Do you ever get hungry? I mean really hungry? Like, “I’m going to gnaw my arm off I’m so hungry”?
What if I were to tell you that proper gut function may be dependent on regularly experiencing this type of hunger? Well, it’s true. This feeling of hunger may be a signal that your gut and brain are working in unison to promote optimal digestion.
If you have a gut disorder such as irritable bowel syndrome(IBS), inflammatory bowel disease(IBD), or small intestinal bacterial overgrowth(SIBO) you know how terrible these conditions can be. Random bloating and discomfort, GERD, anxiety, fatigue, and never knowing when you’re going to go dookie can really take a toll on a person.
On top of the symptoms, these issues are hard to diagnose and, as of now, incurable for the most part. As a result, people tend to deal with bowel disorders for a very long time. A long time to diagnose, a long time to try multiple therapies, and a long time to fail many times.
Even a large number of people who go in to remission for their particular problem eventually relapse. An even larger number just deal with the problem without ever finding a solution.
For those that don’t find a solution, and even those who do go in to remission, many take a number of supplements or pharmaceutical drugs. For people with other issues associated with these problems, avoidance of certain foods is the norm.
The people dealing with commonly associated issues like migraines, histamine intolerance, HPA axis dysregulation, and autoimmune disorders tend to have a very small list of foods they tolerate. A lot of the foods they avoid contain ordinary food components such as salicylates, different alkaloids in nightshades, histamine, and oxalates that most people tolerate just fine and may even benefit from. This can lead to malnutrition in the face of marginal to no improvement in symptoms.
But what if the paradigm people are using to solve their problem is all wrong? From what I can tell, most people think their gut problems center around one or more of the following:
- Leaky gut
- Poor digestive enzyme/bile output
- Low stomach acid
- Poor gut motility
- Parasites living in their gut
- Gut dysbiosis
- Poor microbial diversity in the gut
- Genetic polymorphisms that impair detoxification(MTHFR, etc.)
This list may resonate with you if you have one of the aforementioned gut problems. Maybe you’ve seen some relief from your issues by manipulating these variables through supplementation of enzymes, leaky gut formulas, pro/prebiotics, and the like.
Looking in from the outside, no one actually fixes their problem manipulating these variables. I don’t think this list is inaccurate in terms of what the root cause of your problem is, but the focus on “not enough” and taking supplements to fix it is probably wrong.
Maybe timing is everything. There’s a substantial amount of evidence this may be the case.
In addition to being targets for addressing gut problems, this list of biological processes in the gut that people tinker with has something else in common. Every one of these factors is under circadian control(1). In other words, they follow a set pattern of peaks and valleys throughout the day. But what does that mean to you and your gut problem? And what does hunger have to do with it? Let’s dig in and find out…
Tick-tock goes the circadian clock
You may have heard about circadian clocks before, especially if you read my last blog covering the topic. If not, I suggest you read up on it here.
Circadian clocks help us adjust our physiology to the environment. Generally speaking, there are two basic categories of circadian clocks: the master clock and peripheral clocks.
The master clock is a set of neurons in the suprachiasmatic nucleus(SCN) of the hypothalamus. Even without input, this clock tends to keep time in an approximately 24 hour cycle. But since the cycle isn’t exactly 24 hours, it can get thrown out of sync with the day/night cycle.
Certain environmental factors help set our clocks. The master clock is set by light which is a very easy thing to find. Specifically, by blue light hitting your eye during the day and not hitting your eye at night.
The pineal gland is a major player in regulating the master clock. When blue light hits your eye during the day, the pineal gland is blocked from secreting the hormone melatonin. Once the Sun goes down, blue light no longer blocks the pineal gland and it begins secreting melatonin.
As melatonin accumulates in the brain, it signals your brain that it’s time to sleep. But it also helps set a large number of other important factors for your physiology. Specifically, alertness, sleep, physical activity, hormonal balance, body temperature, immune function, and…you guessed it…digestive activity and rhythm.
But everything is not set solely by the master clock and the day/night cycle. The peripheral clocks, which include clocks in the liver, gut, adrenals, muscles, and basically everything not in the brain, are set by food. And not what you eat, but when you eat. Specifically feeding/fasting cycles.
Under ideal conditions, the master clock and peripheral clocks are all in sync. When this happens, you are optimally set up to interact with the environment. If they get out of sync, problems are sure to follow.
