Diet and specific microbial exposure trigger features of environmental enteropathy in a novel murine model

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.

Causes of Impaired Oral Vaccine Efficacy in Developing Countries

“…These manifestations may begin to appear soon after birth: during a study in India, the majority of infants displayed some degree of villous blunting within the first 30 days of life [164]. The precise etiology of EED is unclear; however, it appears to be associated with poor environmental conditions, and in a murine model, inadequate diet and repeated microbial exposure were sufficient to promote the features of EED [165].…”

“…These manifestations may begin to appear soon after birth: during a study in India, the majority of infants displayed some degree of villous blunting within the first 30 days of life [164]. The precise etiology of EED is unclear; however, it appears to be associated with poor environmental conditions, and in a murine model, inadequate diet and repeated microbial exposure were sufficient to promote the features of EED [165].Owing to its pervasive nature in developing countries and the changes in intestinal immune function with which it is likely associated, EED has been hypothesized to play a key role in shaping geographic trends in oral vaccine performance [162,166,167]. Specific inhibitory effects might include the induction of a hostile pro-inflammatory state in the small intestine, the increased production of short-chain fatty acids or other immunomodulatory molecules that are inhibitory to oral vaccines, and the dampening of immune responses due to alterations in regulatory T-cell or dendritic-cell function [168].…”

Antibacterial and ciprofloxacin modulating activity of Ptaeroxylon obliquum (Thunb.) Radlk leaf used by the Xhosa people of South Africa for the treatment of wound infections

“…are opportunistic bacteria that trigger environmental enteropathy in malnourished condition. [30] These bacteria have been affiliated with multidrug resistance genes that pose a serious challenge in both hospital and community settings, thus necessitating discovery of new drugs. [31] Similarly, Streptococcus spp.…”

Metabolic derangements identified through untargeted metabolomics in a cross-sectional study of Nigerian children with severe acute malnutrition

“…Additionally, specific taxa capable of causing enteropathy when combined with a low protein diet have been identified in mice (Brown et al 2015). Enteropathy resulting in malabsorption and increased intestinal permeability is associated with SAM in humans, as indicated by intestinal biopsies and dual sugar permeability tests (Denno et al 2014).…”

“…This phenomenon may be a more severe form of environmental enteric dysfunction (EED), which occurs almost universally in people exposed to poor hygiene and sanitation. The etiology of enteropathy in SAM is not well understood, but may involve repeated exposure to fecal enteropathogens combined with a low protein diet (Hashimoto et al 2012;Brown et al 2015).…”