New research shows that the gut microbiome influences brain development and adult social behavior in zebrafish.
Two recent publications have shown that, during a critical period of brain development, the gut microbiome – the array of bacteria that grow within it – helps shape the brain system with respect to social skills. Scientists have found this flu in fish, but molecular and neurological evidence plausibly suggests that some form of this flu could also occur in mammals , including humans.
In a paper published in early November in PLOS Biology, the researchers found that zebrafish raised without the gut microbiome were significantly less social than their peers with colonized bacteria, and their brain structure reflected this difference. In a related paper published in BMC Genomics in late September, they described the molecular characteristics of neurons influenced by gut bacteria. Equivalents of these neurons appear in rodents, and scientists can now look for them in other species, including humans.
In recent decades, scientists have come to realize that the gut and brain have powerful influences on one another . Certain types of intestinal ulcers , for example, have been linked to worsening symptoms in people with Parkinson’s . Additionally, doctors have long known that gastrointestinal distress is more common in people who also have neurodevelopmental disorders, such as ADHD and autism spectrum disorder .
The brain has an impact on the gut, but it also works the other way around
“Not only does the brain impact the gut, but the gut can also profoundly affect the brain ,” said Kara Margolis, a pediatric gastroenterologist at New York University Langone Health, who was not involved in the new research. How these anatomically separate organs exert their effects, however, is much less clear.
Philip Washbourne, a molecular biologist at the University of Oregon and one of the lead co-authors of the new studies, has been studying genes implicated in autism and the development of social behaviors for more than two decades. But he and his lab were looking for a new model organism, one that exhibited social behavior but was faster and easier to raise than mice. “Can we do that in fish?” he remembers thinking, and then, “Let’s be very quantitative and see if we can measure how friendly the fish become.” Zebrafish, which are also used extensively in genetic research, reproduce rapidly and are naturally social. After they are two weeks old, they begin to form schools of four to twelve fish. Also, they are transparentinto adulthood, which allows researchers to observe their internal development without having to dissect them – a nearly impossible feat in mammalian models, such as mice.
The team began experimenting with gut ‘bacteria-free’ zebrafish embryos. After the baby fish hatched, the researchers immediately inoculated some of them with a mix of gut bacteria. But they waited a full week before inoculating the bacterial kit to the other fish. This was done to be able to compare the behaviors of fish with gut biome and those without. The fish that were inoculated at birth started moving about in the sea just as expected, at around 15 days old. But when it came time for fish with no microbiota to get started, “surprisingly, they didn’t,” said Judith Eisen, a neuroscientist at the University of Oregon and co-author of the new research.social development of their peers.
When Eisen, Washbourne and the research team examined the brains of the fish, they found clear structural differences . In fish that had spent the first week of life without a microbiome, a specific group of neurons in the forebrain, which influence social behavior, showed more interconnections . The group also had significantly fewer microglia, the neural immune cells responsible for cleaning up debris in the brain. “These are major changes in the nervous system,” Eisen said.
No microbiome, no parties
In the illustration from this study, lines trace the paths of zebrafish swimming in a special experimental tank. Fish raised with a normal microbiome spent most of their time near a clear divider to stay close to fish on the other side. Fish lacking a microbiome for the first week were less social and swam more haphazardly. The team speculated that a healthy gut microbiome somehow allows microglia to thrive in zebrafish brains. In some critical periods of development, microglia act as maintainers, pruning the ramified “arms” of the neurons. With no microglia to cut through them, the social neurons of fish without the microbiome became tangled and grew like an untended bramble.
It’s not clear how gut microbes send signals to the developing brain of fish to produce these effects. Bacteria release a bewildering array of chemicals, and any compound small enough could theoretically cross the blood-brain barrier (which protects brain tissue from harmful elements in the blood). But it’s also possible that immune cells moving between the gut and brain carry signal molecules with them , or that some signals travel up the vagus nerve from the gut .
Similar mechanisms may be at play in the social development of other vertebrates, including humans. Social grouping is a survival strategy common to the entire animal kingdom and is one of the behaviors that has been most conserved throughout evolution. In fact, Washbourne and Eisen had already identified nearly identical social neurons in mice. “If you can find the same cell types in a fish and a mouse, you can probably find the same cell types in humans,” Washbourne said.
- The microbiota promotes social behavior by modulating microglial remodeling of forebrain neurons (journals.plos.org)
- A conserved transcriptional fingerprint of multi-neurotransmitter neurons necessary for social behavior (bmcgenomics.biomedcentral.com)