Circadian timing and fasting
Pretty much every important function of the gut follows a circadian pattern. These patterns are set both by the master clock and the peripheral clocks in the gut.
That’s right, there are actually multiple clocks in the gut we need to worry about: the gut clock itself, and the microbial clock. And while we’re at it, we should throw in the liver clock as well since the microbial clock does a large portion of its work by interacting with the liver clock.
All the peripheral clocks and the microbial clock are set by feeding/fasting cycles. And while when you eat is important, the most important aspect is that there is a feeding/fasting cycle at all.
Mouse studies in circadian disruption bear this out. Even mice fed a diet that normally makes them obese, during the time that they should normally be sleeping, and under constant light conditions are protected from obesity if they follow regular periods of feeding and fasting(2, 3).
What’s more, if you compare them to mice that eat exactly the same food and total calorie load that don’t fast, they’re healthier and leaner. And it’s not that these mice are simply skinnier. Metabolically, they are far healthier even if they’re only exposed to fasting during the weekdays(4).
This is not to say that eating out of sync with the day/night cycle is optimal…it’s not. Humans operate best when both the master clock and peripheral clocks are in sync with each other AND the day/night cycle. What it does indicate is that when you eat is probably not nearly as important as having an extended fast at some point during the day/night cycle. At least as far as avoiding metabolic diseases such as Type 2 diabetes, cardiovascular diseases, hypertension, and obesity are concerned.
There is also evidence that functional bowel disorders may be consequences of disrupted circadian clocks(5, 6, 7). This effect is likely mediated through out of sync clocks, particularly the master, gut, and microbial clock.
Circadian timing and the gut
There are a number of ways that circadian rhythms affect digestion. First, motility and digestive enzyme output both follow a circadian rhythm. Typically, they’re optimized during the day when the master clock, gut clock, and microbial clock are in sync with the day/night cycle.
When this happen the effect is truly amazing. Motility and enzyme output actually precede eating. This anticipatory effect helps optimize your ability to digest and absorb nutrients. It also ensures that things are continually moving along the gut if you know what I mean.
This anticipatory effect becomes entrained when your meal schedule is fairly consistent for a period of time. In other words, eating on an erratic schedule will prevent this beneficial effect whether you eat at night or during the day.
Mucosal defense factors such as mucus production and antimicrobial protein secretion also follow a circadian pattern. Like digestion and enzyme output, these factors are typically optimized during the day.
Detoxification is another aspect of digestion that follows a circadian rhythm. Most people don’t realize this, but the food you eat contains many toxins. These toxins are a defense mechanism to prevent you from eating them. Obviously, we see plants as food but plants don’t quite see it that way.
When our detoxification receptor expression and enzyme output are high, we actually get a benefit from these toxins. We benefit from foods like turmeric, broccoli, and blueberries because our body hyper-responds to them and they induce detoxification pathways.
This works great if detoxification is optimized when we’re eating. If these pathways are not in sync with our eating, these plant-based toxins can accumulate and cause ill-effects. Again, under ideal conditions, this works best when you eat during the day and avoid eating at night.
Many of the herbs people use to treat gut problems are also processed in this way. If everything is out of sync, these herbs may make you feel worse, not better.
When you’re firing on all cylinders from a circadian perspective, detoxification receptors and enzymes are expressed highly during the day and less so at night. Of course, this makes sense since your gut is exposed to the vast majority of toxins while you’re eating. But this has other highly beneficial aspects to gut health that you should care deeply about.
Circadian timing and detoxification
There are a number of additional benefits to having detoxification receptors and enzymes expressed higher during the day. The beneficial effect of foods like turmeric and broccoli being one.
Another important benefit is that beneficial bacteria in your gut communicate with us through these receptors. This allows them to perform many important processes that keep the gut healthy and free of pathogens. Since they also follow a circadian pattern, we have to sync the microbial clock.
The microbial clock is a critical link in regulating the liver clock. Metabolites from the microbiome cross the gut wall and enter the portal vein. From there, they go right to the liver and help sync the liver clock. This has a substantial effect on your metabolism, detoxification capacity, and bile acid metabolism.
