image: Healthy mouse intestine with long, finger-like villi (left) and intestine of mouse with environmental enteric dysfunction with shortened villi (right). view more
Credit: Amrita Bhattacharjee
PITTSBURGH, Aug. 3, 2021 – A chronic gut disorder that occurs in regions with poor sanitation disrupts intestinal immune responses and impairs oral vaccine effectiveness in a mouse model of the disease, according to research led by UPMC Children’s Hospital of Pittsburgh and University of Pittsburgh School of Medicine scientists.
The finding, published today in Immunity, is important because oral vaccines delivered by liquid drops to the mouth, such as polio and rotavirus vaccines, are especially useful in low-income countries that may not have health care workers trained in administering vaccines through needles. They may also stimulate better local immunity in the gut, which is key for fending off diseases contracted by contaminated food and water — including some of the very infections that contribute to the gut disorder, called environmental enteric dysfunction, or EED.
“It is tragic that the exact vaccines that might help prevent EED don’t work in children who have the disease,” said Timothy Hand, Ph.D., senior author of the study and assistant professor of pediatrics and immunology at the R.K. Mellon Institute for Pediatric Research at UPMC Children’s and director of Pitt’s Gnotobiotic Core.
EED is caused by malnutrition and chronic gastrointestinal infection from contaminated food and water. Infection with viruses, parasites or bacteria combined with poor diet can trigger gut inflammation and damage the finger-like 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,” said Hand. “The result is that children with EED are stunted. They end up shorter in stature. But perhaps more importantly, it can significantly affect brain development: These children have less cognitive ability. And this is a lifelong problem; you can’t 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 the rodents a diet deficient in fat and protein and inoculating them with a strain of E. coli bacteria that invades gut cells.
Like humans with the disease, EED mice had stunted growth, shifts in the gut microbiome composition, elevated gut inflammation and shortened gut villi compared with control mice that received a normal diet with adequate fat and protein or animals that 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 those with EED. Vaccine-specific CD4+ T cells in the small intestine were about 18 times lower than in control mice.
Further experiments indicated that oral vaccine failure in EED mice was mediated by their gut microbiome. In response to microbiome-associated inflammation, T regulatory (Treg) cells accumulate in the small intestine of EED mice.
“Treg cells arise because there’s too much inflammation and they help tamp down that inflammation,” said Hand. “But unfortunately, a side effect is that they prevent local accumulation of vaccine-specific CD4+ T cells.”
When the team used antibiotics to eliminate gut bacteria, vaccine effectiveness was restored in EED mice.
According to Hand, these findings support the idea that targeting the microbiome could help treat EED and improve vaccine success in children.
“Judicious use of antibiotics in these children might be able to reset the small intestinal microbiome, reduce inflammation in the small intestine and reduce those Tregs,” he said.
EED is rare in resource-rich countries but common in poorer countries that lack sewage systems and sanitation. About 150 million children worldwide live in conditions that put them at risk of getting the disease.
“If we could get flush toilets and plumbing to the world, we wouldn’t have this disease,” said Hand. “What’s causing these chronic infections is that people are either drinking contaminated water or flies are transporting diseases from sewage to food.”
In the future, Hand and his team plan to collaborate with researchers in countries where EED is a problem to better understand vaccine outcomes in children with this disease.
Additional authors on the research are Amrita Bhattacharjee, Ph.D., Ansen H.P. Burr, Abigail E. Overacre-Delgoffe, Ph.D., Justin T. Tometich and Brydie R. Huckestein, all of Pitt or UPMC, or both; Deyi Yang, of UPMC and Central South University, China; Jonathan L. Linehan, Ph.D., Sean P. Spencer, M.D., Ph.D., Jason A. Hall, Ph.D., Oliver J. Harrison, Ph.D., Denise Morais da Fonseca, Ph.D., and Yasmine Belkaid, PhD., all of the National Institutes of Health; and Elizabeth B. Norton, Ph.D., of Tulane University.
This research was supported by National Institutes of Health awards R21AI142051, 2015/25364-0 and T32AI089443, the R.K. Mellon Institute for Pediatric Research and UPMC Children’s Hospital of Pittsburgh.
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About UPMC Children’s Hospital of Pittsburgh
Regionally, nationally, and globally, UPMC Children’s Hospital of Pittsburgh is a leader in the treatment of childhood conditions and diseases, a pioneer in the development of new and improved therapies, and a top educator of the next generation of pediatricians and pediatric subspecialists. With generous community support, UPMC Children’s Hospital has fulfilled this mission since its founding in 1890. UPMC Children’s is recognized consistently for its clinical, research, educational, and advocacy-related accomplishments, including ranking in the top 10 on the 2021-2022 U.S. News Honor Roll of America’s Best Children’s Hospitals. UPMC Children’s also ranks 15th among children’s hospitals and schools of medicine in funding for pediatric research provided by the National Institutes of Health (FY2019).
About the University of Pittsburgh School of Medicine
As one of the nation’s leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1998. In rankings recently released by the National Science Foundation, Pitt ranked fifth among all American universities in total federal science and engineering research and development support.
Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region’s economy. For more information about the School of Medicine, see www.medschool.pitt.edu.
Journal
Immunity
Method of Research
Observational study
Subject of Research
People
Article Publication Date
3-Aug-2021