It may seem like our brains are physically distant from our gut, but in recent years, research has given strong evidence to suggest that the huge communities of microbes concentrated in our gut provide a connection between the brain and the gut. The gut microbiome influences cognitive function and emotions, affects mood and mental health problems, and even how information is processed. But it was difficult to understand how the microflora does this.
Until recently, studies of the connection between the gut and the brain mainly showed only a correlation between the state of the intestinal microflora and the processes taking place in the brain. But new discoveries are helping to create a more detailed picture based on research that demonstrates the microbiome's involvement in stress responses. By focusing on responses such as feelings of fear, and in particular on how fear disappears over time, the researchers have now examined how the behavior of mice with reduced microflora differs. They identified differences in neural networks, brain activity and gene expression, and also found the presence of a short time window after the birth of an individual, when the restoration of microflora, that is, bacterial colonization,still able to prevent the onset of behavioral disorders in adults. They even identified four specific substances that may contribute to these changes. It may be too early to predict what therapies might be offered once we understand this connection between gut microflora and brain, but these specific differences support the hypothesis of a deep relationship between the two systems.
Determining these mechanisms of interaction with the brain is a major challenge in microbiome research, according to Christopher Lowry, assistant professor in the Department of Integrative Physiology at the University of Colorado at Boulder. “Scientists have some interesting ideas,” he said.
Coco Chu, lead author of the new study and researcher at Weill Cornell Medicine College, became interested in the concept that microorganisms living in our bodies can influence both our feelings and our actions. Several years ago, she decided to study these interactions in great detail in collaboration with psychiatrists, microbiologists, immunologists and scientists from other fields.
The researchers conducted a classic exercise to develop behavioral skills with mice, some of which were given antibiotics to dramatically reduce the amount of microflora in their bodies, and some of them were raised in isolation so that they had no microflora at all. All mice learned equally well to fear sound, followed by electric shock. When scientists stopped using electric shocks on mice, ordinary mice gradually learned not to be afraid of sound. But in "sterile" mice, in which the amount of microflora was reduced or there was no microflora at all, fear did not disappear - at the sound of a signal, they, as a rule, more often fell into a stupor than ordinary mice.
Looking inside the medial prefrontal cortex, the region of the cerebral cortex that processes fear responses, the researchers noticed distinct differences in mice with reduced microflora: the activity of some genes was lower. Glial cells of the same species were not developed. The so-called dendritic spines - protrusions on neurons associated with the process of information processing and learning, appeared less often and disappeared more often. A lower level of neuronal activity was observed in cells of one species. The impression is that mice without healthy microbiomes cannot forget about fear and learn not to be afraid. And the researchers were able to see it at the cellular level.
The researchers also set out to find out how the state of the intestinal microflora caused these changes. One possible option was for microbes to send signals to the brain through the long vagus nerve, which transmits sensation signals from the digestive tract to the brain stem. But after cutting the vagus nerve, the behavior of the mice did not change. In addition, it seemed possible that the intestinal flora could trigger immune responses that affect the brain. But the number and percentage of immune cells in all mice were the same.
However, the researchers found four types of substances secreted by intestinal microorganisms that affect neural connections, which were much less in serum, cerebrospinal fluid and stool of mice with insufficient microflora. Some of these substances have already been linked to neurological disorders in humans. According to microbiologist David Artis, director of the Institute for Inflammatory Bowel Disease Research at Weill Cornell Medicine College and lead author of the study, scientists working under his direction suggested that microflora can excrete certain substances in large quantities, and some molecules penetrate into brain.
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Interest is growing in many laboratories in identifying specific substances secreted by bacteria that are involved in the transmission of signals from the nervous system, says Melanie Gareau, assistant professor in the department of anatomy, physiology and cytology at the University of California, Davis. Numerous metabolites are likely to be involved in such processes and metabolic pathways are involved.
