Is It the “Terrible Twos”? Or Is It a Disrupted Gut Microbiome?

Written by Chris Kresser

Kids out of control? New evidence suggests that a disrupted gut microbiome could be partly responsible for unruly behavior in children. Read on to learn how the brain develops, the role of the gut in this process, and how bad temperament in early childhood might be associated with gut dysbiosis.

Parents often complain about the “terrible twos,” which more often than not turn into the “terrible threes and fours.” Ritalin is one of the most prescribed drugs to children, and the number of prescriptions doled out for attention-deficit/hyperactivity disorder (ADHD) is increasing each year.

Beyond just attention and ability to focus, temperament also includes characteristics like introversion and extraversion, self-control, adaptability, intensity, and mood. Ratings of temperament in early childhood are good predictors of personality, behavior, and risk for psychopathology in later childhood, adolescence, and adulthood (1).

Previous articles on my blog have covered the basics of the gut–brain axis and how microbes can control food cravings. In this article, I will focus on how microbes might influence temperament in children, though much of what I will cover applies to adult behavior as well.

The developing brain

The development of a child’s brain lays the foundation for all future behavior and learning. In the first few years of life, an estimated 700 to 1,000 new synapses (connections between neurons) form every second (2). After this period of rapid growth and proliferation, the number of synapses is reduced via a process called pruning. During pruning, specialized immune cells of the brain called microglia break down synaptic material. This allows other connections to be strengthened and become more efficient. Studies have shown that pruning by microglia is essential for normal postnatal brain development (3).

The interaction of the child’s biology with his or her environmental conditions and experiences is what ultimately determines which connections are maintained. A synapse that is constantly activated will tend to be strengthened, while a synapse that never receives input will be pruned. In this “use it or lose it” fashion, the brain is extremely malleable during this critical period.

How the gut controls maturation and function of the CNS

What would happen to this process if you took away your gut microbes? Researchers in Germany sought to answer that very question. Using germ-free mice, they found that compared to conventional animals, mice lacking a gut microbiota exhibited abnormal microglial function and had abnormal development of the central nervous system (4).

The researchers wondered if microbial metabolites could be involved. The gut microbiota are constantly processing fermentable fibers from the diet and producing a wide range of metabolic end products, including short-chain fatty acids (SCFAs). SCFAs are known to be absorbed into circulation and influence host physiology by binding to free fatty acid receptors (FFARs) on cells throughout the body (5). Following this thread, the researchers genetically engineered mice to lack FFAR2 and found that these mice had similar microglial defects to those found in germ-free animals. They concluded that microbial metabolites are essential to microglia maturation and function (4).

Gut microbiome composition is associated with temperament in early childhood

A group of researchers at Ohio State University wanted to determine how human gut microbes might be associated with behavior in early childhood. They studied 77 children between the ages of 18 and 27 months. Ratings of temperament were provided by the mothers of the children using a standardized questionnaire, and fecal samples were collected from the children’s soiled diapers for microbial DNA sequencing (6).

The results of the study, published in 2015, were quite interesting. For both girls and boys, higher surgency/extraversion scores were associated with greater genetic diversity of microbes. In boys, higher sociability scores were also associated with greater microbial diversity. As the authors of the study explain, “the surgency/extraversion scale reflects a trait aspect of emotional reactivity characterized by a tendency towards high levels of positive affect, engagement with the environment, and activity.” Higher surgency/extraversion scores in children have previously been associated with lower depressive symptoms (1).

The researchers next wanted to look at specific groups of bacteria to see if there were any “bad behavior bugs.” They observed significant correlations between relative abundance of bacteria in the Rikenellaceae and Ruminococcaceae families and the Parabacteroides and Dialister genera and temperament. While it is unknown whether this relationship is causal, the researchers hypothesized a connection between the gut microbiota and the HPA axis.

The HPA axis, leaky gut, and temperament

The hypothalamic–pituitary–adrenal (HPA) axis is an area of particular interest in relation to temperament. Studies in animal models suggest that early life exposure to mild or moderate stressors enhances HPA regulation and promotes lifelong resilience to stress. In contrast, exposure to extreme or chronic stress early in life can induce an over-reactive HPA axis and encourage vulnerability to stress throughout the lifetime (7). Changes in the function of the HPA axis have been linked to temperament in several studies (8, 9).

Notably, germ-free mice show an exaggerated HPA response compared to conventional mice, an effect that can be partly corrected by reintroduction of a microbiota, but only at a very early stage (10). If you’re an avid reader of my blog, you’ve probably already heard me talk about leaky gut. When the gut barrier is compromised, bacterial components and other materials from the gut lumen (endotoxin) can leak into the bloodstream. It turns out that endotoxin is a potent stimulator of the HPA axis, causing prolonged activation (11, 12).

We can now see clearly how gut dysbiosis and intestinal barrier disruption can lead to abnormal HPA function and behavior. Nonetheless, this is just one of many potential connections between the gut microbiota and temperament. We’ll explore a few more in the next section.

Other mechanisms: Neurotransmitters and the blood–brain barrier

In addition to regulating the immune system in the maturing brain, the gut also manufactures neurotransmitters throughout the lifetime. More than 90 percent of your body’s serotonin and 50 percent of your body’s dopamine are produced in your gut, along with about 30 other neurotransmitters (13, 14). The gut microbiota has also been shown to regulate the production of myelin in the prefrontal cortex, a region that is important for self-control and executive function (15). Myelin is like “insulation” for neurons, helping them to properly conduct electrical impulses.

Antibiotics provide another way to study the role of microbes in CNS function. Antibiotic-induced microbial dysbiosis in mice has been shown to impair cognition and decrease anxiety. Depletion of the gut microbiota from weaning onwards altered components of the tryptophan metabolic pathway and significantly reduced oxytocin, vasopressin, and brain-derived neurotrophic factor (BDNF) expression in the adult brain (16).

Lastly, the gut microbiota is essential for the maintenance of the selectively permeable blood–brain barrier. Just like in the gut, tight junction proteins between epithelial cells maintain the integrity of this barrier and prevent large molecules from entering the cerebrospinal fluid that encases the brain. Studies have shown that germ-free mice have reduced expression of these tight junction proteins and increased blood–brain barrier permeability (17). A compromised blood–brain barrier can easily lead to neuroinflammation and altered behavior.

Healthy gut, happy child

While there are certainly many things that influence a child’s behavior, the collective body of research in this area suggests that the gut microbiota may play an important role. Cultivating a healthy gut flora for your child may not only improve his or her behavior in the short term, but will also reduce the chance of mental health issues later in life. Here are a few ways to improve your child’s gut health:

Probiotics or fermented foods
In several studies, probiotic bacteria have been shown to reduce anxiety and depressive-like symptoms (18, 19, 20). One study in rats even found that probiotic supplementation reduced leaky gut and attenuated the HPA response to acute psychological stress (21).

Prebiotics
Specific groups of microbes break down prebiotic fibers to form beneficial metabolites. Many microbial metabolites are small enough to penetrate the blood–brain barrier (22, 23) and influence brain chemistry. Butyrate, for example, has profound effects on behavior and mood (24).

Remove inflammatory foods and include bone broth in your child’s diet
Healing the gut lining is essential to reducing gut and systemic inflammation that in turn can affect the brain.

Avoid antibiotics unless absolutely necessary
Most ear infections and upper respiratory infections are viral and are not influenced by antibiotic treatment. If your child does need antibiotics, see my steps on how to mitigate the damage.