It also has a powerful effect on the health of your gut. Detoxification, inflammation, and the intestinal barrier are co-regulated with one another. Having a high expression of detoxification receptors and enzymes during the day when you eat helps keep your gut sealed, inflammation at a minimum, and helps regulate the microbiome.
When detoxification receptor levels are high, inflammation is suppressed in at least 2 ways. First, inflammation is suppressed at the genetic level through inhibition of nuclear factor kappa beta. NF-kb is a key regulator of inflammation throughout the body.
Inflammation is also suppressed through a decrease in toll-like receptor(TLR) expression. Toll-like receptors are monitors of the gut that are chiefly looking for components of pathogenic bacteria. When they find what they’re looking for, they fire up inflammation in a big way. Reducing TLR count lowers your sensitivity to bacteria, good and bad. I’ve covered all these factors in a previous blog you can find here.
A higher level of detoxification receptors also prevents so called “leaky gut”. When detoxification receptor levels are high, tight junction proteins that help seal the gut are also high. This prevents the contents of your gut, both food and bacteria, from interacting directly with your immune system and causing inflammation.
There’s definitely a synergy to all of these effects with the microbiome. Having a higher expression of detoxification receptors allows the beneficial bacteria in your gut to communicate in a way that promotes a healthy gut environment.
It also allows the microbial clock to interface with the gut and liver clocks to sync the 3 clocks together. The ultimate result is a healthy gut and a healthy metabolism.
Syncing your circadian clocks is all about communication. If the lines of communication between your clocks aren’t working properly, you could be in for a host of problems.
Taken from: http://www.lagunabeachbikini.com/standard-sports-photos/2011/AngelsBrewers-24Mar2011/bin/images
The importance of circadian communication
Imagine if you will, 2 people playing catch with each other. This seemingly simple act relies on communication. The person catching the ball has to know that the person holding the ball is going to throw it. In essence, the catcher needs to anticipate when the thrower will throw it.
In the same way, hormones form a line of communication between cells that are basically playing catch with one another. High glucose causes the pancreas to secrete insulin. This insulin will bind to a muscle cell and cause it to take in glucose.
Unless, of course, that cell isn’t sensitive to insulin. In such a case, the muscle cell doesn’t “catch” insulin or glucose and blood levels of both rise. The muscle cell drops the ball.
Since insulin sensitivity is under circadian influence, if the muscle clock isn’t in sync with the pancreas clock, they can’t play catch. The pancreas may throw the ball but the muscle cell drops it, high insulin and glucose in the blood being the net result.
This underlies the importance of properly syncing your clocks and the consequences bear this out in the scientific literature. People who work the late shift and/or experience regular circadian disruption are at a higher risk for Type 2 diabetes and cardiovascular disease(8). All because their cells don’t play well together.
Circadian communication: peripheral clocks
This simple illustration of playing catch gets a whole lot more complex when you’re dealing with interrelated systems in the body. When certain factors are dependent on others, it’s more like 4 people playing catch with one another. And if the 2nd player doesn’t catch the ball, it completely throws off players 3 and 4.
Your peripheral clocks must be synced together for everything to run smoothly. Your microbial clock must be in sync with your gut clock which must be in sync with your liver clock which must be in sync with your adrenal clock, and so on. Nothing illustrates this better than the rhythm of cholesterol, bile, and cortisol.
One critical factor for optimal digestion that I’ve brought up repeatedly in my blogs is bile output. Bile is an intersection between many systems . We process and remove toxins through bile, remove excess hormones through bile, regulate our microbiome with bile, and digest and absorb fats with bile.
Bile output follows a circadian rhythm that gets set by periods of fasting and feeding. Activity of the rate-limiting enzyme that synthesizes bile from cholesterol, cholesterol 7alpha-hydroxylase(CYP7A1), is under circadian regulation. The general trend leads to higher levels during the day and lower levels at night(9). But this game of catch has many players which makes it a bit nuanced.
Since cholesterol also follows a circadian pattern, CYP7A1 is effectively playing catch with the rate-controlling enzyme of cholesterol synthesis, HMG-CoA reductase. Serum cholesterol follows an almost opposite trend as bile acids, peaking at night and dropping during the day.
The circadian variation of HMG-CoA reductase is regulated both by light and feeding/fasting cycles. Therefore, cholesterol synthesis is regulated by both the master and peripheral clocks. But bile acids aren’t the only important molecules synthesized from cholesterol.
