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A study of patients with a chronic intestinal condition has helped demystify—but not totally solve—a puzzling disorder that is widespread in low-and middle-income countries, but is largely unseen in wealthier regions of the world.

The condition is called environmental enteropathy. Environmental enteropathy is a subclinical condition of the small intestine that is highly prevalent in low- and middle income countries. While it is relatively common, it remains a stubbornly mysterious malady and a cure is nowhere in sight. The intestinal disorder is characterized by inflammation without overt diarrhea, occurring primarily in people exposed over extended amounts of time to poor sanitation and hygiene.

The small intestine in patients with intermediate (left) and severe (right) environmental enteropathy. Credit: C. Kummerlowe, et al., Science Translational Medicine (2022)

Pathologically, the disorder's biggest impact is on the small intestine's villi, the finger-like projections that are intimately involved with the absorption of nutrients. Instead of their usual configuration, the villi in these patients are blunted and inflamed. The disorder affects millions of children and adults worldwide, and is a risk factor for a host of additional debilitating side effects. Scientists attribute the condition to repeated exposure to bacteria that infect the intestinal tract.

The environmental enteropathy is responsible for a significant number of side effects. It is thought to be a key contributing factor to childhood malnutrition, growth stunting, and diminished oral vaccine responses.

Interventions based on the implementation of sanitation and hygiene measures have so far failed to prevent environmental enteropathy. More puzzling still, efforts to develop treatments have stalled due to a poor understanding the condition's core mechanisms.

The team studied the cellular and molecular signatures of environmental enteropathy and performed RNA sequencing on 11 people from Lusaka Zambia, all of whom were diagnosed with environmental enteropathy. The scientists additionally sequenced the RNA of adult controls from the United States and South Africa. Their aim was to compare samples of the three groups and determine the biological impact of a medical condition caused by devastating environmental conditions.

In the Zambian patients, the study's tests revealed damaged epithelial cells and impaired villi. The vast rows of finger-like structures are arrayed inside the inner walls of the small intestine. Their role in the gut is to absorb digested food. Each villus contains a network of blood vessels close to its surface, which is where nutrients are drawn in.

The team were able to link classic environmental enteropathy signatures, especially stunted intestinal villi, to an unusually high abundance of surface mucosal cells and impairments throughout the small intestine.

Additionally, individuals with environmental enteropathy had disruptions in two key signaling pathways, the study revealed. The WNT and MAPK pathways were both flawed, and there was excessive inflammatory activity involving a subset of tissue-resident memory T cells.

The initials WNT are a portmanteau derived from the terms Wingless and Int-1. In healthy cells, the WNT signaling pathway can use either nearby cell-to-cell signaling or signaling within individual cells. Damage to the WNT signaling pathway can lead to serious medical conditions, such as breast, prostate and brain tumors. Pathway disruptions are also associated with type 2 diabetes.

MAPK stands for mitogen-activated protein kinase. A mitogen is a small biologically active protein or peptide that triggers a cell to begin cell division. Known as either MAP kinase or MAPK signaling, the pathway is involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammatory cytokines.

The team concluded that a therapeutic treatment that targets these pathways might provide a method of medical intervention for people diagnosed with environmental enteropathy.

Conner Kummerlowe et al, Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation, Science Translational Medicine (2022). DOI: 10.1126/scitranslmed.abi8633

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