Emeran Mayer, professor of medicine at the University of California Los Angeles and director of the Oppenheimer Center for the Neurobiology of Stress and Resilience to Stress, notes that research findings on other disorders, such as depression, also point to a link to certain substances released by microbes. But there is still no consensus on which of them contribute to the occurrence of any violation. And while many people with brain disorders have clearly changed gut microflora, it is often unclear whether the change is a cause or a consequence of the disease, he says. Changes in the state of the microflora can lead to neurological problems, but diseases can also cause changes in the state of the microbiome.
In this area, there are disagreements not only about the consequences of microflora disturbances, but also about healthy microflora. “We have long focused on the fact that we could identify specific types of bacteria that either pose a risk of stress-related disorders and diseases, or provide resistance to them, and it may not have to be a specific microbe”Says Lowry. Even in healthy people, the microflora is very different. Specific microbes may not matter if the microflora is sufficiently diverse - just as with many different types of healthy woodlands, one particular type of tree may not be needed.
However, the study of the effects of microflora on the nervous system is a new area of science, and there is uncertainty even about what this effect is. The conclusions drawn from the results of previous experiments about whether changes in microflora contribute to the fact that animals forget the learned skill and stop feeling fear were either unfounded or contradictory. As for the conclusions reached by Coco Chu and her colleagues, they are of particular importance, since scientists can provide evidence for the existence of a specific mechanism that causes the behavior they observed. Such animal studies are especially important for strengthening the clear connection between the nervous system and gut microflora, even if they are not aimed at finding ways to treat humans, says Kirsten Tillisch. Professor of Medicine at the David Geffen School of Medicine at the University of California Los Angeles. “The way we 'process' emotions, physical sensations and knowledge in the human brain is so different from how it happens in animals that it's just very difficult to apply,” she says.
In theory, the presence of certain substances released by microflora could help determine who is most vulnerable to disorders such as post-traumatic stress disorder (PTSD). Experiments like these could even identify pathways of interactions between the brain and the microbiome that can be influenced by treatment. “These experiments with mice always give us great hope that we are approaching the stage of interventional research,” says Emeran Meyer, and through the use of accurate methods, these studies often produce amazing results. But the processes taking place in the brain of mice do not quite correspond to the activity of the human brain. In addition, in humans and mice, the processes of interaction between the brain and intestinal microflora differ, and this discrepancy is aggravated by the fact thatthat their intestinal microflora is different due to the difference in food consumed.
In humans, interventions to alter the gut microflora may be most effective during infancy and early childhood, when the gut microflora is still developing and initial programming is taking place in the brain, Mayer says. In their latest study, the researchers saw a particular time window in infancy, when mice needed common microflora to develop the ability to suppress fear in adulthood. The mice, which for the first three weeks were completely isolated from the effects of microbes, were then placed in conditions where they were together with mice that had the usual intestinal microflora. The "sterile" mice picked up microbes from other mice, and as a result they developed a rich microflora. But when they grew up, and with them the same experiments were carried out on "weaning from fear",their results were still low. At the age of only a few weeks, they were all too old early to acquire the normal skill of learning how to suppress their fear.
But when microflora was restored in newborn mice, which received a rich microbiome after placement with foster parents, the mice grew up and behaved normally. It turned out that in the first few weeks after birth, microflora is very important - and this observation fully fits the more universal concept that the neural circuits that govern the ability to experience fear are sensitive at an early age, says Tillisch.
The ability to “wean from fear,” which the researchers studied, is evolutionarily a fundamental skill, Artis said. Knowing what triggers fear and the ability to adapt when it is no longer a threat can be critical to survival. Failure to suppress fear is also seen in people with PTSD and is associated with other brain disorders, so deepening scientific knowledge of the mechanisms that affect this neural network can help understand basic human behaviors and set the stage for treatment options.
On an evolutionary scale, human gut flora has changed with the growth of the urban population, and brain damage is becoming more prominent. The numerous microbes that live in each of us have evolved with our species, and it's important that we understand how they affect physical and mental health, Lowry says. Through the microflora, the environment can also influence our nervous system, which further complicates the process of studying the health and diseases of the brain.
Elena Renken