A link has been established between gut disease and brain injury in premature babies.
In a landmark study, the way by which necrotizing enterocolitis (NEC) – a potentially lethal inflammatory condition that destroys a premature infant’s intestinal lining – is linked to the brain has been discovered for the first time.
Working with mice, researchers at Johns Hopkins Medicine and the University of Lausanne in Switzerland have identified an immune system cell which travels from the gut to the brain and attacks cells rather than protect them as it normally does.
Statistics show that as many as 12 per cent of babies weighing under 3.5lbs at birth are affected by NEC, a rapidly progressing gastrointestinal condition in which bacteria invade the wall of the colon and cause inflammation that can ultimately destroy healthy tissue. If a hole is created in the intestinal wall, bacteria can enter the bloodstream and cause life-threatening sepsis.
In a 2018 mouse study, researchers at Johns Hopkins Medicine and the Fred Hutchinson Cancer Research Center found that animals with NEC make a protein called toll-like receptor 4 (TLR4) that binds to bacteria in the gut and precipitates the intestinal destruction.
They also determined that TLR4 simultaneously activates immune cells in the brain known as microglia, leading to white matter loss, brain injury and diminished cognitive function – although the link at that time was not established.
“Our research strongly suggests that helper T cells from intestines inflamed by NEC can migrate to the brain and cause damage,” says lead study author David Hackam, surgeon-in-chief at Johns Hopkins Children’s Center and professor of surgery at the Johns Hopkins University School of Medicine.
“The mouse model in our study was previously shown to closely match what occurs in humans, so we believe that this is the likely mechanism by which NEC-related brain injury develops in premature infants.”
The team’s findings are published in the journal Science Translational Medicine.
In the first of a series of experiments, the researchers induced NEC in infant mice and then examined their brains. As expected, the tissues showed a significant increase in CD4+ T cells as well as higher levels of a protein associated with increased microglial activity.
In a follow up test, the researchers showed that mice with NEC had a weakened blood-brain barrier. This could, the researchers surmised, explain how CD4+ T cells from the gut could travel to the brain.
Next, the researchers determined that accumulating CD4+ T cells were the cause of the brain injury seen with NEC, by biologically blocking the movement of the helper T cells into the brain and then in a separate experiment, neutralising the T cells by binding them to a specially designed antibody.
To further define the role of CD4+ T cells in brain injury, the researchers harvested T cells from the brains of mice with NEC and injected them into the brains of mice bred to lack both T and B lymphocytes. Compared with control mice that did not receive any T cells, the mice that did receive the lymphocytes had higher levels of the chemical signals which attract killer T cells.
Researchers further found that a specific chemical signal from the T cells – an inflammatory protein known as interferon-gamma (IFN-gamma) – increased in the organoids as the amount of myelin decreased. This activity was not seen in the organoids that received CD4+ T cells from mice without NEC.
The researchers concluded that IFN-gamma directs the process leading to NEC-related brain injury. Their finding was confirmed when an examination of brain tissues from mice with NEC revealed higher levels of IFN-gamma than in tissues from mice without the disease.
This finding was confirmed by genetically sequencing the same portions from both the brain-derived and gut-derived T lymphocytes from mice with and without NEC. The sequences of the helper T cells from mice with NEC, on average, were 25 per cent genetically similar while the ones from mice without NEC were only two per cent alike.
