Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation in severe disease

Abstract

Environmental enteropathy (EE) is a subclinical condition of the small intestine that is highly prevalent in low- and middle-income countries. It is thought to be a primary cause of most global growth-stunting cases and a key contributing factor to childhood malnutrition and diminished oral vaccine responses. While EE has been shown to be the by-product of recurrent enteric infection, to date, its full pathophysiology remains unclear. Here, we mapped the cellular and molecular correlates of EE severity by performing high-throughput single-cell RNA-sequencing on 33 small intestinal biopsies from 11 adults with EE from Lusaka, Zambia (8 HIV-negative, 3 HIV-positive) and 6 adults without EE in Boston, USA. Using the resulting cellular atlas, we scored existing bulk-transcriptomic signatures of reduced villus height and decreased plasma LPS levels in EE, finding that these signatures may be driven by an increased abundance of surface mucosal cells–a gastric-like subset previously implicated in epithelial repair in the gastrointestinal tract. In addition, we identified several cell subsets whose fractional abundances associated with histological determined EE severity, small intestinal region, and HIV infection. Furthermore, by comparing distal duodenal EE samples with those from two U.S. control cohorts, we identified broadly decreased epithelial proliferative signaling, lower fractional abundances of goblet cells, and a T cell subset highly expressing a transcriptional signature of tissue-resident memory cells but with increased pro-inflammatory cytokine expression in EE. Altogether, our work illuminates the epithelial and immune correlates of EE severity and provides new molecular targets for intervention.