This unknown molecule is the hidden gut healer

• Bloating

• Brain Fog

• Low mood

• Low energy

• Constipation

All of these issues arise from a dysbiotic gut, leading to destroyed defensive mechanisms in the whole GI tract.

These issues will spread over systemically, as the gut is the centre of our health potential.

Now, what if may tell you, that there is a compound in charge of deciding, which type of microbes harbor our gut?

That there is a regulatory molecule, steering the ship of inflammation, gut homeostasis & digestion?

The same compound increasing survival rate in sepsis mice by 60%.

From 20% up to 80%.

Sepsis is a surge in pathogen load in the body, which leads to an inflammation response so big, that the consequence might be death.

Now, to set that into context, in conditions of SIBO or any other gut issue, there is a small increase of so called endotoxins, toxins produced by bad bugs.

On a micro level, if you suffer from these issues, you slowly die from a slow drip sepsis.

Last but not least, is that this compound is associated with longer life spans. You might call it a pro longevity molecule.

So, what is this miracle molecule?

What the hell are IAPs?

IAPs or intestinal alkaline phosphatases are enzymes belonging to the class of alkaline phosphatases. The ones I talk about today are mainly expressed in the gut, where they have their impact.

The general reaction these enzymes catalyze (=do), are cleavages of so called phosphate groups.

We all know and love ATP, the energy currency of our cell. IAPs are able to cleave of one of the three (adenosine-tri-phosphate) and turn it subsequently into ADP (adenosine-di-phosphate).

Simple as that, right?

The same goes for other nucleotides, harboring phosphate groups like ADP, UTP, GTP, TTP.

Now you might ask, what is so special about them that they are actually preventing sepsis, steering the ship of inflammation & are a pro longevity compound.

The main is reason is its endotoxin lowering abilities.

Endotoxin is the main enemy of gut health

Endotoxins are toxins produced by pathogenic bacteria.

One of the most famous ones is LPS (lipopolysaccharides). You should care about them as this stuff is heavily associated with:

• cancer

• obesity

• brain fog

• alzheimers

• low energy

• liver damage

• septic shocks

• lower lifespan

• type 2 diabetes

So all of the stuff we don’t want is associated with this toxin. But why is that?

Simple, as our body sees LPS as a marker of bacterial infections. We do not like bacterial infection.

So whenever LPS is present, a huge increase in inflammatory reactions & molecules takes place.

To understand the role of IAPs in this scenario, we have to do a little deep dive into the mechanisms at play.

LPS & the Toll-Like-Receptor 4 pathway

LPS is a ligand to the toll-like-receptor 4 (TLR4). Whenever the LPS binds to that receptor, an inflammatory cascade gets into play via two pathways:

• Myd88 dependent

• Myd88 independent

We do not have to know the nitty gritty details here, but remember, that the binding of LPS to TLR4 leads to a massive surge of inflammatory cytokines like NF-kappa-b, TNF-alpha, Il-6,…

All of these cytokines are at play when we talk about gut dysbiosis & diseases.

These all wreck havoc on our 4 main defending mechanisms of gut health:

• IAPs

• gut barrier

• IAMPs

• mucosa layer

If these fall, our health will start falling soon after. So LPS is one of THE MAIN ways of disease.

But what awards LPS this affinity to TLR4? It is a small molecule inside the LPS, called the lipid A. This lipid is the sole reason LPS can induce such a damage via the TLR4 pathway.

Here steps in our IAP. This enzyme has the ability to cleave of one of the two phosphate groups of Lipid A, reducing the affinity to TLR4 by 100x.

This is MASSIVE. So now, even if there is some LPS present, the damage done is minor compared to the normal pathway.

You remember the septic shock thing? One reason why this is so deadly is because of a rapid influx of inflammatory cytokines, brought up by, you guessed it

LPS or endotoxin

Giving IAPs lowered the affinity of it to TLR4, lowering the amount of inflammation in the body. This is crazy, right?

But the magic doesn’t stop here.

Microbiome regulation

IAPs play a huge role in microbiome regulation. They not only decide wether microbes are allowed to grow or not, they are also in charge of overseeing good bugs & bad bugs.

