Study Sheds Light on Oral Vaccine Failure in Mouse Model of Chronic Bowel Disorder

A chronic intestinal disorder that occurs in areas with poor sanitation disrupts intestinal immune responses and impairs the effectiveness of the oral vaccine in a mouse model of the disease, according to research conducted by scientists at UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh School of Medicine.

The report, published today in Immunity, is important because oral vaccines given by liquid drops in the mouth, such as polio and rotavirus vaccines, are particularly useful in low-income countries which may not have health workers trained in the administration of vaccines with needles. They can also stimulate better local immunity in the gut, which is essential for fighting diseases contracted from contaminated food and water -; including some of the same infections that contribute to bowel disorders, called environmental enteric dysfunction, or EED.

It is tragic that the exact vaccines that could help prevent EED are not working in children with the disease. ”

Timothy Hand, Ph.D., lead author of the study and Assistant Professor of Pediatrics and Immunology at the RK Mellon Institute for Pediatric Research at UPMC Children’s and Director of Pitt’s Gnotobiotic Core

EED is caused by malnutrition and chronic gastrointestinal infections caused by contaminated food and water. Infection with viruses, parasites or bacteria combined with a poor diet can trigger inflammation in the gut and damage finger-shaped projections called villi that help absorb nutrients from food.

“EED can affect anyone, but it’s a major problem in children because they’re still developing,” Hand said. “The result is that children with EED are stunted. They end up getting a smaller size. But perhaps more importantly, it can significantly affect brain development: these children have less cognitive ability. And this is an ongoing problem; you cannot restore that. development later in life. “

To learn more about the mechanisms behind oral vaccine failure, Hand and his team developed a mouse model of the disease. They induced EED-like symptoms by feeding rodents a diet deficient in fat and protein and inoculating them with a strain of E. coli bacteria that invades intestinal cells.

Like humans with the disease, EED mice exhibited growth retardation, changes in the composition of the gut microbiome, elevated intestinal inflammation, and shortened intestinal villi compared to control mice that were given a normal diet with sufficient fat. and protein or animals that have received a normal diet and bacteria or a poor diet without bacteria.

After giving the mice an oral vaccine, the researchers found that immune responses were severely compromised in people with EED. Vaccine-specific CD4 + T cells in the small intestine were approximately 18-fold lower than in control mice.

Further experiments indicated that oral vaccine failure in EED mice was mediated by their gut microbiome. In response to inflammation associated with the microbiome, regulatory T cells (Treg) accumulate in the small intestine of EED mice.

“Treg cells appear because there is too much inflammation and they help alleviate that inflammation,” Hand said. “But unfortunately, a side effect is that they prevent the local build-up of vaccine-specific CD4 + T cells.”

When the team used antibiotics to kill gut bacteria, the vaccine’s efficacy was restored in EED mice.

According to Hand, these findings support the idea that targeting the microbiome could help treat PAD and improve vaccine success in children.

“The judicious use of antibiotics in these children may be able to reset the microbiome of the small intestine, reduce inflammation in the small intestine, and reduce these Tregs,” he said.

EED is rare in resource-rich countries but common in poorer countries that lack sewage and sanitation systems. About 150 million children around the world live in conditions that put them at risk of contracting the disease.

“If we could put flush toilets and plumbing in the world, we wouldn’t have this disease,” Hand said. “What causes these chronic infections is that people drink contaminated water or that flies carry diseases from sewage to food.”

Going forward, Hand and his team plan to collaborate with researchers in countries where PED is a problem to better understand vaccine outcomes in children with this disease.

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