A simple gastrointestinal virus can do a lot of damage. There are 100 million neurons scattered along the gastrointestinal tract – right in the line of fire – that can be eradicated by intestinal infections, potentially leading to long-term GI disease.
But an intestinal infection can have an advantage. A new study shows that mice infected with bacteria or parasites develop a unique form of tolerance that is very different from the textbook immune response. The research published in Cell describes how gut macrophages respond to an earlier attack by shielding enteric neurons and preventing them from dying when future pathogens strike. These results may ultimately have clinical implications for conditions such as irritable bowel syndrome, which has been linked to uncontrolled death of bowel neurons.
We are describing a type of innate memory that persists after the primary infection is gone. This tolerance does not exist to kill future pathogens, but to cope with the damage an infection causes – to maintain the number of neurons in the intestine. “
Daniel Mucida, Rockefeller University
Neural cause of death
The enteric nervous system, known as the body’s “second brain”, houses the largest depot of neurons and glia outside the brain itself. The gastrointestinal tract’s own nervous system exists more or less autonomously, with no significant input from the brain. It controls the movement of nutrients and waste through fiat, coordinating local fluid exchange and blood flow with an authority not seen anywhere else in the peripheral nervous system.
When enough of these neurons die, the gastrointestinal tract gets out of control.
Mucida and colleagues reported last year that intestinal infections in mice can kill rodents’ enteric neurons, with catastrophic consequences for intestinal motility. At the time, researchers found that the symptoms of IBS reflected exactly what one might expect if enteric neurons died en masse – increasing the possibility that otherwise minor bowel infections could deplete enteric neurons more in some people than others, leading to constipation and other unexplained gastrointestinal conditions.
The researchers wondered if the body has a mechanism to prevent the loss of nerve cells after infection. In previous work, the lab had actually shown that macrophages in the gut produce specialized molecules that prevent neurons from dying in response to stress.
A hypothesis was taking shape. “We knew that enteric infections cause neuronal loss, and we knew that macrophages prevent neuronal cell death,” says Mucida. “We wondered if we were really looking at a single path. Does a previous infection activate these macrophages to protect the neurons from future infections?”
Bacteria against parasites
Postdoctoral fellow Tomasz Ahrends and other laboratory workers first infected mice with a non-fatal strain of salmonella, a common bacterial source of food poisoning. The mice healed the infection in about a week and lost a number of enteric neurons in the process. They then infected the same mice with another comparable foodborne bacterium. This time the mice suffered no further loss of enteric neurons, suggesting that the first infection had created a tolerance mechanism that prevented neuronal loss.
The scientists found that common parasitic infections also have similar effects. “Unlike pathogenic bacteria, some parasites like helminths have learned to live inside us without unduly damaging the tissues,” he says. In fact, this family of parasites, which includes leeches, tapeworms, and nematodes, infects more subtle ways than highly hostile bacteria. But they also provide even greater and more far-reaching protection.
During a primary bacterial infection, Mucida noted, neurons call macrophages that rush into the area and protect its vulnerable cells from future attack. However, when a helminth creeps into the intestine, T cells recruit the macrophages and even send them to distant parts of the intestine to ensure that the full range of enteric neurons is protected from future damage.
At the end of the day, both bacterial and helminth infections resulted in the protection of gut neurons in a variety of ways.
Next, Ahrends repeated the experiments on mice from a pet store. “Animals in the wild have likely had some of these infections,” he says. “We would expect a preset tolerance to neuronal loss.” In fact, these animals did not suffer any neuronal loss from any infection. “They generally had a lot of helminths,” says Mucida. “The parasitic infections did their job preventing the neuronal loss that we saw in isolated animals in the laboratory.”
A gut feeling
Mucida now hopes to determine the precise effects of the neuronal loss in the GI tract. “We have observed that after neuronal loss, animals use more calories without gaining more weight,” he says. “This could mean that the loss of enteric neurons also affects nutrient absorption, metabolism, and caloric absorption.”
The neural loss can have more consequences than we expected, “he adds.
Mucida believes this research could contribute to a broader understanding of the underlying causes of irritable bowel syndrome and related conditions. “One speculation has been that the number of enteric neurons throughout your life is determined by infections in early childhood that keep you from losing neurons after each subsequent infection,” explains Mucida.
People who do not develop tolerance for any reason may lose enteric neurons for their entire life with any subsequent infection. Future studies will explore alternative methods of protecting enteric neurons and hopefully pave the way for therapies.
Ahrends, T., et al. (2021) Intestinal pathogens induce tissue tolerance and prevent neuronal loss from subsequent infections. Cell. doi.org/10.1016/j.cell.2021.10.004.