Is bile the key that turns on the gut clock?

If you’ve found your way to this blog, chances are you’ve heard of the term “leaky gut”.  You’re also probably familiar with how chronic inflammation can wreak havoc on your health.  In a previous blog I went over how the gut regulates how leaky and inflamed it is via the pregnane X receptor.  If you haven’t read that blog, check it out here because it will be important to grasp that concept a little later.

One of the problems with a lot of the information out there on gut health, particularly the stuff on leaky gut, is that it’s never given in the proper context.  Most people are left with the impression that the gut is either leaky and it leads to poor gut health and disease, or it’s not and you’re gut is a picture of health.  Well the problem with this is that it’s flat out wrong.

It may come as a surprise to you, maybe even a shock, but your gut becomes leaky every day.  Not a day goes by where there’s not some period of the day where the gut is leakier than it normally is.  And this is completely normal.  Tight junction proteins, the things that anchor the cells of your gut together and keep them tightly packed, are regulated by circadian rhythms(1).  This means that they vary throughout the day based on the environment.

Taken from: http://d13geadg2uyg93.cloudfront.net/content/jap/107/6/1972/F1.large.jpg

Circadian rhythms and gut health

I’m not going to jump down the 3000 word blog rabbit hole and go all comprehensive on the way circadian rhythms regulate gut health because I already did that here.  In this blog we’re going to take more of a philosophical look at how circadian rhythms are important for gut health and why proper bile flow is crucial for it all to work.  More on that a little later.

Circadian rhythms adjust our physiology so that we are more successful at adapting to our environment.  Environmental cues called zeitgebers send information about the environment to our organ systems through hormone and protein signaling .  These hormones and proteins alter genetic expression in target tissues which adjusts our physiology to the environment.

Each target tissue(Liver, gut, pancreas, kidney, etc.) has its own clock.  Even your microbiome has its own clock.  These clocks are called peripheral clocks and are primarily set by the feeding/fasting cycle.  The master clock, found in area of the brain called the suprachiasmatic nucleus(SCN), is set by light.  The master clock also holds some control over the peripheral clocks, but the peripheral clocks beat to their own rhythm even in the absence of light signals to the master clock.

In order for your body to function optimally, all of your clocks need to be synced with one another.  When your clocks are misaligned, everything functions on its own schedule.  As you can probably guess, organs doing random things at randoms times is very bad, especially organs that are dependent on properly timed signals from other organs.

Thus, circadian rhythms have a huge effect on many aspects of our health, including gut health.  With regard to digestion, circadian rhythms help prepare the gut for food by preparing an anticipatory secretion of gastric acid and digestive enzymes right before we eat.  They also increase the expression of transporters that carry digested nutrient in to the circulation.  This optimizes nutrient digestion and absorption.

But that isn’t the only important gut factor regulated by circadian rhythms.  When we consume food, there are hitchhikers along for the ride.  These hitchhikers include bacteria, environmental toxins, and a bunch of other things that we don’t want entering through the front door.  As such, the gut needs to be ready for these things before they get there, and circadian rhythms do just that.

Pregnane X receptor and the gut

The pregnane x receptor(PXR) is a xenobiotic receptor found ubiquitously in the gut and liver.  The reason there’s a high level of PXR expression in these tissues is that they are the primary detoxification organs in the body and, among other things, PXR binds toxins, turns them water soluble, and eliminates them from the body in the feces or urine.

When a ligand binds to PXR, a couple of other interesting things happen(note: a ligand is something that activates a receptor).  First, there is an increase in the expression of tight junction proteins, our friends I mentioned above that reduce the leakiness of the gut.  This makes sense, you wouldn’t want to turn a toxin water soluble, spit it back in to the gut, only to have it slip right back in through a leaky gut.

