Is your gut spiking cortisol at 3 a.m?
The gut-brain loop behind "tired but wired”
Sleep and the gut.
Two areas of longevity science I keep coming back to — both in my own work and in my own health. I think the gut-sleep connection is one of the more underappreciated intersections in health, and it’s something I’ve wanted to explore in a focused conversation for a while.
Today I get to do that — through a written Q&A with Scott C. Anderson.
Scott is a science journalist and co-author of The Psychobiotic Revolution: Mood, Food, and the New Science of the Gut-Brain Connection — a National Geographic bestseller he wrote alongside John F. Cryan and Ted Dinan, the researchers who coined the term psychobiotics. He also writes on Substack about the gut-brain connection.
I asked Scott six questions about the gut-brain axis, cortisol, probiotics, and what the research says about improving sleep through the microbiome.
Here’s what he had to say:
The Gut-Sleep Axis
Scott, you describe chronic psychological stress thinning out beneficial microbes and subsequently degrading sleep. For someone who lies awake at 3 a.m. replaying worries, what signs suggest “this now involves a gut-brain loop,” not just ‘that person needs more breathwork’ issue?
Hi Kat! People wake up at 3 a.m. for a lot of reasons. Our world is stressful in a way that is completely disconnected from our evolutionary background. A few millennia ago — a blink in evolutionary time — the main stressor was a predator. Those encounters typically ended up with one or the other as lunch. This kind of stress is appropriate, with cortisol flooding the system, ramping up the blood flow and pouring sugar into the muscles. This is the flight-or-fight system that has worked well enough to make us the dominant species on the planet, for better or worse.
Today, the top predator is an overbearing boss who is ready to pounce at any moment, providing unending stress. You never get a chance to recover, shredding your resilience. This has an impact on your psyche, but also your gut. The two are tightly linked by the gut-brain axis. A poorly balanced microbiome, called dysbiosis, can create anxiety and vice-versa. It’s a vicious cycle that can be hard to break out of — especially if you don’t even know it exists.
There are signs that your problem may be more than just mental rumination. If you also note bloating or abdominal discomfort, you may have dysbiosis on top of your worries. In this case, microbes may have breached your gut lining, allowing toxins and even microbes to seep into the bloodstream. That can trigger a low-grade inflammation, which your brain helpfully interprets as anxiety and hyper-vigilance. If this is the case for you, look into a Mediterranean-style diet with lots of fiber and ferments. Check out this Substack article for some of the particulars.
Be sure to start slowly to let your microbiome adjust. If you have IBS, Crohn’s, or IBD, don’t start during a flare-up. It may be just a diet, but it contains some serious nutrients and fiber that most Westerners have lost contact with. The biggest problems I see are people who get gassy and quit. Take it slow and be persistent. Once you get used to real food, you won’t go back.
Many people feel “tired and wired” – exhausted but keyed up. Mechanistically, how do you think the microbiome is contributing to that state via cortisol and inflammatory chemistry?
Your gut microbes, when they are well-balanced, produce chemicals that calm the immune system and keep it in maintenance mode. Think about it: your immune system is designed to kill bacteria, so how does your microbiome get a pass? The secret is that they were grandfathered in before your first 1,000 days, when your immune system was being educated about these special bacteria. They are old friends, and your immune system can sense when everything is copacetic.
But when pathogens get a foothold — as with food poisoning — they produce toxins that ring alarm bells for the immune system. It roars into action and sends signals via the vagus nerve and chemicals called cytokines to the brain. Two parts of the brain, the hypothalamus and the pituitary, sense the danger and send signals to the adrenal glands. This is the HPA axis, and it is a major component of the gut-brain connection.
The end product of this complex machinery is the secretion by the adrenals of cortisol. This is the stress drug, and it acts just like the above scenario, with anxiety and hypervigilance. Except this time, the predator is on the inside.
So, both the outer environs and the inner environs can lead to stress. However it happens, these threats are going to keep you buzzed and on the alert for an all-clear signal, no matter how sleepy you are. But if your gut is always dysbiotic, that signal may never come. Worse yet, you don’t always know your gut is involved, so you don’t have a clue why you’re so wired.
We can handle stress and inflammation in small doses just fine, but over extended periods, it can wear down the immune system and allow chronic diseases to take hold. Sleeplessness is a killer in its own right, but it may also be a warning of future disease.
You describe prebiotic fibers increasing butyrate and improving REM and non-REM sleep in animals. If you were designing a practical “sleep-better microbiome” experiment for a 55-year-old, what would the first 30 days of food changes look like?
