Summary

Severe acute malnutrition (SAM) is a high morbidity and mortality condition characterised by very low weight-for-height (wasting). Children with high levels of blood and gut inflammatory mediators have worse clinical outcomes than children with less overt inflammation for reasons that are unclear. One theory is that increased immune cell activation can affect the epithelial cells that make up the gut barrier, leading to reduced gut function and more serious infections and inflammation.

Our unpublished data indicate that circulating levels of mediators associated with activation of monocytes, a type of circulating innate immune cell, and pro-inflammatory monocyte responses to bacteria are altered by SAM, suggesting that monocytes may play a role in this process. In this project we will assess whether monocytes exposed to the pro-inflammatory environment of children with SAM impair gut barrier function using laboratory models. To do this, we will co-culture THP-1 cells, a monocyte-like cell line, with blood samples collected from children admitted to hospital with SAM versus blood from healthy control children. SAM- and control-exposed THP-1 cells will then be added to gut epithelial cell monolayers and gut-on-a-chip models so that we can compare their impact on gut epithelial barrier functions including monolayer integrity, cell death, monocyte binding to the epithelial surface, proinflammatory signalling and mediator release.

This work will establish a proof-of-principle that monocytes may play a role in the negative health effects of SAM and validate laboratory methods for future studies of gut barrier function in paediatric malnutrition.