However, how the diseased intestine ‘communicates’ its devastation to the newborn brain has remained largely unknown
Physicians have long known that necrotizing enterocolitis (NEC), a potentially lethal inflammatory condition that destroys a premature infant’s intestinal lining, is often connected to the development of severe brain injury in those infants who survive. However, how the diseased intestine ‘communicates’ its devastation to the newborn brain has remained largely unknown.
Now, working with mice, researchers at Johns Hopkins Medicine and the University of Lausanne in Switzerland have identified that missing link — an immune system cell that they say travels from the gut to the brain and attacks cells rather than protect them as it normally does.
The team’s findings have been published in the journal Science Translational Medicine.
Seen in as many as 12 per cent of infants weighing less than 3.5 pounds at birth, NEC is a rapidly progressing gastrointestinal emergency in which bacteria invade the wall of the colon and cause inflammation that can ultimately destroy healthy tissue at the site. If enough cells become necrotic (die) so that a hole is created in the intestinal wall, bacteria can enter the bloodstream and cause life-threatening sepsis.
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.
For this study, the researchers speculated that CD4+ T lymphocytes — immune system cells also known as helper T cells — might be the link. CD4+ T cells get their ‘helper’ nickname because they help another type of immune cell called a B lymphocyte (or B cell) respond to surface proteins — antigens — on cells infected by foreign invaders such as bacteria or viruses.
Activated by the CD4+ T cells, immature B cells become either plasma cells that produce antibodies to mark the infected cells for disposal from the body or memory cells that remember the antigen’s biochemistry for a faster response to future invasions.
CD4+ T cells also send out chemical messengers that bring another type of T cell — known as a killer T cell — to the area so that the targeted infected cells can be removed. However, if this activity occurs in the wrong place or at the wrong time, the signals may inadvertently direct the killer T cells to attack healthy cells instead.
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 the increased microglial activity.
In a follow-up test, the researchers showed that mice with NEC had a weakened blood-brain barrier — the biological wall that normally prevents bacteria, viruses, and other hazardous materials circulating in the bloodstream from reaching the central nervous system.