Thymus, undernutrition, and infection: Approaching cellular and molecular interactions

Abstract

Undernutrition remains a major issue in global health. Low protein-energy consumption, results in stunting, wasting and/or underweight, three deleterious forms of malnutrition that affect roughly 200 million children under the age of five years. Undernutrition compromises the immune system with the generation of various degrees of immunodeficiency, which in turn, renders undernourished individuals more sensitive to acute infections. The severity of various infectious diseases including visceral leishmaniasis (VL), influenza, and tuberculosis is associated with undernutrition. Immunosuppression resulting from protein-energy undernutrition severely impacts primary and secondary lymphoid organs involved in the response to related pathogens. The thymus—a primary lymphoid organ responsible for the generation of T lymphocytes—is particularly compromised by both undernutrition and infectious diseases. In this respect, we will discuss herein various intrathymic cellular and molecular interactions seen in undernutrition alone or in combination with acute infections. Many examples illustrated in studies on humans and experimental animals clearly revealed that protein-related undernutrition causes thymic atrophy, with cortical thymocyte depletion. Moreover, the non-lymphoid microenvironmental compartment of the organ undergoes important changes in thymic epithelial cells, including their secretory products such as hormones and extracellular matrix proteins. Of note, deficiencies in vitamins and trace elements also induce thymic atrophy. Interestingly, among the molecular interactions involved in the control of undernutrition-induced thymic atrophy is a hormonal imbalance with a rise in glucocorticoids and a decrease in leptin serum levels. Undernutrition also yields a negative impact of acute infections upon the thymus, frequently with the intrathymic detection of pathogens or their antigens. For instance, undernourished mice infected with Leishmania infantum (that causes VL) undergo drastic thymic atrophy, with significant reduction in thymocyte numbers, and decreased levels of intrathymic chemokines and cytokines, indicating that both lymphoid and microenvironmental compartments of the organ are affected. Lastly, recent data revealed that some probiotic bacteria or probiotic fermented milks improve the thymus status in a model of malnutrition, thus raising a new field for investigation, namely the thymus-gut connection, indicating that probiotics can be envisioned as a further adjuvant therapy in the control of thymic changes in undernutrition accompanied or not by infection.

Primary and secondary defects of the thymus

“…An endogenous rise glucocorticoids is measurable upon emotional, physical, or biological stress events, including infection and starvation, thereby offering a common mechanism underlying thymic atrophy upon different insults. [347][348][349][350][351] When adult mice are implanted with corticosterone-releasing pellets, inducing serum glucocorticoid levels similar to those observed during infections, the thymus size is reduced by more than 80%. 352 In an avian model, intense glucocorticoid treatment leads to similar effects as observed after surgical thymectomy, with a profound reduction of naïve T-cell count in the periphery.…”

“…347 In both undernourished animals and children, the volume of the cortical and medullary epithelial tissue is decreased, and cortico-medullar differentiation is diminished. 15,347 Breastfeeding was associated with larger thymuses compared to formula feeding, possibly due to the presence of human IL-7 in breast milk. 382 Malnutrition-induced thymic atrophy may be mediated by hormonal factors.…”

“…Endogenous rise of androgens and estrogens may occur with age progression and of progestin during pregnancy. An endogenous rise glucocorticoids is measurable upon emotional, physical, or biological stress events, including infection and starvation, thereby offering a common mechanism underlying thymic atrophy upon different insults 347–351 . When adult mice are implanted with corticosterone‐releasing pellets, inducing serum glucocorticoid levels similar to those observed during infections, the thymus size is reduced by more than 80% 352 .…”

“…Thymus atrophy has been reported even in mild malnutrition prospective studies using imaging to measure thymus size 15 . Poor nutrition causes depletion of the intrathymic lymphocyte compartment by apoptosis, particularly of the DP cells 15,347 . Accordingly, even in mildly undernourished mice, there is a significant change of the intrathymic cytokines, with reduced levels of IL‐6, IL‐2, and IL‐4 and increased levels of IFN‐ γ, IL‐10, and TNF‐α 381 .…”

“…Accordingly, even in mildly undernourished mice, there is a significant change of the intrathymic cytokines, with reduced levels of IL‐6, IL‐2, and IL‐4 and increased levels of IFN‐ γ, IL‐10, and TNF‐α 381 . The degree of thymocyte depletion in severely malnourished mice and children correlates with an increase of thymic intralobular connective tissue composed of fibronectin, laminin, and type IV collagen 347 . In both undernourished animals and children, the volume of the cortical and medullary epithelial tissue is decreased, and cortico‐medullar differentiation is diminished 15,347 .…”