Steroid hormones, which include sex hormones as well hormones secreted by your adrenal glands are also made from cholesterol. This includes:
- Androgens(Testosterone and it’s metabolites)
And these guys want to play catch too. Therefore, cholesterol is playing catch with both bile acids and steroid hormones.
Taken from: https://classconnection.s3.amazonaws.com/33/flashcards/602033/jpg/cholesterol_metabolism1314336276354.jpg
If the circadian rhythm of cholesterol availability is thrown out of sync with the rhythm of bile synthesis, you won’t be able to make enough bile. If your adrenals are calling for glucocorticoid production but they are out of sync with cholesterol availability, you won’t be able to make adequate cortisol. If both are out of sync with one another and cholesterol availability, the whole system is thrown out of whack.
We can see here the importance of syncing your peripheral clocks. What’s interesting is that both bile and cortisol are high first thing in the morning while cholesterol is high at night. This may indicate, at least in a general sense, that the high cholesterol synthesis at night is in preparation for the high synthesis of bile acids and cortisol that occurs in the morning.
This not only underscores the importance of proper communication and syncing of the peripheral clocks, it brings in to focus the importance of syncing your master clock to your peripheral clocks. While bile acid synthesis isn’t directly regulated by the master clock, it’s indirectly linked through the need for cholesterol to synthesize it.
Both cholesterol and cortisol are directly regulated by the master clock to some extent. If everyone wants to play catch, the master clock must sync to the peripheral clocks. And that requires communication between the master clock and peripheral clocks.
Circadian communication: Master and peripheral clocks
If you’re having trouble seeing the importance of proper communication and syncing your clocks, think about this scenario. You eat under a normal schedule but exposure to light during your usual dark period throws your cholesterol rhythm out of whack.
Now, cholesterol synthesis peaks a few hours later but you’re still a slave to waking up at 7am and eating breakfast before work. You still need high cortisol output in the morning to wake up, but your cortisol rhythm is also out of sync since it too is regulated by the master clock and exposure to light. Now, you don’t wake up so easy. You also have a problem going to sleep at a decent hour and staying asleep once that happens.
Groggy, you make your breakfast and sit down to eat it. You need bile to help digest fats, but since your bile rhythm is dependent on your cholesterol rhythm, it’s out of sync too. You need bile now to digest your food, but it’s just not there. But that’s not the only problem.
Bile is also responsible for regulating your gut and microbiome. You’re putting food down your pie-hole and exposing yourself to microbes and toxins but you aren’t getting the antimicrobial or gut sealing effects of bile. This increases inflammation, the likelihood that pathogens and commensals can overgrow, and makes you more sensitive to the toxins in your food.
It’s not that your liver doesn’t know you need bile. But without sufficient time to convert cholesterol in to bile, it can’t get it to the gallblader in time to anticipate your meal. Now, your bile is highly saturated with cholesterol and sitting in your gallbladder which can lead to gallstones. All this simply because your master clock is running slightly out of sync with your peripheral clocks.
But that’s not all. With your cholesterol rhythm out of whack, your cholesterol levels appear elevated. I say appear because serum cholesterol is a fasting test that’s almost always taken in the morning. Very few people set that appointment in the afternoon or they’d have to fast all day long.
With this test, all we know is that your cholesterol is elevated at the time your blood was taken. The assumption is that since it’s elevated when you have it taken, it’s always elevated. Make no mistake, unless you measure it several times throughout the day, this is only an assumption.
But what if it’s not elevated chronically? What if your circadian cycle of serum cholesterol is just off and is now high in the morning when it should be low? Does lowering your cholesterol with a statin or PCSK9 inhibitor seem like an effective solution to this problem?
As you can see, it’s critically important that your peripheral clocks communicate with your master clock. But how do they communicate? The answer may surprise you.
Hunger-A signal that all your clocks are in sync?
We obviously need some lines of communication between the brain and peripheral clocks for them to sync properly, but are there any candidates up to the task? The vagus nerve, which connects the gut to the brain forming the gut-brain connection, is a pretty good candidate. It probably plays some role, but I think there may be an even better candidate.
