Abstract
Environmental enteropathy (EE) is a subclinical chronic inflammatory disease of the small intestine and has a profound impact on the persistence of childhood malnutrition worldwide. However, the aetiology of the disease remains unknown and no animal model exists to date, the creation of which would aid in understanding this complex disease. Here we demonstrate that early-life consumption of a moderately malnourished diet, in combination with iterative oral exposure to commensal Bacteroidales species and Escherichia coli, remodels the murine small intestine to resemble features of EE observed in humans. We further report the profound changes that malnutrition imparts on the small intestinal microbiota, metabolite and intraepithelial lymphocyte composition, along with the susceptibility to enteric infection. Our findings provide evidence indicating that both diet and microbes combine to contribute to the aetiology of EE, and describe a novel murine model that can be used to elucidate the mechanisms behind this understudied disease.
Highlights
Environmental enteropathy (EE) is a subclinical chronic inflammatory disease of the small intestine and has a profound impact on the persistence of childhood malnutrition worldwide
The expression of other claudin transcripts (CLDN4/15) was similar between the groups of mice (Fig. 1e). To measure whether these gene expression changes had a functional impact on barrier function, mice were fed fluorescein isothiocyanate (FITC)-labelled dextran and subsequent FITC levels were measured in the serum
Cultured intraepithelial lymphocytes (IELs) from the duodenum of Bacteroidales– E. coli challenge (BG)-exposed malnourished mice secreted significantly greater quantities of tumour necrosis factor alpha (TNF-a) and interferon gamma (IFN-g), as well as a trend for elevated IL-17A compared with unexposed malnourished and control mice, after T-cell specific stimulation (Fig. 6e). These findings suggest that the malnourished diet is sufficient to induce the IEL influx; heightened cytokine production by these cells is only triggered with exposure to the BG, and this may contribute to the inflammation and villous blunting observed in the BG-exposed malnourished mice
Summary
Environmental enteropathy (EE) is a subclinical chronic inflammatory disease of the small intestine and has a profound impact on the persistence of childhood malnutrition worldwide. The aetiology of EE has not been experimentally demonstrated, but one hypothesis in the literature is that the increased ingestion of faecal-associated bacteria early in life (due to poor sanitation and hygiene) can lead to a pathological shift in microbe–host interactions in the small intestine and chronic inflammation exacerbating malnutrition[15,18,19] This hypothesis would explain the benefit of antibiotic treatment before therapeutic food interventions for malnourished children. We describe the first animal model of EE and we demonstrate that both diet and oral microbial exposure to specific bacteria are required for the induction of EE in a mammalian host Utilizing this model, we were able to achieve for the first time, an in-depth characterization of the impact of malnutrition on the microbiota, metabolism and immune system in the mammalian small intestine, along with assessing the impact of enteric infection.
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