There have been hundreds of studies that show the benefits of a Mediterranean diet. But there are similar good reports for Norwegian or Okinawan diets. What they all have in common is a connection to a wide variety of natural foods from their region. Lots of veggies, a little fish or meat, plenty of grains, fruits, nuts, and a little dairy.
They also consume fermented foods like yogurt, pickles, kraut, kimchi, kefir, kvass, and many more regional specialties. These foods all contain probiotic species which don’t typically colonize the gut, but moderate your microbiome in passing. Certain Lactobacillus species in yogurt, for instance, lower the pH as they transit the gut, killing pathogens on the way.
Many of us are overworked and find it hard to cook, so we rely on processed food from the store, or fast food from a restaurant. The problem there is that manufacturers and chefs tend to concentrate on unctuous flavors at the expense of fiber. That’s why most people are not getting enough of the fiber that your good microbes crave. Fiber is the single most important part of a restful gut microbiome.
For a 30-day intro, I would start slowly, because your gut needs time to adapt. Start by adding veggies to your dinner. You’ll find that they can be cooked in about 10 minutes and they can be delicious. Steam them and add a dab of olive oil or butter and a squeeze of lemon. Or roast them with a little oil and hit them with a dash of salt or parmesan. That’s a good start: a veggie on the side each night.
For snacks, start weaning yourself from processed food like Cheetos and chips and move toward nuts. Almonds and walnuts are excellent substitutes, providing healthy polyphenols that your gut microbes love. Don’t overdo it: nuts are great but they have plenty of fat, so limit yourself to a couple of small handfuls a day.
Moving to more potent gut-pleasers, try ferments. Start by adding a spoonful of yogurt to your breakfast. Make sure the yogurt has live microbes. Don’t get the sweetened or fruity versions: they may do more harm than good. Add your own fresh fruit, concentrating on berries. These fruits have a lot of fiber because we eat their seeds.
Slowly add more fruit and veggies with each passing week. Start adding fibrous veggies like onions, asparagus, artichokes, and beans. Avoid too many carbs — especially sugar and refined flour — which tend to support the wrong kind of bacteria in the wrong places.
You may find that you are producing more gas than usual. As long as it doesn’t cause bloating, that’s perfectly natural. Farting is funny; insomnia is not. If you get any gastric distress, scale back a bit on the fiber. Fiber is surprisingly potent. Your gut will adjust over time, so don’t give up!
If you absolutely can’t get enough veggies, you might try a supplement. I have personally never found probiotics to be useful, but you may have better luck. I suffered for years from painful IBS, my sleep was terrible, and nothing helped me until I tried prebiotics — basically fiber in powder form. Prebiotics are food for probiotics.
Along with switching to a mainly plant-based diet, I banished my IBS with a mix of what are called “oligosaccharides”, complex sugars derived from artichokes, chicory and other veggies. They aren’t absorbed like sugar, but instead survive the trip to the colon where they feed your good microbes. Those microbes in turn produce short-chain fatty acids like butyrate that both feed and heal your gut lining.
Two oligosaccharides in particular, galacto-oligosaccharide (GOS) and fructo-oligosaccharide (FOS), eliminated my IBS and depression and changed my life. This is how I ended up studying psychobiotics, microbes that can heal your gut and improve your mood.
A caveat here: what worked for me may not work for you. We all have different genetics, different microbes, different environments, and different diets. There are a head-spinning number of variables. So, as you start your journey to better health, take notes. It can take four weeks or more for things to start working, and it can be confusing without keeping notes on your progress.
Are there any specific probiotic strains with evidence for mood and sleep you’re excited about for anxiety-driven insomnia and 3 a.m. wakeups, or do you think most of the benefit still comes from broad diversity + fiber-rich diet rather than named strains?
I have not found much luck with probiotic supplements myself, but some people swear by them. In particular, there are four probiotics that have shown good results in studies.
Lactobacillus plantarum PS128 is one of the most researched strains, and it seems to improve sleep quality by producing GABA, a calming neurotransmitter. That’s right, bacteria can produce neurotransmitters, which is a shocking revelation. Bacteria don’t have brains, but they communicate with each other using some of the same neurotransmitters our brain uses. And they use them to talk to us as well!
Another probiotic is Bifidobacterium longum 1714. Studies show that this strain improves sleep quality at night while also reducing daytime sleepiness.
Lactobacillus reuteri can also produce GABA and interact with melatonin receptors in the gut, helping to regulate circadian rhythms.
Finally, Lactobacillus helveticus has been shown to reduce the dreaded 3 AM wakening, particularly in the elderly.
