Why malnutrition is an immune disorder

Malnourished children are most likely to die from common infections, not starvation. New experimental evidence, reviewed May 26 in Trends in Immunology, indicates that even with a healthy diet, defects in immune system function from birth could contribute to a malnourished state throughout life. Researchers speculate that targeting immune pathways could be a new approach to reduce the poor health and mortality caused by under- and overnutrition.

"That traditional image of malnutrition that we're unfortunately so familiar with--of someone wasting away--that's just the external picture," says Review first author Claire Bourke, a postdoctoral research assistant in the Centre for Genomics and Child Health at Queen Mary University of London. "Those height and weight defects that we see are the tip of the iceberg--there are a whole range of pro-inflammatory conditions, impaired gut function, weakened responses to new infections, and a resulting high metabolic burden underlying them."

The most common form of undernutrition globally is stunting -- where children fail to achieve their full height potential. Despite looking healthy, children in developing countries who are stunted in height may also have stunted immune development, making them more vulnerable to death by common infections.

Only recently have researchers had access to technology that can accurately study immunodeficiency. Even though immune parameters in undernourished children have been looked at for decades, much of that data is outdated. How malnutrition and immune function are related is actually still poorly understood; however, there is wide acceptance that malnutrition comes with a range of immune problems. These include reduced numbers of white blood cells, skin and gut membranes that are easier for pathogens to break through, and malfunctioning lymph nodes.

What's also emerging is that the relationship between malnutrition and immune dysfunction may be a bit "chicken and egg," with both causing and being the consequence of the other. Immune dysfunction results when people consume too few calories because of lack of food or have an excess of fat and sugar in their diet. That dysfunction is recorded in the DNA through epigenetic marks, so that if malnourished people have offspring, their children inherit an altered immune system (even after multiple generations). This altered immune system may then cause malnutrition even if children have an adequate diet.

"It's been thought for a long time that the immune system is driving pathology, but new experimental tools have made it possible to separate out the effects of the immune system from those of the diet alone," says Bourke. "There are new models for environmental enteric dysfunction in mice, a growing interest in microbiota and epigenetics--all of these studies show that the more we look into the immune system, the more it has a role to play in a really wide array of physiological systems. It doesn't just fight infection; it affects metabolism, neurological function, and growth, which are things that are also impaired in malnutrition."

Bourke imagines a future where clinicians could generate individualized immune readouts that can identify young people most susceptible to infection as a result of malnutrition. This could reduce the burden of a leading cause of child mortality by helping those who are most vulnerable get treated more often and sooner with targeted interventions.

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