There are a number of core processes going on in your gut that help maintain healthy digestion.  For the most part, you’re completely unaware that these processes are plugging along until something goes wrong.  Once these processes go awry, havoc ensues.  Rampant inflammation, altered motility, sluggish detoxification, and leaky gut quickly transform your healthy gut in to a daily nuisance.

There’s a trio of processes that work together to keep your gut healthy.  These 3 processes are detoxification, inflammation, and tight junction protein expression.  Proper gut function involves the co-regulation of these 3 processes.  When the process of cellular detoxification gets initiated, inflammation is inhibited and tight junction protein expression is increased.  When inflammation gets initiated, detoxification is inhibited and tight junction protein expression is decreased.

At the center of this triumvirate is the Pregnane X receptor(PXR).  PXR initiates the 3 phases of detoxification; reduction, conjugation, and transport.  Get this puppy to fire up and you’ll detox, crush inflammation in it’s tracks, and seal up a leaky gut.  Not sure this is the case?  There’s evidence all over the place(1, 2, 3, 4).  PXR is heavily studied because it regulates pharmaceutical drug metabolism.  In fact, Xifaxan induces PXR as an added bonus to its antibiotic effect.  It’s parent drug Rifampicin induces PXR more than any other compound.

Another important factor in maintaining a healthy gut is the production of bile acids.  Bile acids help you emulsify and absorb fats and also have antimicrobial effects.

Two attributes of bile also keep bacteria from overgrowing in to the intestine.  Bile acids disrupt bacterial cell membranes as they travel through the small intestine.  When they reach the ileum, they bind to bile receptors that release antimicrobial proteins.

When bile acids bind to the Farnesoid X Receptor(FXR), enterocytes release antimicrobial proteins(5).  Of particular interest to SIBO in the ileum, FXR is highly expressed there.  Little bile makes it in to the large intestine, that’s why far more bacteria live there.  Having FXR in the ileum provides a protective measure against bacterial migration from the colon.

Vitamin A: A common link

Note: A ligand is the molecule that binds to a receptor and causes those genes to be expressed

When we look at the receptors involved in these processes, one common link pops up.  Both PXR and FXR form heterodimers with the Retinoid X Receptor(RXR).  This means they bind to RXR to form a sort of super receptor that are triggered by ligands for either or both receptors.  When a ligand binds to either PXR or FXR, genetic expression of that process increases.  When 9-cis retinoic acid binds to RXR at the same time, it’s like pressing the turbo button on gene expression.  (9-cis retinoic acid is an analogue of vitamin A and the ligand for RXR)

These 2 receptors aren’t the only nuclear receptors that form a heterodimer with RXR.  Other nuclear receptors that form a heterodimer with RXR include:

• Thyroid receptor(TR)
• Vitamin D receptor(VDR)
• Liver X Receptor(LXR)
• Constitutive androstane receptor(CAR)
• Peroxisome proliferator-activated receptor(PPAR).

In the gut, CAR functions in cellular detoxification and energy metabolism(6), PPAR helps regulate inflammation and energy metabolism(7), TR regulates energy metabolism, and the VDR regulates inflammation, the microbiome, and bile acid detoxification(8).  A deficiency of vitamin A negatively impacts all these functions.

Getting enough vitamin A

The solution to this problem seems simple enough, get more vitamin A.  The problem is, the type of vitamin A matters.  There are 2 forms of vitamin A, retinoids and carotenoids.  We’re interested in retinoids since we’re looking to fire up the retinoid x receptor and it is the active form of vitamin A in filthy animals such as ourselves.  Retinoids are found in animal-based foods while carotenoids come from plants.

Carotenoids do get converted to the retinoid form in the gut, but this process is variable.  Factors that can affect your ability to convert carotenoids in to retinoids include:

• Genetic factors
• Bacterial imbalances
• Alcohol
• Certain medications and supplements

Furthermore, the fat soluble vitamins (A, D, E, & K) affect the absorption of one another.  In other words, people who supplement with vitamin D must also supplement with the other 3.  Not doing so can cause a deficiency in one or more of them.

Based on my Ubiome data, a Paleo diet was not providing a lot of retinoids.  Bacterial retinoid metabolism in my gut was 40% of most people.  I was eating a lot of meat, but wasn’t getting enough retinoids.  Adding liver 2x/wk increased this 400%.  This doesn’t mean I wasn’t converting carotenoids to retinoids in the body, only that I wasn’t eating much of it.  Although, I do have a couple of the genetic SNPs that impair conversion of carotenoids to retinoids.

 

The first step in getting enough vitamin A is to eat both kinds.  In my experience muscle meat doesn’t supply enough retinoids.  My recommendations are pretty simple, eat 4oz of liver every 4-5 days.  Other animals products with significant amounts of retionids include eggs and ghee.

You should also eat sweet potatoes, yams, carrots, or other high vitamin A veggies.  I recommend doing this daily.  You want to eat vitamin A from both sources as each performs different functions.  Since we’re looking to manipulate RXR, a weekly source of retinoids is important.  Keep in mind there’s the potential for toxicity from retinoids which isn’t an issue for carotenoids, but this is probably more of an issue in people who supplement with them and not people who eat foods high in retinoids.

This is why I shoot for liver a little more than once per week.  Eating something like liver weekly should provide you with ample retinoids to power your day to day without risking overdose.  Most fat soluble vitamins don’t need to be eaten every day since you store them, so you don’t have to go crazy eating them every day.

One of the drawbacks for people with IBS, SIBO, or IBD is that many have poor fat absorption.  Since fat soluble vitamins get absorbed with fat, fat malabsorption is always accompanied by poor fat soluble vitamin status.  Fats need bile acids to emulsify them.  This allows enzymes to break fats up so they can enter micelles and get absorbed.

 

Many believe that the issue is due to poor bile production, but vitamin A is a player here.  More bile would be better from an absorption perspective, but if you’re low on vitamin A you’ll have a problem detoxifying bile acids.  This process is performed by PXR and VDR, and not doing so can cause more damage.  The inflammation that toxic secondary bile acids can cause will almost certainly throw the entire digestive process off.

I realize that most people don’t like liver, but there are many more reasons to eat it.  It has other nutritional factors that make it a powerhouse to improve digestion including folate and choline.

We all know how important our liver is for so many of the processes that keep us alive and functioning optimally.  Other animals, particularly mammals, have these same functions that are powered by the same nutrients.  Naturally, liver from these animals supports our liver function with these very nutrients.

As far as dessicated liver tablets, I’m not sure they are a good choice.  A lot of them are de-fatted and I’m not sure how well the fat soluble nutrients fare in the dessication process.  Some people cook liver, chop it in to tiny pieces, freeze it, and take it like a pill.  This is an acceptable option provided you aren’t overcooking it.  Rare/Med rare is better.

In the future I will go over multiple ways you can improve bile flow as well as fat digestion and absorption.  Most of these tips will only be available to facebook members, so stay tuned!  If you’re interested in joining the group, request to do so here.

Got questions?  Need more info?  Post in the comments section.  I know this one was pretty thick on the science but I have some companion blogs coming out shortly to clarify some things.