Diarrhea is no longer the killer it was in the mid-20th century, when an estimated 4.5 million children under the age of 5 died from it each year. Although life-saving oral rehydration therapy has reversed the trend, it does not prevent infection. Millions of children in low- and middle-income countries still suffer from repeated bouts of diarrhea that weaken their bodies and make them vulnerable to malnutrition and stunting, and less able to fight off a wide range of infections .
Researchers at Washington University School of Medicine in St. Louis have determined, in studies of human cells as well as mice, how certain types of diarrhea-causing diseases Escherichia coli (E.coli) bacteria damage the intestines and cause malnutrition and stunted growth. And they showed that vaccination against a toxin produced by E.coli protects infant mice from intestinal damage.
The results suggest that a vaccine against this type of E.coli could spur global efforts to ensure that all children not only reach age 5, but thrive. The study is available online in Nature Communications.
“Ideally, we would like to have a vaccine that prevents acute diarrhoea, which still kills half a million children a year, and also protects against long-term effects such as malnutrition, which is perhaps the greatest part of the problem now,” said lead author James M. Fleckenstein, MD, professor of medicine and molecular microbiology. “When children are malnourished, their risk of dying from any cause increases . The World Health Organization is deciding how to prioritize vaccines for children in low- and middle-income countries, and I think these data suggest that vaccinating children against E.coli diarrhea could be extremely beneficial in places that struggle with this.
Fleckenstein studies a kind of E.coli called enterotoxigenic E.colior ETEC – so named for the two toxins it produces – and its effects on children who live where the bacteria are rampant. E.coli is a common cause of diarrhea around the world, but strains found in the United States and other high-income countries generally do not carry the same toxins found in low- and middle-income countries. And that can make all the difference.
A 2020 study by Fleckenstein and Alaullah Sheikh, PhD — then a postdoctoral researcher in Fleckenstein’s lab and now an instructor in medicine — indicated that one of ETEC’s two toxins, heat-labile toxin, does more than trigger a case. leak. The toxin also affects gene expression in the gut, increasing genes that help bacteria stick to the gut wall.
In the latest study, Fleckenstein and Sheikh found that the toxin suppresses a whole host of genes related to the lining of the intestines, where nutrients are absorbed. The so-called brush border of the gut is made up of microscopic finger-like projections called microvilli that are packed tightly to the surface of the intestines like bristles on a brush. When Fleckenstein and Sheikh applied the toxin to clumps of human intestinal cells, the brush border disintegrated.
“Instead of being nice and tight and straight with thousands of microvilli per cell, they’re short and fluffy and sparse, a bit like you’ve plucked out most of the hair, and what’s left is a bit jagged,” said said Sheikh, who led the 2020 and current studies. “That alone would negatively impact the body’s ability to absorb nutrients. But on top of that, we found that genes linked to the absorption of specific vitamins and minerals, including vitamin B1 and zinc, were also down-regulated. This could explain some of the micronutrient deficiencies we see in children repeatedly exposed to these bacteria.
Children in low- and middle-income countries tend to have diarrhea repeatedly, and the risk of malnutrition and stunting increases with each episode. By studying baby mice, the researchers discovered that a single infection with E.coli was sufficient to damage the brush border, while repeated infections resulted in severe intestinal damage and growth retardation. Puppies infected with a strain of E.coli who did not have the toxin showed no intestinal damage or growth retardation.
If the toxin is the problem, a toxin-neutralizing immune response can prevent long-term effects, Fleckenstein and Sheikh explained. To find out, they vaccinated mothers of lactating mice with the toxin. The nursing mice are too young to be immunized themselves, but their vaccinated mothers produce antibodies that pass to the young through breast milk. The researchers found that the intestines of infant mice from vaccinated mothers appeared healthy, suggesting that vaccination may protect against intestinal damage leading to malnutrition.
“This is an argument for developing a vaccine against this type of E.colisaid Fleckenstein. “There are lifelong consequences of being infected repeatedly in childhood. Vaccination combined with efforts to improve sanitation and access to clean water could protect children from long-term effects and give them a better chance of a long, healthy life.
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