Moderate Acute Malnutrition: Inflammatory Response, Microbiota, and Potential Treatments

Acute malnutrition is directly or indirectly responsible for nearly half of all deaths in children under five. Even when treatment is provided in a timely manner, some children fail to recover and others relapse within months. Recovery has traditionally been measured by anthropometric scores, but metabolic and immunological recovery takes longer than weight gain. Thus, markers are needed that signify recovery not just of weight, but of metabolism and immunity. An understanding of the underlying pathology of malnutrition is required to identify markers that indicate full recovery. While the pathology of SAM and resultant attenuated inflammatory response have been characterized, there is minimal and often conflicting data available about the effects of MAM on inflammation and response to inflammatory stimuli. In this work, we observed increased inflammatory cytokine production at baseline and in response to LPS in whole blood of children with MAM. These children also exhibited signs of impaired fatty acid metabolism, intestinal damage, and liver dysfunction. Markers of these dysfunctions (iFABP and LBP) may have potential as markers of recovery from MAM. Studies in a mouse model of MAM corroborated the chronic inflammatory state and metabolic dysfunction observed in children. MN mice also exhibited intestinal dysbiosis and increased bacterial translocation. Use of the antibiotic vancomycin further exacerbated intestinal dysbiosis in MN mice by increasing the proportion of Gammaproteobacteria; these mice also had increased inflammatory cytokine response to LPS challenge. Conversely, MN mice fed anti-inflammatory omega-3 PUFAs exhibited heightened intestinal immune function, decreased proportion of intestinal Gammaproteobacteria, and reduced inflammatory response during intradermal LPS challenge. Malnutrition-induced expansion of Gammaproteobacteria may therefore drive systemic inflammation and inflammatory response via heightened exposure to LPS. Mice fed omega-3 PUFAs were also able to better maintain weight during systemic LPS challenge, suggesting that omega-3 supplementation may provide protection from malnutrition-related morbidity even during the recovery process. These results provide new insight into the pathology of MAM and identify targets for intervention and monitoring during the course of treatment.