But how are they doing that?

As you know, we harbor millions & millions of bacteria in our gut. Some are good, some are bad. Whats important is that the good overweight the bad by some margin.

Now, as these bugs are living creatures, they have metabolic byproducts & die someday. This leads to an accumulation of not only LPS, which is under control if there is sufficient IAP, but also ATP.

ATP seems nice, right? It is the energy currency, after all, we need it to live. We all could need some more.

But this could not be farther from the truth:

eATP or extracellular ATP in the gut lumen is a marker of intestinal dysbiosis, leads to inflammation,leaky gut & shifts the microbiome towards pathogenic bugs.

No bueno at all.

Studies show, that eATP inhibits the growth of ALL bacteria, but does that more so in gram-positive bacteria, which tend to be the commensal bacteria we want to have in our gut.

Meaning, that this eATP is the reason for a shift in our gut microbiome.

You know that ATP can be broken down into subsequent nucleotides:

ATP → ADP → AMP → Adenosine

The difference in these is the number of phosphate groups.

You know which enzyme is able to cleave of these groups in the gut lumen?

Exactly, IAPs.

If there is a rise in eATP with sufficient IAPs to handle this load, the IAPs simply cleave of these functional groups and break down ATP.

The intermediary metabolites have been shown to not cause the same inflammation response.

On the contrary, the nucleotide adenosine is highly anti-inflammatory through its scavenging of ROS.

So, first, this is how IAPs can lower inflammation, as the signaling by ATP is stopped, leading to lower inflammation.

Second, because there is less eATP, commensal (=good) bacteria now can start thriving again, as the inhibition by ATP is stopped. Our gut microbiome shifts towards the good.

Third, pH is also regulated by IAPs ability to hydrolyze ATP, as eATP can lower pH.

Lower pH down regulates IAP expression, which leads to higher levels of inflammation.

Also it drives up intestinal dysbiosis, as our beloved bugs do not like an acidic environment.

There is the positive feedback loop between good pH & good levels of IAP, as you can see.

These are all reasons IAPs are one of the master regulatory system of our gut.

There is no regeneration without IAP

So now, we covered defensive mechanisms of the IAPs. But what is even more interesting that newer studies looked on the effects IAPs have on inducing autophagy.

Autohpagy is a process by which cells are recycled without causing swelling & inflammation. It is the natural reparation mechanism we all need.

So gut healing is hugely dependent on this state.

Fasting increases autophagy, but the problem for many is that fasting cannot be the first option in treating their gut.

The sole reason being that there stress levels are probably too high & nutrients to low, leading to a worsening of the condition.

One reason might also be insufficient IAPs.

Studies show that IAPs can induce autophagy of gut epithelial cells & macrophages, meaning that IAP is needed for proper restoration of gut functioning.

Interestingly, for this to happen, IAPs need to have TLR4 present. Without this pathway, autophagy isn’t induced by IAP, showing the duality of the TLR4 pathway.

High levels of IAP are correlated to higher levels of cell-cell-junction protein expression, like ZO-1 or Claudin-1. These are proteins needed for barrier function of junction proteins.

On the other hand, IAP is correlated to lower levels of markers of leaky gut, like Claudin-2 or SNAIL transcription factor.

So while inducing autohpagy, high levels of IAP also aid in providing the building blocks for rebuilding that gut barrier.

Overall, IAPs are crucial for gut health and are one of the main areas of concern when working with clients.

But how do we support healthy IAP levels?

IAP Masterclass: How to achieve top class levels

Magnesium, Zinc & Calcium

IAPs are homodimers, meaning that there are two equally built subunits which fulfill the functional, catalytic role.

Each of these subunits consists of two zinc & one magnesium cation, which regulate the catalytic role of these enzymes.

So ensuring adequate intake of these is crucial.

For zinc, I do not think that we need supplementation if we hit 10mg of it each day.

Eating animal based, with lots of meat, eggs, dairy & cheese will get you at least these 10mg.

Always try to incorporate copper weekly, through liver or other organs, which is important in regulation of zinc.

Magnesium is a fan favorite supplementation of mine. I highly recommend you taking it, as it is the ultimate pro-metabolic, anti-stress supplement, without a downside if taken the right way.