That’s not the only beneficial effect of having a ligand bind to PXR.  There’s also a pretty robust anti-inflammatory effect due to inhibition of nuclear factor-kappa beta(NF-kb).  Again, this makes sense.  High levels of inflammation promote cell death and decrease tight junction protein levels.  Having a lot of inflammation in your gut when you’re putting food through it can cause major problems with gut function.

But what binds to PXR and activates it?  There are a number of things.  A large swath of pharmaceutical drugs and herbs activate PXR.  In fact, Xifaxan is a powerful PXR ligand that increases PXR levels in cells.  Many environmental toxins also bind to PXR.

Even your gut bacteria get in on the action.  Metabolites such as indole 3-propionic acid generated by beneficial bacteria in your gut bind to PXR(2).  This is how certain bacteria prevent leaky gut and block inflammation in the gut.  But in order for these things to work, PXR expression needs to increase at some point during the day.

Taken from: https://upload.wikimedia.org/wikipedia/commons/thumb/7/7d/Microbiota-derived_3-Indolepropionic_acid

This is why it’s important to have context.  If you have a leaky gut when you’re sleeping, that’s probably not an issue and probably even normal.  Having a leaky gut when you’re putting food in your piehole…that’s not a good thing.

The underlying circadian dichotomy

If you haven’t noticed, the purpose of circadian rhythms is to form a sort of dichotomy.  In order for an organ system to work properly, there needs to be a portion of the day when it’s doing it’s job and a portion of the day when it’s doing maintenance to repair any damage caused by using it.

This is where the proper exposure to zeitgebers is important.  The zeitgebers are effectively communicating to the body that the best time to function is x and the best time to repair is y.  If you manipulate them properly, you can take advantage of the powerful effect circadian rhythms have on improving your gut health by sending the appropriate signals at the appropriate times.

Now all we need to know is the hormone or protein that’s regulated by zeitgeber exposure and turns on the clocks.  Since we know PXR has a pretty powerful effect on regulating the gut, there’s a pretty good chance that whichever protein is turning the gut clock on is activating PXR.  We happen to have a pretty good candidate for that in bile.

Bile helps set the circadian clock

Bile is a fluid secreted by the liver in to the gallbladder for storage or directly in to the gut.  It serves many functions in the gut including emulsification and absorption of fat and fat soluble nutrients, modulating the microbiome, and promoting gut health.  I covered this in a blog you can find here.

Bile is composed of bile acids, bile pigments, phospholipids, and processed toxins.  Bile acids do the bulk of the work with regard to digestion and absorption as well as regulating the microbiome.  Bile acids are antimicrobial, and they cause the release of antimicrobial peptides in the ileum when they bind to a bile acid receptor call the farnesoid x receptor(FXR).

The primary role of FXR is to promote the recycling of bile acids.  When bile acids bind to FXR, they get sent back to the liver and are reused for your next meal.  This also limits the synthesis of new bile acids by the liver.  Approximately 95% of the bile acids entering the gut every day get recycled.  The 5 % that escape enter the colon and are acted on by bacteria there.  This low level of bile acids entering the colon is a good thing, but high levels of bile acids in the colon causes bile acid diarrhea.

FXR also has a secondary effect.  It appears that FXR also also regulates PXR.  When bile acids bind to FXR, it causes an induction of PXR in the cell.  As mentioned above, more PXR means more tight junction proteins, better detoxification, and less inflammation.  This indicates that bile may play a crucial role in preparing the gut for food by increasing mucosal defense.  In other words, it may start the gut clock.

Evidence for the role of bile in regulating circadian rhythms

In order for a hormone or protein to help regulate circadian clocks, it has to affect multiple organ systems.  Bile fits this role as it’s made in the liver, secreted in to the gut, and may play a role in regulating metabolism in peripheral tissues such as the pancreas, brown adipose tissue, skeletal muscle, and cardiac muscle.  While we don’t know exactly how bile affects these tissues, they all express bile acid receptors.  The current thought is that bile acids help regulate metabolism in these tissues, but the evidence is sparse and conflicting(3).  Below is a graphic overview of the potential functions of bile in peripheral tissues.

