Altered Fear Response, Changes in Brain Chemistry Seen in Mice with Poor Gut Microbiota

Depleting microbes in the gut of mice led to an altered fear response, changes in gene expression in brain immune cells and changes in brain chemistry — returning to a more normal state after their gut microbes were restored, but only if done early in life, a study reports.

Researchers believe these results have implications for people with mood disorders associated with inflammatory autoimmune diseases such as multiple sclerosis (MS). 

The study, “The microbiota regulate neuronal function and fear extinction learning,” was published in the journal Nature, and was conducted by researchers at Cornell University, Broad Institute at the Massachusetts Institute of Technology and Harvard University, and Northwell Health.

“Our study provides new insight into the mechanisms of how the gut and brain communicate at the molecular level,” David Artis, PhD, director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease, director of the Friedman Center for Nutrition and Inflammation, the Michael Kors professor of immunology at Weill Cornell Medicine, and the study’s co-senior author, said in a Cornell news release written by Jane Langille.

In recent years, research has identified a genetic link between autoimmune disorders and a number of psychiatric conditions. People with MS, as well as those with autoimmune disorders such as inflammatory bowel disease (IBD) and psoriasis, experience anxiety, depression, and mood disorders.

Research has also found a link between mood disorders and bacteria that live in the digestive tract, known as gut microbiota. It has been suggested that a depleted gut microbiota in people with autoimmune disorders may affect their mental well-being. 

However, the mechanisms underlying how gut microbiota affects brain health is not fully understood.

Scientists, using a mouse model, set out to learn more about the changes that occur in brain cells when gut microbiota are depleted.

Mice were either given antibiotics to reduce the number and variety of their gut microbes, or were bred to be microbe-free.

Interestingly, these mice had an altered fear response — they lost an ability to learn that a threatening danger was no longer present. 

For a deeper understanding of the molecular basis of these behaviors, immune cells from the brain, called microglial cells — the primary immune cells in the central nervous system (CNS) — were genetically analyzed. Compared to microglia cells in healthy mice, gene expression (activity) was altered in the experimental mice and that affected how brain cells connect during the learning process. 

“Changes in gene expression in microglia could disrupt the pruning of synapses, the connections between brain cells, interfering with the normal formation of new connections that should occur through learning,” said Conor Liston, MD, PhD, the study’s co-principal investigator, associate professor of neuroscience in the Feil Family Brain & Mind Research Institute, and associate professor of psychiatry at Weill Cornell Medicine.

The team also found that the levels of certain metabolites — known to be associated with human neuropsychiatric disorders such as schizophrenia and autism — were changed in microbe-free mice, “suggesting that microbiota-derived compounds may directly affect brain function and behaviour,” the researchers wrote.

“Brain chemistry essentially determines how we feel and respond to our environment, and evidence is building that chemicals derived from gut microbes play a major role,” said Frank Schroeder, a professor of chemistry and chemical biology at Cornell and at Boyce Thompson Institute.

The researchers were able to reverse learning problems in these mice by restoring their gut microbiota in the early stages of life.

“We were surprised that we could rescue learning deficits in germ-free mice, but only if we intervened right after birth, suggesting that gut microbiota signals are required very early in life,” Liston said. “This was an interesting finding, given that many psychiatric conditions that are associated with autoimmune disease are associated with problems during early brain development.”

“We don’t know yet, but down the road, there is a potential for identifying promising targets that might be used as treatments for humans in the future,” Liston added. “That’s something we will need to test going forward.”