. This suggests that a plausible mechanism of susceptibility is reduced neutrophil migration towards the leptin expressed at the site of inflammation due to the diminished signaling capability of the R223 leptin receptor, ultimately resulting in a smaller neutrophil population unable to clear E. histolytica. This result sheds light on the effect that reduced leptin could have in malnutrition, and as this is a common mutation could represent a common defense mechanism against infection.
Malnutrition in children cannot always be rescued by nutritional supplementation. It has been modelled that stunting would only be reduced by a third if all cases of malnutrition were treated with food therapy. Oral vaccines such as the oral polio vaccine also have reduced efficacy in malnourished populations. Environmental enteropathy, a condition of chronic enteric inflammation seen in developing countries, is thought to play a role in exacerbating or causing malnutrition. The causes of environmental enteropathy are not clear, but repeated enteric infections could be a source. We evaluated markers of enteric inflammation in a cohort of children in Dhaka, Bangladesh, to determine association with malnutrition and oral polio vaccine performance. We also measured enteric infections, nutrition, and markers of systemic inflammation. We found that up to 82% of the children had abnormally high levels of enteric inflammatory markers, and high enteric pathogen presence. Markers of both enteric and systemic inflammation correlated with malnutrition, as well as with oral polio vaccine antibody response. We also found that diarrheal incidence did not correlate with enteric inflammation, but with systemic inflammation. This result suggested that environmental enteropathy could be the result of subclinical enteric infections, while overt disease drove a more systemic response. Furthermore, both pathways can result in malnutrition. These results have exciting implications for how we consider the interaction of nutrition with inflammation.