Taken from: http://www.kalsbeekgroup.nl/mediapool/133/1333280/resources/27793125.jpg
Interesting note: bile acids found in the brain may be made there and not coming from the liver

Another important feature is that the protein must be regulated in a circadian manner.  Studies have shown that circadian misalignment alters bile acid homeostasis and disrupts the gut(4).  One study even found that secondary bile acids, products of bacterial fermentation of the primary bile acids produced in the liver, help regulate circadian genes in the ileum, colon, and liver(5).  Since the production of secondary bile acids are effectively one clock(microbial clock) changing the product of another clock(liver clock) to communicate with a third clock(gut clock), you can see how important bile acids are in the communication between peripheral clocks.

Zeitgebers and bile ouput

As I mentioned above, the master clock is primarily regulated by light exposure while the peripheral clocks are primarily regulated by the feeding/fasting cycle.  But these aren’t the only important zeitgebers for regulating bile flow.  Physical activity is also an important zeitgeber for bile output.

During cardiovascular exercise, red blood cells die and release their hemoglobin, which is broken down in to carbon monoxide, iron, and biliverdin.  Biliverdin is quickly converted to bilirubin which gets sent to the liver and in to the gut with bile.  Bilirubin and biliverdin form the majority of bile pigments secreted with bile.

It’s very important that bilirubin not accumulate in the blood as it is toxic at high levels.  So exercise increases bilirubin in the blood which increases bile output from the liver.  Although bilirubin is toxic at high levels, at the levels normal seen in a healthy individual, it functions as a fat soluble antioxidant and probably helps repair damage in the gut and throughout the body.  For more info on the powerful antioxidant effect of bilirubin, check out this blog here.

Optimizing bile flow

At this point you’re probably wondering how you can determine if you have good bile flow.  Probably the only way accessible to you is the color of your feces and urine.  Bacteria in your gut act on the bile pigments to give feces its distinctive dark brown color and urine its straw yellow tint.

There is a problem with this approach, however.  Since the bile pigments need to be converted by bacteria, if you lack the bacteria necessary to convert bile pigments your feces will be orange or green and your urine clear even if you have good bile flow.  I have a feeling that some of these bacteria are always present since you will always have some level of bile flow.  But increasing bile flow too quickly could lead to bile acid diarrhea or the aforementioned green/orange poo.

To optimize bile flow, the most important factors involve manipulating your exposure to the zeitgebers mentioned above.  This includes proper light exposure, regular feeding/fasting windows, and properly timed physical activity.  Doing this right will optimize your bile flow and help improve your gut.

If you have problems even after doing that, there are a few foods and supplements that can help improve bile flow.  These include artichokes, taurine, and guggulsterones.  It’s important to note that it’s probably not a great idea to randomly increase bile output as it is almost certain to lead to bile acid diarrhea if you don’t yet have the machinery to recycle bile acids.  That’s why it’s important to optimize circadian rhythms first as this will promote the expression of FXR and PXR in the gut.

Conclusion

Bile flow is very important to gut health.  Based on the evidence to date, I think it’s safe to say that bile plays an important role in aligning your peripheral clocks.  Therefore, optimal bile flow is contingent on proper circadian alignment between your master and peripheral clocks.

The proper place to start on improving bile flow is the manipulation of zeitgeber exposure.  This includes properly timed light exposure, feeding/fasting cycles, and physical activity.  This will dramatically improve gut function and help determine if there is an issue somewhere else down the line.

If you still have issues after syncing your clocks, you may have a microbial dysbiosis issue.  Bacteria act on bile pigments and bile acids, converting them to other molecules that perform various functions.  For the most part, improving zeitgeber exposure will help with this gradually, but you may need some extra help.  Adding artichokes to your diet, supplemental taurine, or guggulsterones can get you moving if you are still having issues.  As always, consult with your healthcare practitioner before beginning any therapeutic approach with supplements.

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