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NIAID Study Identifies Immune Sensors of Malnutrition

In a new study, NIAID scientists describe how the immune system responds to malnutrition by adjusting the types of immune cells in the gastrointestinal tract. In a mouse model of vitamin A deficiency, they observed the expansion of type 2 innate lymphoid (ILC2) cells, which are essential for immune responses against nutrient-depleting helminth, or parasitic worm, infections. The study appears in the January 23, 2014, online issue of Science.

map showing global public health significance

Vitamin A deficiency as a public health problem in pre-school age children, 1995–2005.
Credit: World Health Organization

Background

The impact of nutrition on the immune system is an important research focus with broad impact. Vitamin A deficiency is estimated to affect up to 250 million children worldwide, particularly in regions where chronic helminth infections and malnutrition are prevalent. It is the leading cause of preventable blindness in children and is associated with higher rates of severe diarrheal disease.

In the body, vitamin A is broken down into a product called retinoic acid (RA), which is essential for growth and development. RA also is necessary for the immune system, and without it, classes of T cells fail to develop or function, enhancing susceptibility to infections.

Yasmine Belkaid, Ph.D., and her research team in NIAID's Laboratory of Parasitic Diseases reasoned that the immune system compensates for the effects of vitamin A deficiency because people can survive for extended periods of malnutrition. One of the minimum requirements for survival is to maintain immunity at barrier surfaces, like the gastrointestinal tract and lungs. These locations are enriched for innate lymphoid cells, which come in three classes: ILC1, ILC2, and ILC3. The NIAID team sought to examine how vitamin A deficiency impacts ILCs and barrier defenses.

Results of Study

Dr. Belkaid and colleagues used a mouse model of vitamin A deficiency to examine how malnutrition affects immunity along the gastrointestinal tract. In mice lacking vitamin A or RA, the ILC3 subset, which typically provides antibacterial immunity, was diminished in the gut. As such, the malnourished mice were more susceptible to infection with the bacterium Citrobacter rodentium, a model for the disease-causing forms of Escherichia coli.

Surprisingly, however, mice lacking vitamin A or RA had significantly more ILC2 in the gut. The ILC2 subset typically provides immune defense against helminths. Compared to nourished mice, the malnourished ones had similar or even better immune responses against infection with the parasitic worm Trichuris muris.

Significance

This study identifies ILCs as sensors of malnutrition that alter gut immunity in response to diet. For vitamin A deficiency, RA is the key switch that directs these changes. Contrary to common belief, this work shows that nutrient deficiency does not equal global immunosuppression, as antihelminth immunity is actually promoted and enhanced.

The results of this study also correlate with observations of children who suffer from vitamin A deficiency. They are more susceptible to gastrointestinal bacterial infections but also tend to live in areas with chronic helminth infections, which compete with their hosts for essential nutrients.

While more work is needed to address the role of malnutrition on ILCs in people, this shift in cell types may be a response to temporarily boost survival against debilitating helminth infections during malnutrition.

Next Steps

The researchers will examine how other nutrient deficiencies affect the immune system and how this may influence vaccination outcomes. Vaccines are developed to enhance specific immune responses, but the nutritional state of intended recipients is rarely incorporated into studies. Understanding how nutrition affects the immune system promises to help optimize vaccine design and development, particularly for diseases that affect regions where malnutrition is prevalent.

The ILC2 subtype also is important for tissue repair. Understanding how nutrition influences ILC2 activity will provide new insight on effective therapies for inflammatory diseases like Crohn's disease, an inflammatory bowel disorder, and autoimmunity.

Reference

Spencer SP, Wilhelm C, Yang Q, Hall JA, Bouladoux N, Boyd A, Nutman TB, Urban JF Jr, Wang J, Ramalingam TR, Bhandoola A, Wynn TA, Belkaid Y. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science (2014)

In Mouse Study, NIH Investigators Observe the Immune-Boosting Properties of Vitamin A
Dr. Belkaid's lab page

Last Updated January 23, 2014

Last Reviewed January 23, 2014