Fear and the Microbiome

Changes in the gut microbiome of infants can induce fear—and possibly anxiety and depression later in life.

You’ve seen it before: Some well-intentioned strange man tries to make a goofy face at a small child, hoping for a smile, but he winds up making them cry instead. Nice going! Poor kid. Stupid guy. 

But a recent study in Nature Communications suggests that if you’re that guy, you shouldn’t take it too personally. The physiology of fear that makes a tiny baby cry in terror is less about your gloomy brow than that child’s rumbly gut. And not because they are colicky—as grandmas everywhere will always claim is the cause of all baby woes. Sorry granny! Those tears are more likely because there’s a dysbiosis or a reduction in diversity in the child’s intestinal microbiome.

When the microbiome is out of balance, the bacterial colonies causing the dysbiosis can inflict all sorts of human illnesses, ranging from gut and skin problems to neurologic performance. But fear?! 

The notion that changes to the intestinal microbiome are also at the root of antisocial, fearful, or pathological behaviors is nothing new. It’s been observed in rats and zebrafish before. Scientists have also linked reduced diversity in the gut microbiome composition in humans to anxiety and stress—an association that’s been common knowledge in the scientific community for some time. However nobody has ever understood whether the microbiome influences anxiety or the other way around.

“There’s obviously been a lot of studies looking at adults with anxiety or depression and [their] microbiome,”  says Rebecca Knickmeyer, a pediatrician at the University of Michigan, and co-author of the Nature Communications study. “But it’s always difficult in those cases to know which came first—the altering microbiome or the psychiatric condition.”

Because of the “chicken-and-egg” nature of the problem, the researchers decided the way to find out which came first would be to look at the youngest range of human ages so that the contaminating effects of environmental “nurture” could be excluded.

“Infancy is a critical period in both brain development and microbiome development. So, we thought these two processes were going on in parallel,” Knickmeyer says. “We know they talk to each other in animals. So, maybe they’re doing the same thing in humans.”

To exclude factors influencing early microbiome development, the researchers chose to sample one-month-old children who had been breastfeeding and had recently switched to infant formula. Not only that, but to exclude the impact of certain drugs on the children’s intestinal flora, the researchers chose children whose mothers hadn’t had any antibiotics for at least the two final weeks of pregnancy, who had been delivered vaginally, and had not been exposed to antibiotics or other drugs during delivery or in the months since birth.

The children were given two different tests. In one, the researchers observed how they responded to a Halloween mask, and in the other, to the face of a person they had never met before. 

Those who scored big on the variety of their microbial flora saw low levels of reactive anxiety.

Though they may appear whimsical, these two tests legitimately assess the preponderance and the nature of human fear. The choice of exposing the children to a Halloween mask, in particular, maybe a bit jarring, but in fact, is an adaptation of a larger test called the Infant Laboratory Temperament Assessment Battery, a test generally used in behavioral psychology to assess the temperament of a child by exposing the subject to episodes that mimic everyday situations. 

The mask portion in Knickmeyer’s study was used to measure the children’s expression of fear. In the study, a research assistant presented 34 infants with four different Halloween masks depicting either an apple, a horse, a monkey, or an alien, while calling the child’s name. The children, who during the test sat in a highchair, were startled, and reacted to each exposure by expressing facial fear, vocal distress, bodily fear, and physical aversion.  

Two types of fear

People experience two distinct kinds of fear: reactive and cognitive. “Reactive fear” is what you feel watching a horror movie or when a plate suddenly comes crashing to the ground behind you. The brain processes the jarring sensory input as an immediate threat, using circuits associated with the fight-and-flight response governed by the periaqueductal gray (PAG) and mid-cingulate cortex regions of the brain. Situated grossly in the central region of the brain behind the mid-ear, the periaqueductal gray area plays a critical role in autonomic function, motivated behavior, and behavioral responses to threatening stimuli. It also contains the primary brain regions that control pain—all of which make reactive fear an extraordinarily useful evolutionary adaptation. You hear threat—you move!

Cognitive fear” circuits, on the other hand, are associated with protracted escape decisions. These decisions are less instinctive and more cognitively complex, involving avoidance strategies buffered by the intellect and learned behavior. In these situations, rather than acting instinctively and bolting off for the hills, a person analyzes the situation attentively before reacting. Cognitive fear circuits are associated with the posterior cingulate cortex, the hippocampus, and some areas of the prefrontal cortex. 

Based on visual assessment of the children’s fear reactions, molecular assessments of their fecal samples, brain images taken of them throughout the study, and information gleaned from parent questionnaires, the researchers saw a strong association between the characteristics of the infant microbiome and their fear reactivity.

“We had a couple of different interesting relationships,” explains Knickmeyer. “First, we saw that alpha diversity [the relative homogeneity of the bacterial flora] at one month of age when the kids first came in predicted their fear reactivity a year later. So that suggested there may be some very early influences of the microbiome on the brain circuits involved with processing threats. And the other thing we saw is that beta diversity—the kinds and the relative abundance of different strains of bacteria—at one year was concurrent with the reactivity.” 

In other words, children who scored high on the presence of a specific genus of bacteria in their guts—for example, Veillonella and Actinobacterium—expressed higher levels of reactive fear, while those who scored big on the variety of their microbial flora—including several species of Bacteroides—saw lower levels of reactive anxiety.

“Existing literature shows that kids who have extreme emotional responses may be at increased risk for anxiety and depression when they’re older,” comments Federica Scarpina of the University of Turin, Italy, who was not part of the Nature Communications study but who conducted parallel research discovering similar associations on microbiome-induced fear in obese women.  

Early treatment of depression

Knickmeyer says the findings could lead to a whole new way of addressing anxiety and depression in adults by effectively intervening in early childhood, while the brain is still developing. That could make all the difference, especially given the fact that antidepressant drugs can be slow to work, hard to take, and ultimately ineffective for many people.

The first year of life may represent a critical period for the development of healthy fear response.

“Take it as prevention science,” she says. “We hope to identify therapeutic interventions like encouraging longer breastfeeding or introducing pre- and probiotics support in the mother during pregnancy or introducing beneficial bacterial strains such as Bacteroides in the infants before one year of age. That could help support brain development early on and thereby actually reduce risk later.” 

Since microbiome manipulations in rodents have shown that fear results in structural and biochemical changes to the amygdala, the hippocampus, and the medial prefrontal cortex—interfering particularly with early affective learning, behavior, and the development of life-long stressors—the researchers believe that the first year of life may represent a critical period for the development of healthy fear response and of all the brain circuitry to which it is connected.

Scarpina of the University of Turin agrees and points out that the discovery has a significance that goes beyond child development and brain pathology. She speculates that it may find application also in the general population leading to the adoption of better diagnostic tools and standards of care for mental health. However, she believes that researchers should do more to verify that the conditions of the infant microbiome have a life-long lasting impact on the individual. The studies should be longitudinal and follow the subjects throughout their life, which will be costly and challenging.

But short of a longitudinal study, the next step, Knickmeyer says, is to introduce children’s microbiomes into adult lab mice and see if their fear response changes.

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