An Exposome Perspective on Environmental Enteric Dysfunction.

BACKGROUND: Environmental exposures to chemicals have been shown to influence gastrointestinal function, yet little is known regarding whether chemical mixtures may be involved in the development of a subclinical enteric dysfunction found in infants and children born into poor hygiene and sanitation. Advances in gastrointestinal and immunotoxicology fields merit inclusion in complex discussions of environmental enteric dysfunction (EED) that severely affects children in developing countries. OBJECTIVE: We aimed to highlight exposome approaches for investigating the potential influence of environmental chemical exposures on EED development, including a role for toxicant modulation of gut immune system and microbiome function. DISCUSSION: A major focus on fecal-oral contamination in impoverished living conditions already exists for EED, and should now expand to include environmental chemicals such as pesticides and heavy metals that may be anthropogenic or dietary or from microbial sources. A comprehensive characterization of environmental chemical exposures prenatally and occurring in infants and young children will enhance our knowledge of any associated risks for EED and stunting. CONCLUSIONS: Integrating EED, chemical exposure, and stunting at various ages during childhood will enhance our apparent limited view when evaluating EED. Etiology and intervention studies should evaluate the suite of environmental chemical exposures as candidates in the composite of EED biomarkers. CITATION: Mapesa JO, Maxwell AL, Ryan EP. 2016. An exposome perspective on environmental enteric dysfunction. Environ Health Perspect 124:1121-1126; http://dx.doi.org/10.1289/ehp.1510459.

Catechols in caffeic acid phenethyl ester are essential for inhibition of TNF-mediated IP-10 expression through NF-κB-dependent but HO-1- and p38-independent mechanisms in mouse intestinal epithelial cells.

SCOPE: Caffeic acid phenethyl ester (CAPE) is an active constituent of honeybee propolis inhibiting nuclear factor (NF)-κB. The aims of our study were to provide new data on the functional relevance and mechanisms underlying the role of CAPE in regulating inflammatory processes at the epithelial interface in the gut and to determine the structure/activity relationship of CAPE. METHODS AND RESULTS: CAPE significantly inhibited TNF-induced IP-10 expression in intestinal epithelial cells. Using various analogues, we demonstrated that substitution of catechol hydroxyl groups and addition of one extra hydroxyl group on ring B reversed the functional activity of CAPE to inhibit IP-10 production. The anti-inflammatory potential of CAPE was confirmed in ileal tissue explants and embryonic fibroblasts derived from TNF(ΔARE/+) mice. Interestingly, CAPE inhibited both TNF- and LPS-induced IP-10 production in a dose-dependent manner, independently of p38 MAPK, HO-1 and Nrf2 signaling pathways. We found that CAPE did not inhibit TNF-induced IκB phosphorylation/degradation or nuclear translocation of RelA/p65, but targeted downstream signaling events at the level of transcription factor recruitment to the gene promoter. CONCLUSION: This study reveals the structure-activity effects and anti-inflammatory potential of CAPE in the intestinal epithelium.