A new model of the newborn human intestine reveals how helpful bacteria activate the processes that lead to a mature, healthy gut, according to a study in eLife.
The research provides important insights into normal gut development after birth, and could help reveal why some infants born prematurely go on to develop an inflammatory condition of the gut known as necrotizing enterocolitis.
Gut microbes have long been appreciated for their driving role in the development of innate immunity in newborns, and more recently the make-up of our gut bacteria has been linked to digestion, metabolism and even ageing. But it remains unclear exactly how the surface of the human intestine adapts to initial colonisation by bacteria – whereby bacteria grow in the intestine without causing infection – and what role this colonisation has in gut development.
One barrier to this understanding is the ethical and practical limitations of studying the intestines of newborn babies; so, in this study, researchers developed a new model using organoids – 3D miniaturised human organs generated from human stem cells.
“We have previously shown that human intestinal organoids (HIOs) closely resemble the immature human intestine,” explains lead author David Hill, Postdoctoral Fellow at the University of Michigan Medical School. “In this study, we wanted to discover the effects of colonisation on the intestine with a non-harmful strain of E. coli bacteria that is commonly found in the guts of newborn babies.”
The team microinjected E. coli into HIOs and achieved stable colonisation of the organoids for several days, allowing for detailed studies.
They started by looking at the effects of E. coli colonization on different genes in the immature intestine. In the presence of the bacteria, they found activation of genes needed for producing antimicrobial substances and mucus, development of new and mature intestinal cells, and adaptation to low oxygen – which is caused by bacterial metabolism and is a hallmark of the mature adult intestine.
The maturation caused by E. coli colonisation led to improvements in intestinal function, including secretion of antimicrobial proteins and production of mucus. These improvements ultimately resulted in enhanced resistance to inflammation-causing stimuli, thereby reducing damage to the intestinal epithelium in the organoids that had been exposed to E. coli.
“Our results show that colonisation of the immature intestinal tract with E. coli results in intestinal tissue that is more robust to challenge by potentially damaging pathogens or inflammatory substances,” concludes senior author Dr. Jason Spence, Associate Professor at the University of Michigan Medical School.
Co-senior author Dr. Vincent Young, Professor at the same institution, adds: “We have developed a system that faithfully reproduces the physiology of the immature human intestine, and will now make it possible to study a range of host-microbe interactions in the intestine to understand their functional role in health and disease.”
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About eLife
eLife aims to help scientists accelerate discovery by operating a platform for research communication that encourages and recognises the most responsible behaviours in science. We publish important research in all areas of the life and biomedical sciences, which is selected and evaluated by working scientists and made freely available online without delay. eLife also invests in innovation through open-source tool development to accelerate research communication and discovery. Our work is guided by the communities we serve. eLife is supported by the Howard Hughes Medical Institute, the Max Planck Society and the Wellcome Trust. Learn more at https://elifesciences.org.
About the University of Michigan Medical School
Since 1850, the U-M Medical School has been a leader in medical and graduate education, patient care and biomedical research. Ranked 9th in the country by U.S. News & World Report, it has an annual research budget of $485 million, a faculty of 3,500 physicians and scientists, and a learning community of more than 3,200 students, medical residents and fellows. It is a vital part of Michigan Medicine, the university’s academic medical center, and of the broader University of Michigan, one of the nation’s premier public institutions. Learn more at http://medicine.umich.edu/medschool.