My favorite form is MgCl because of its high content of elemental Mg. I take anywhere from 6-10gr daily.

Yes you heard that right. 6-10gr daily. You will thank me later.

To calcium, we might need rougly 1000mg of it daily. In many cases, going higher will lead to massive benefits, as it surpresses PTH & was shown to aid massively in obesity.

Ensuring optimal intake through cheese, milk and the king of Vitamin K2, natto, is the way.

Protein

There are interesting things about protein types, aiding in IAP expression.

Glycine, the most scarce amino acid in todays world has been shown to increase IAP activity.

I believe that it is because of the anti-inflammatory effects glycine has on the body, leading to an overall better environment for IAPs to be expressed.

Currently taking 15-20gr through collagen & glycine supplementation. Split the dosage throughout the day.

Lactoferrin, a compound found in human & bovine milk, is, as the name suggests, a regulator of iron homeostasis. It is hugely anti-microbial, anti-inflammatory & immune modulating.

It might also help with lactose intolerance.

Studies show that the activity of IAP can be increased through lactoferrin. I am not saying you need to supplement it, as I see it as a tool, rather than an everyday supplement.

I’d say consume raw (grass fed) milk daily, either directly or as kefir, to get at least some of it.

The holy sun

As always, the sun plays a huge role, as it has been found that enough Vitamin D leads to an up-regulation of genes involved in IAP production.

As you can see, exposing your whole body, especially the eyes & belly in this instance, will aid massively in combatting inflammation & disease.

For those who are really deficient in Vitamin D, studies show that supplementation of 1,25-dihydroxyvitamin D3 even helps with expression.

In this instance taking anywhere from 4-6k IU per day, in the morning with fatty food, might be a good way to rebuilt some of that IAP levels.

Long term, sun is king tho.

Vitamin K

The most underrated of the fat soluble vitamins, Vitamin K has also been shown to increase mRNA expression of IAPs, leading to higher levels of said enzyme.

At least 50% of people are heavily deficient in it, which might explain some of the problems people tend to have with their gut.

I try to shoot for at least 200ug a day, which is hard to get by if you do not consume eggs, dairy, cheese & natto daily.

My favorite is 10gr of natto a day, just as a side to any dish, to hit the mark.

Vitamin K supplementation in the form of Vitamin K2-MK7 (in MCT or olive oil) is a good alternative route, if you cannot hit it daily.

As always, try to incorporate as much of it as real food and in the occasion of not hitting it, a supplement is safe to use.

The role of resolvins

Resolvins are compounds deriving from the omega-3 fatty acids EPA & DHA.

In the gut, these compounds, especially RvE1, is an agonist to Chem R23, a receptor involved in inflammatory pathways. Not only does this directly combat inflammation itself, already leading to higher levels of IAP.

But it also leads to an up-regulation of IAP in the gut, showing the huge impact DHA & EPA have on our system.

The way I go about omega-3s is to eat a lot of seafood & fish. For a lot of people a supplementary option might also be beneficial for some time, but not without incorporation of taurine, iodine & vitamin E, to enhance incorporation to the cell membrane and prevent oxidation of these PUFAs.

Butyrate

Butyrate is the king of so called short chain fatty acids (SCFAs). These are produced by comensal bacteria if you feed them prebiotic food, like fiber or certain phenols.

It has been shown that butyrate upregulates IAP expression through inhibiting histone deacetylase, leading to better genetic expression of genes encoding for IAPs.

Interestingly, butyrate is positvely associated with autophagy, as this SCFA induces autophagy.

High levels of IAP = more autophagy

High levels of butyrate = more IAP

So might this be the reason for butyrate inducing autophagy? Certainly it is one, but as you can see this compound is highly beneficial.

Eating plenty of soluble fiber through fruit, certain seeds & veg is crucial for restoring gut homeostasis & IAP.

To conclude this section, here is a good summary of everything about IAPs.

This was it, the role of IAPs in the dynamics of gut disease.

I hope you enjoyed this one as much as I did.

Now, if you suffer from

• poor energy

• chronic disease

• metabolic problems

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