Ghrelin is a hormone secreted by the stomach when it’s empty. When the stomach is stretched due to food intake, ghrelin secretion is stopped. Thus, ghrelin levels are typically highest right before you eat and lowest right after. This makes it a reliable indicator of the feeding/fasting cycle that entrains your peripheral clocks
Ghrelin has a couple of important roles in the gut and throughout the body. It increases growth hormone secretion, but also plays an important role in the gut by stimulating stomach acid production and gut motility during fasting(10, 11). It also helps regulate blood glucose by blocking insulin secretion by the pancreas. Note: Insulin is a powerful regulator of peripheral clocks.
Ghrelin also has a very important distinction from most other proteins in the body: it can cross the blood brain barrier. This indicates that ghrelin could function as a communication factor between the master and peripheral clocks.
Ghrelin in the brain
When ghrelin crosses the blood brain barrier it binds to receptors in the hypothalamus to induce hunger. This effect has given ghrelin the nickname “The hunger hormone”.
The perception of hunger is an indication that the stomach is secreting ghrelin and this ghrelin is binding to receptors in the hypothalamus. In a general sense, the brain and gut are communicating and hunger tells you this.
Since ghrelin is regulated by the feeding/fasting cycle and it crosses the blood brain barrier, it’s an attractive target to be the ball that the central and peripheral clocks are playing catch with. In other words, it may help sync your clocks.
There is a good amount of evidence that this is the case. In the stomach, ghrelin secretion is set by clock genes that are regulated by food intake and still follows that rhythm without input from the master clock(12).
However, ghrelin receptors in the hypothalamus receive direct input from the SCN(13), indicating interaction with the master clock. Evidence also indicates that there is at least some modulation by the master clock as mice without ghrelin receptors show opposing effects when housed in constant light vs constant dark conditions(14). The most pronounced effect was a change in physical activity/movement that typically precedes feeding.
The effects of ghrelin in the brain are not reserved to the perception of hunger and increased movement. Once it crosses the blood brain barrier, ghrelin has a few interesting effects. In addition to inducing hunger, it also helps regulate mood, food reward, the HPA axis and stress response(15), and functions as a neuroprotectant(16).
Ghrelin and the migrating motor complex
It probably seems a bit counter-intuitive that a hormone secreted while fasting would stimulate gastric acid secretion and gut motility. But the stimulation of these factors by ghrelin is specialized to the fasting cycle and optimizes the housecleaning effects of the migrating motor complex(17). For more on the migrating motor complex, this blog covers it in detail.
Ghrelin induces phase III MMC contractions in the stomach. MMC cycles that begin in the stomach are the strongest and most effective at cleaning the gut. This means that hunger may be a signal that the gut is getting the thorough cleaning it needs regularly to help set the microbiome and microbial clock, which helps set the liver and gut clocks. Once it enters the brain, it may help sync the master and peripheral clocks.
Hunger is a feeling most people avoid these days. With 24 hour access to any type of food you could imagine, there is no need for hunger. Or is there?
Many people in today’s society are living completely out of sync with their biology. In recent years, a lot of research has been focused on how living out of sync with light and the day/night cycle affects health. The evidence points to a substantially increased risk of Type 2 diabetes, cardiovascular disease, and neurodegenerative diseases in those who interrupt the day/night cycle with constant exposure to light and disrupted sleep.
There’s also a good deal of evidence that eating out of sync with the day/night cycle can have ill effects. Eating at night due to shift work creates the same sort of problems as constant exposure to artificial light, but it may not be the most important food-related cue.
Despite an increasing body of evidence on how detrimental it is to have disrupted circadian clocks, very little attention has been paid to fasting/feeding cycles, at least in humans. In mice, it appears that having a regular fasting period is more important than when they eat or even, to some extent, what they eat.
For most people, this opens up an unexplored avenue in improving health. The more we learn about the importance to the clocks and how they help adapt us to the environment, the more important it becomes to find ways to be more in sync with your environment.
Fasting is not really new, but as a therapeutic application to improving gut problems, it may be the most important therapy you’ve never tried.
Think you’re living out of sync with your clocks? Need help getting your clocks in sync with one another? I’ve been tinkering on my lonesome with a program I’ve developed and have some pretty incredible results. Interested in knowing what changes I saw? Join my private facebook group here and you can get the deets.
In the near future I’m going to release this program for a few people on a pilot basis at a reduced cost. Believe me when I tell you, what you get from this program will completely change your life and perspective on health.