The HPA axis is regulated by the microbial clock

The HPA axis, or hypothalamic-pituitary-adrenal axis, plays a major role in how we look, feel, and function. This axis is fundamental to how we regulate the stress response and our survival.

When exposed to stress, our hypothalamus secretes corticotropin releasing hormone(CRH) which makes it a short distance to the pituitary gland. Consequently, the pituitary gland releases a hormone called adrenocorticotropic hormone(ACTH). ACTH circulates in the blood to the adrenal glands.

When exposed to ACTH, the adrenal glands secrete the stress hormone cortisol. Cortisol circulates throughout the body setting the circadian rhythm and causing tissue specific functions. Because of this, cortisol is very important to health and proper function.

Cortisol also follows a circadian rhythm, so our lifestyle is important too. As mentioned, stressors also affect cortisol secretion. But there’s another factor that regulates sensitivity of the HPA axis, and thus, cortisol levels. I’m talking about the microbiome.

Complicating things, the microbiome also follows a circadian rhythm. Therefore, optimizing the HPA axis and our sensitivity to stress requires synchronizing the microbial clock to our own circadian rhythm.

Microbiome circadian HPA axis

The vagus nerve: Connection between the HPA axis and microbial clock

The vagus nerve is the 10th cranial nerve and the communication line in the gut-brain axis. It contains sensory nerves that communicate the status of various organs to the brain. Conversely, it also contains motor nerves that allow the brain to affect these tissues.

Approximately 80% of the nerves that make up the vagus are sensory. It’s these sensory nerves that the microbiome uses to affect the brain and stress response. Different metabolites created in the microbiome bind to receptors on the vagus nerve and alter brain activity.

These metabolites also alter gut health. Short chain fatty acids are one type of microbial metabolite that alters our physiology. For example, butyrate is a SCFA that decreases inflammation and seals up the gut. But these SCFAs can’t be viewed in isolation. There are other SCFAs that matter and timing also plays a role. And SCFAs aren’t the only metabolites that matter.

However, SCFAs are a great model of how complex our microbiome is. Creating butyrate is great, but for it to help us, our cells have to absorb it. If we don’t absorb butyrate, it sits in the colon and causes dysbiosis.

Many factors affect butyrate absorption. Physical activity and the presence of butyrate increases absorption by increasing transport via Monocarboxylate transporter 1(MCT1). Inflammation decreases MCT1 transport, as does THC from marijuana and EGCG from green tea. The presence of butyric acid in and of itself isn’t great unless it’s absorbed.

Getting butyrate in to the colon and absorbing it improves gut health and helps balance the HPA axis. But it’s important to keep in mind that there’s a circadian rhythm here. Since it follows a rhythm, more butyrate isn’t necessarily better. And timing is probably equally, if not more, important.

Propionate: Another microbial signal for the HPA axis

Propionate is another SCFA generated by the microbiome. And just like butyrate, propionate follows a circadian rhythm, and more isn’t necessarily better. In fact, it’s presence in processed food as a preservative may mess up the circadian rhythm.

A study looking at propionate in mice and humans found that feeding propionate:

  • Activated the sympathetic nervous system
  • Elevated blood glucose
  • Caused hyperinsulinemia

Like other SCFAs, propionate crosses the blood brain barrier. However, the effects of different SCFAs can diverge tremendously. For instance, butyrate has a calming influence on the brain, inhibiting inflammation and maintaining resident immune cells in a reparative state. However, propionate does the exact opposite, increasing inflammation and activating immune cells.

While it’s tempting to blame processed food, our microbiome makes both. Children with autism have an increased prevalence of propionate producing microbes and decreased butyrate producers. In other words, I don’t think merely avoiding processed food will do the trick.

Another issue is that you wouldn’t want to eliminate propionate. It has it’s purpose. At low levels it seems to improve mitochondrial function while at higher levels it impairs it. And in children with autism, it’s much worse. This indicates that other things are going on.

I suspect this is a circadian issue, as children with autism have disrupted circadian rhythms. Also, propionate is damaging when oxidative stress is high, which occurs in circadian disruption and autism. Thus, propionate is likely beneficial at the proper time and at appropriate levels.

I highly suspect that both butyrate and propionate are important circadian signals from the microbial clock. They are also apparently linked, so to address one you have to address both.

Factors affecting the microbial clock

The primary entraining cue for the microbial clock is the feeding/fasting cycle. Therefore, when you eat is probably the most important cue for setting the microbial clock. But it’s definitely not the only important factor.

Both the quality and quantity of food you eat is important as well. Microbes in our microbiome use prebiotics in our food to make SCFAs and other important signaling molecules that synchronize their circadian rhythm to ours.

Too much food can cause hyperglycemia that damages the vagus nerve. It also causes leaky gut by altering the way the cells in our gut take in glucose. The chronic inflammation that comes with this can disrupt the circadian rhythm of cortisol.

Eating at night was recently shown to disrupt the microbiome in mice. Physical activity is also important. In addition to improving butyrate uptake, it also builds resistance to stress by directly affecting HPA axis sensitivity. Recent evidence indicates the exercise-induced hormone irisin reduces inflammation and inflammatory bowel disease immune alterations.

Proper sleep is another important factor affecting the microbial clock. And mice maintained on funky light/dark cycles have an altered microbiome. Thus, food is not the only important circadian cue for the microbial clock.

Integration between all systems throughout the body is required to build and maintain a healthy microbiome synchronized to our circadian rhythm.


The microbiome has recently gained prominence as an important regulator of human health. One of the most important ways that the microbiome shapes our health is through synchronizing with our circadian rhythm.

Cortisol is one of the major outputs of our master circadian clock. There is strong evidence that the microbiome helps regulate our circadian rhythm through the secretion of metabolites such as serotonin, biogenic amines, indoleamines, and SCFAs. The evidence in mice is overwhelming.

But it’s a 2-way street, so in order to harness the power of the microbial clock, you have to put in the effort to build a strong circadian rhythm as well. The great thing is that strengthening your circadian rhythms also strengthens the microbial rhythm.


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