Gut microbes acquired early in life can impact brain development in mice and subsequent behavior, such as decreasing physical activity and increasing anxiety, according to a study published this week in the Proceedings of the National Academy of Sciences.
This paper opens the door to new studies in at least two directions," Yale University microbiologist Andrew Goodman, who was not involved in the research, told The Scientist in an email. "First, determining how differences between complete host-associated microbial communities lead to differences in behavior, and second, exploring the contributions of microbes during specific developmental periods in the host."
Gut microbiota often colonize their hosts early in life, either during pregnancy or following birth, and play an integral role in the health of developing organisms. Previous research has shown that the bacteria affect the development of liver function, the protection epithelial cells afford underlying digestive tissue, gut regulation and the growth of new capillary blood vessels. But this is the first time gut flora have been linked to brain development and behavior.
Harmful microbial infections, on the other hand, have been linked to neurodevelopmental disorders, including autism and schizophrenia. And rodents infected by microbial pathogens before and after birth demonstrated behavioral abnormalities, such as anxiety-like behavior and impaired cognitive function, leading Rochellys Diaz Heijtz, a neurobiologist at the Karolinska Institute in Sweden, and her colleagues to wonder if the gut's normal microbial residents may similarly influence brain development.
The researchers tested exploratory activity in germ-free mice and mice with normal gut microbiota by tracking their movements across open space. They also tested anxiety of the two groups in two classic rodent behavioral tests -- the light-dark box and the elevated maze. Spending more time in lit areas and along unwalled, elevated maze portions equated to less anxiety.
Germ-free mice appeared to be more exploratory than mice with normal microbiota, venturing farther and to more areas of the space provided. Germ-free mice also spent more time in the light and engaged in riskier behavior in the maze, indicating they suffered from less anxiety than their microbe-filled counterparts.
The team then infected germ-free mice with normal gut microbiota when they were born to test whether the gut flora could alter the mice's activity and anxiety levels. Sure enough, the newly infected mice spent less time exploring and engaging in risky behavior, like the normal mice in the initial experiments. The results further supported the argument that the microorganisms can affect brain and behavior when introduced early enough in development.
"These microorganisms communicate in a systemic fashion to the developmental programming of a new individual and can influence fundamental aspects of behavior," said Diaz Heijtz. "We should start to consider the possibility that the microbiome and/or its composition may contribute to psychiatric problems."
Looking more closely at the gut flora's effects on the brain, the researchers found that germ-free mice had lower turnover rates of certain neurotransmitters in the striatum, the part of the brain involved in the regulation of motor and cognitive function, than in mice with normal gut microbiota. There were also differences in the levels of key synaptic-related proteins and signaling molecules involved in central nervous system communication.
"This all means that there has been an evolutionary adaption of host-microbe interactions to the most complex organ in the body, the brain," said coauthor Sven Pettersson, a neuro- and microbiologist at the Karolinska Institute.
The scientists stress that there are still many unanswered questions and further research is needed to understand the broad implications of the research. For example, the study didn't distinguish the effects of maternally inherited microbes from those acquired shortly after birth, Goodman noted. "It is also not clear whether microbes residing in other body habitats are playing a role," he said, such as those located in the nose, ears, mouth or vagina.
Next up, Diaz Heijtz and her colleagues are hoping to pinpoint which gut microbiota are affecting brain development and behavior. They also plan to identify which brain cells are responding, and work out the details of the signaling pathways that allow the microbiota to communicate with the brain.
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