Home Health Chronic disorder occurring only in low, middle income countries prompts study to understand it at molecular level

Chronic disorder occurring only in low, middle income countries prompts study to understand it at molecular level

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Small intestines of patients with moderate (left) and severe (right) environmental bowel disease. Credit: C. Kummerlowe, et al., Science Translational Medicine (2022)

Studies of patients with chronic bowel disease have helped shed light on a mysterious disease prevalent in low- and middle-income countries, but not entirely, but in wealthier parts of the world. Almost never seen.

This condition is called environmental enteropathy. It is relatively common, but remains a stubborn enigma with no cure anywhere. occurs in people. poor hygiene and hygiene.

Pathologically, the greatest impact of the disorder is on the villi of the small intestine, finger-like projections closely involved in the absorption of nutrients. Instead of their usual configuration, the villi in these patients are dulled and inflamed. The disorder affects millions of children and adults worldwide and is a risk factor for many additional debilitating side effects. Scientists believe it is caused by repeated exposure to bacteria that infect the intestinal tract.

“Environmental bowel disease is an asymptomatic disease of the small intestine and is highly prevalent at low and low grade. middle income countrywrites computational biologist Conor Camerlow, along with a large team of colleagues at the Massachusetts Institute of Technology.

report in Science Translational MedicineKummerlowe notes that environmental bowel disease is responsible for a significant number of side effects. It is considered.”

However, interventions based on the implementation of hygiene and hygiene measures have so far failed to prevent environmental enteric disease. Even more puzzling, efforts to develop treatments are stalled by a poor understanding of the core mechanisms of this condition.

Undaunted by the lack of a detailed catalog of data on environmental bowel disease, Kummerlowe and colleagues decided to study the disease at the molecular level. cell level— to understand the state at its most basic roots. This pursuit will help shine a spotlight on a vast number of commonly overlooked diseases and could spark a new wave of research to better understand them. Unlike environmental bowel disease, many other neglected conditions cause life-threatening acute diarrhea. As with environmental enteropathy, all are strongly associated with poor sanitation.

On a macro scale, inadequate clean water supplies, lack of toilets, inadequate sanitation, and lack of sanitation measures continue to coalesce in many parts of the world, affecting tens of millions of people. creating a chain of infections.

Open defecation, contaminated water, and lack of simple hand washing underlie bouts of diarrhea caused by bacteria, amoebas, and parasites. Transmission of these organisms is usually via the fecal-oral route, say global health experts.

For more than 20 years, the United Nations has promoted the WASH programme, an acronym for water, sanitation and hygiene. This is part of the agency’s efforts to improve the health of the environment and eradicate diseases that are often preventable through simple means.

An estimated 1 billion people worldwide still defecate in the open. Even more alarming, tens of millions of people worldwide (an estimated 750 million) lack access to a daily clean supply of safe drinking water. According to United Nations data, diarrhea has killed an estimated 2,300 people every day in recent years, mostly children. Given the scale of harmful environmental exposures, it is no coincidence that chronic disease (environmental bowel disease) has become a global health problem.

their Science Translational Medicine Kummerlowe and the MIT team reportedly studied cellular and molecular signatures of environmental bowel disease, RNA-sequencing 11 people from Lusaka, Zambia, all of whom were diagnosed with environmental bowel disease. .

The scientists also sequenced the RNA of US and South African adult controls. Their aim was to compare samples from three groups and determine the biological effects of disease states caused by devastating environmental conditions.

“Single-cell RNA sequencing has been shown to be a powerful tool for understanding the pathophysiology of many diseases,” said Kummerlowe, who turned to RNA-sequencing technology, noting that it could help people I knew that it was possible to clarify the molecular characteristics of epithelial remodeling in the small intestine, and asserted. With environmental bowel disease.

“We performed high-throughput single-cell RNA-sequencing on 33 small-bowel biopsies obtained from 11 adults with environmental bowel disease in Lusaka, Zambia, to clarify the pathogenesis of environmental bowel disease. We mapped cellular and molecular correlations: eight HIV-negative and three HIV-positive: adults without environmental bowel disease in Boston, USA, and two adults in Durban, South Africa,” said Kummerlowe. .

In Zambian patients, research tests revealed damaged epithelial cells and damaged villi. The inner wall of the small intestine is lined with countless finger-like structures. Its role in the intestine is to absorb digested food. Each villus contains a network of blood vessels near its surface where nutrients are drawn.

Kummerlowe and team were able to link classic environmental bowel disease hallmarks, specifically underdeveloped intestinal villi, to abnormally abundant surface mucosal cells and dysfunction throughout the small intestine.

In addition, studies revealed that patients with environmental bowel disease had impairments in two major signaling pathways. Both the WNT and her MAPK pathways were defective and there was excessive inflammatory activity involving a subset of tissue-resident memory T cells.

The initials WNT are portmanteau words 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 pathologies such as breast, prostate and brain tumors. Pathway disruption is also associated with type 2 diabetes.

MAPK stands for mitogen-activated protein kinase. Mitogens are small biologically active proteins or peptides that trigger cells to initiate cell division. This pathway, known as MAP kinase or MAPK signaling, is involved in inducing cellular responses to diverse stimuli such as mitogens, osmotic stress, heat shock, and proinflammatory cytokines.

The Kummerlowe and MIT team concluded that therapies targeting these pathways may offer avenues of medical intervention for people diagnosed with environmental bowel disease.

“By comparing samples of duodenal environmental enteropathy with samples from three control cohorts, we have highly elucidated the dysregulation of WNT and MAPK signaling in environmental enteropathy epithelia and the transcriptional signature of tissue-resident memory cells.” We identified increased pro-inflammatory cytokine gene expression in a T-cell subset expressing an environmental bowel disease cohort,” Kummerlowe added, adding, “Our study elucidates the epithelial-immune correlation of environmental bowel disease. , to nominate cellular and molecular targets for intervention.

For more information:
Conner Kummerlowe et al, Single-cell profiling of environmental bowel disease reveals signs of epithelial remodeling and immune activation, Science Translational Medicine (2022). DOI: 10.1126/scitranslmed.abi8633

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