Supplements are not a substitute for a good diet. A plant-based diet with plenty of fiber will help you support those microbes as well as building up your own homegrown sleep-enhancing microbes.
In addition to probiotics, one of the prebiotics I mentioned before, GOS, has been shown to improve sleep quality by feeding beneficial microbes that then produce butyrate and help to lower cortisol.
You write that laughter lowers cortisol and changes gut microbes. If someone in midlife feels emotionally flat or anxious, what “dose” of deliberate positive emotion would you love to see them test for 30 days?
One way to put a smile on your face is to increase psychobiotics in your diet. As mentioned, psychobiotics are microbes that improve your mood, and the term now encompasses prebiotics as well. Psychobiotics include the microbes mentioned before, but there are others as well. Two bacterial species often studied together are Lactobacillus helveticus R0052 and Bifidobacterium longum R0175. They have been shown to reduce cortisol levels and thus alleviate anxiety. You can find this pairing in a supplement called Probio’Stick. It is the first government-approved psychobiotic (in Canada), although it may be hard to find.
The world has seemed to go mad recently, with politics more polarized than I’ve ever seen it. We have some big problems, like pandemics, climate change, pollution, and war. This is no time to be divisive. We need all hands on deck, working on solutions, not rancor. Stop doom-scrolling and pay more attention to science articles like Kat Fu’s or my Substack. Science is awe-inspiring and spirit-lifting. Scientific discoveries cure diseases, save lives, and reduce misery. All the cool things in the world like smart phones, movies, and the internet come from science. There is nothing quite like it!
Smile more. That can surprisingly improve your mood. It sounds backward — don’t we smile when we’re happy, not the other way around? But try it, it actually works!
Stop watching dystopian or horror movies and go for comedies. The more we laugh, the better our health seems to get. The gut-brain axis goes both ways. You can improve your microbiome to boost your mood, but you can laugh your way to a better microbiome as well. And that can help you sleep and stay asleep.
Many say, “I’ve tried probiotics and nothing changed.” From your vantage point, what is the biggest misconception people have about probiotics, and why do probiotic supplements so often underdeliver for improving gut health?
Probiotics certainly work in the form of yogurt or other ferments, but there seems to be less efficacy for probiotic supplements. Partly, that is because these are not well-targeted. Many supplement manufacturers use bacteria that are repurposed from brewing and other kinds of ferments, not necessarily the bacteria that target mood or sleep, like the ones listed earlier.
These bacteria are not normal denizens of the human colon, and are unlikely to take up residence there. That is good news for the manufacturers, who know that we will need to continue supplementing forever.
That is changing, and we are starting to see some new formulations that include the bacterial species I mentioned earlier, some of which may actually colonize the gut and stick around.
The other problem may be the dosage. A now-discontinued probiotic formula that tested well had hundreds of billions of CFUs (colony-forming units — basically a live bacteria count), unlike the tens of billions in most popular supplements. It is possible that we need far more microbes than most supplements provide in order to benefit. Remember that these microbes need to survive acids in the gut and enzymes in the small intestines to make it to the holy land of the colon. The attrition rate is huge.
The other problem with probiotics is that they need to be living to work well, and most of them start dying within weeks at room temperature. Old jars may contain dead probiotics, and a lot of them sit on the shelf for a while. This is a real problem for the probiotic business.
Researchers are working hard to improve these situations, so keep an eye out for news on this front. I’ll be sure to let people know as soon as we get better results, so watch this space!
I loved this conversation.
The gut-sleep connection is one of those areas where the more you look, the more you find — and Scott’s perspective on prebiotics and butyrate in particular I think gives us all a lot to think about.
Warmly,
—Kat
P.S. Cortisol timing and gut-driven inflammation are two of the patterns behind 3am wakeups — but there are a few others. If you're curious which one fits your situation, my 3AM Decoder walks you through it in about 2 minutes:
During medical training, chronic stress and erratic eating produced IBS symptoms that followed me for years. What resolved them was not medication but a sustained increase in dietary fiber. They have not returned.
What Scott describes here explains the mechanism: butyrate, gut lining integrity, and HPA axis signaling do not operate in isolation. In my metabolic patients, gut dysbiosis, disrupted sleep, and elevated inflammatory tone almost always present together. Fiber is underappreciated precisely because it works slowly and requires consistency rather than a single dramatic intervention.
Loved the framing. I especially appreciated the move away from treating three a.m. waking as a single villain and toward pattern recognition: timing, inflammation, rumination, and the gut - all may conspire.