Food chain mycotoxin exposure, gut health, and impaired growth: a conceptual framework

Abstract

Childhood stunting is an important and intractable public health problem that underlies ~20% of deaths among children aged <5 y in developing countries. Environmental enteropathy (EE), a subclinical condition of the small intestine characterized by reduced absorptive capacity and increased intestinal permeability, is almost universal among children in developing countries and may mediate stunting. However, the etiology of EE is poorly understood. Mycotoxins are metabolites of fungi that frequently contaminate the staple foods of children living in developing countries. We review evidence from human and animal studies that exposure to mycotoxins, particularly aflatoxin (AF), fumonisin (FUM), and deoxynivaenol (DON), may impair child growth. Although these toxins have distinct actions, they all mediate intestinal damage through: 1) inhibition of protein synthesis (AF, DON); 2) an increase in systemic proinflammatory cytokines (DON); and 3) inhibition of ceramide synthase (FUM). The intestinal pathology that arises from mycotoxin exposure is very similar to that of EE. We propose that future studies should address the role of mycotoxins in the pathogenesis of EE and evaluate interventions to limit mycotoxin exposure and reduce childhood stunting.

Figure 1

A conceptual framework for the effect of mycotoxin exposure on growth retardation. The proposed pathways are: 1) inhibition of protein synthesis (AF, DON); 2) increase in systemic cytokines (DON); and 3) inhibition of ceramide synthase (FUM). Inhibition of protein synthesis can result in physical alterations to the intestine, leading to malabsorption of nutrients and impaired intestinal barrier function, similar to the pathology in EE. Increases in systemic cytokines can lead to impaired hepatic protein synthesis and reduced production of IGF-ALS and IGF-1. DON inhibits protein synthesis, which affects several important proteins, including claudin-4, SGLT1, GLUT5, L-serine transporters, IGF-1, and IGF-ALS. Claudin-4 is important in the proper functioning of tight junctions, and reduced expression of claudin-4 increases intestinal permeability. Reduced expression of SGLT1, GLUT5, and L-serine transporters leading to glucose-galactose malabsorption and impaired reabsorption of water in the colon may cause diarrhea, which could affect intestinal permeability as well as the uptake of key nutrients such as copper and zinc. IGF-1 mediates the effects of growth hormone, which is required for linear growth; the ALS forms a ternary complex with IGF-1 and its major binding protein (IGFBP3). FUM-induced inhibition of ceramide synthase affects sphingolipid metabolism, which compromises the cellular wall and may also lead to increased intestinal permeability directly or by inhibiting regeneration of the epithelial barrier. AF, aflatoxin; DON, deoxynivalenol; FUM, fumonisin; GLUT 5, fructose transporter; IGF, insulin-like growth factor; IGF-ALS, insulin-like growth factor acid labile subunit.