The dangerous molecule in your gut that causes chronic inflammation

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Your gut is home to thousands of different species of bacteria that number in the trillions.  Many of these microbes are your friends.  They help you:

  • Digest and absorb nutrients
  • Optimize your immune system
  • Synthesize nutrients you can’t
  • Regulate your mood and behavior.

On the other end are your enemies.  They make you sick, anxious, cause you to pack on the pounds, and contribute to many of the chronic inflammatory conditions we experience. This includes:

  • Type 2 diabetes
  • Cardiovascular disease
  • Alzheimer’s disease
  • Autoimmune conditions (Type 1 diabetes, multiple sclerosis , allergies, arthritis)

The single common thread among these conditions is chronic low level inflammation.  During the initial stages of infection or injury to tissues, the immune system generates inflammation.  The primary role of inflammation is to attract immune cells to the area under invasion and increase blood flow to bring nutrients to damaged tissue.

The inflammatory response is critically important to your survival.  However, the inflammatory response is meant to be acute.  Take out the invaders, heal the damaged tissue, and get the hell out of there.

Within the general process of inflammation are many different molecules that help with all phases of the healing process, one group of which is called cytokines.  There are many different cytokines that play a role in each of the stages of healing.  This process should last days not weeks, month, or years.

During chronic inflammation, it’s basically an orgy of damaging cytokines without resolution.  Over time, this changes energy metabolism and basic functions necessary for long-term health.  The result:  Type 2 diabetes, cardiovascular disease, Alzheimer’s disease, etc.

In these inflammatory conditions, the inflammation never resolves.  The result is low level inflammation that lasts, and lasts, and lasts.  Over time this throws off every system in the body.  Endocrine, immune, digestive, nervous, you name it.

Where is all that inflammation coming from?

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So the question that’s entering your mind is, “Where is all this inflammation coming from?”  I wish I could tell you for sure, but the science isn’t completely settled.  At this point, the most attractive theory involves your gut.  This theory is the endotoxin model of systemic inflammation(1, 2)

This theory ties together quite a few principles that have garnered a ton of interest in the scientific community.  Basically, a little molecule in your gut called lipopolysaccharide(LPS), enters the circulation via the lymphatic system or a “leaky gut” and wreaks havoc on your body.

Additionally, inflammation generated in the gut because of this molecule manages to make it in to the circulation and find your weak spots.  You know that knee or shoulder pain that seems to stick around or comes back from time to time?  Chronic inflammation prevents it from healing properly.

So let’s take a look at how this whole mess happens.

The gut, LPS, and chronic inflammation

The microbial defense system in your gut is tasked with the difficult job of picking through all the microbes and deciding who stays and who goes.  But, there’s an ebb and flow to this process.  Bacteria are always going to be in your gut, and if microbial defense threw off an inflammatory response every time a bad guy enters your gut you’d be in big trouble.

Of course, you don’t want bad guys to enter the circulation and steal your health.  It’s important that the immune system recognize and neutralize them in the gut before they gain access to your blood.  This is where the delicate balance needs to be reached.

As I mentioned, there are thousands of different bacterial species in your gut.  Leaving the good guys alone and tossing the bad guys out requires some method of differentiating between the 2.  The microbial defense system has receptors that recognize certain cellular components found in bacteria that are detrimental to human health and removes them.

Determining friend from foe

When I refer to bacteria, you’ll often hear me talk about commensals and pathogens.  Commensals are your friends, it’s the pathogens that are your enemy.

Pathogen-associated molecular patterns, or PAMPs, are molecules that pathogens contain that microbial defense recognizes as foreign and initiates an inflammatory response to.  This happens not only in the gut, but in the liver and throughout the body.

LPS is a common PAMP and a component of the cell wall of gram negative bacteria.  Of all the PAMPs we know, LPS is the most inflammatory.  In fact, injecting LPS in to rats is one of the ways that scientists induce the same chronic inflammatory conditions mentioned above.

LPS amplifies the inflammatory response.  It puts the immune system on high alert leading to chronic inflammation.  It’s also a good target because everyone has LPS in their gut and, at the very least, low levels in their bloodstream.

Even healthy people have low levels in their blood.  People with Type 2 diabetes(3, 4) and cardiovascular disease(3, 5) have higher levels than those without these conditions.  Levels of LPS in the blood also correlate with the severity of these diseases.

In the mouse brain, injecting LPS causes dysfunction in the area where it’s injected.  They not only develop Alzheimer’s(6, 7) or Parkinson’s(8, 9) disease, but the local environment looks identical to humans with these conditions.

The same can be said about chronic traumatic encephalopathy(CTE), which shares a lot of similarities to Alzheimer’s disease(10).  It can also be induced by injection with LPS in rats suffering a traumatic brain injury.  The injury never heals and collateral damage from chronic inflammation induces the changes in brain function.

This all may seem like doom and gloom, but it’s not.  Not only are we learning that LPS is a major problem, we know how it causes inflammation.  Understanding this process gets us closer to a solution.

LPS and inflammation: What’s the cause?

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Originally from:…

Although we don’t have smoking gun evidence that LPS is causing these problems, we know a ton about LPS.  Most importantly, we know how LPS causes inflammation.

Receptors on cells throughout the body that recognize PAMPs are called pattern recognition receptors(PRR).  Some of the most studied PRRs include the toll-like receptors(TLRs).  When PAMPs bind to TLRs, this initiates the inflammatory response.  TLR4 is one of the specific TLRs that initiate the inflammatory response to LPS.

It may come as a surprise to you, but the binding of LPS to TLR4 is what ultimately causes LPS induced damage.  LPS isn’t doing anything directly to you, but LPS is a component of something that the body just doesn’t want around.

If bacteria with LPS bind to TLR4 and it’s quickly resolved, there’s no collateral damage.  It’s the continual assault on the body due to chronic stimulation of TLR4 by LPS that causes dysfunction and contributes to chronic inflammatory disease.

The reason LPS is so problematic is because TLR4 expression is high in immune cells and the spleen(11).  If LPS  enters the circulation, it will trigger an inflammatory response.  However, TLR4 expression in the gut is normally low which prevents it from being activated all the time(12).  This is good because of continual presence of LPS in the gut.

When inflammation presents itself in the gut, that’s when problems begin to occur.  Inflammation increases expression of TLR4 in the gut and makes it more responsive to LPS(13).  Now the gut is more inflamed and sensitive to LPS.  This can increase intestinal permeability, also known as “leaky gut”.

“Leaky gut” and chronic inflammation

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Taken from:…

Inflammation triggers a response that decreases tight junction protein synthesis by cells in your gut.  If you’ve heard of the term “leaky gut”, this is basically what’s happening.

Inflammation and tight junction protein synthesis are reverse regulators of one another.  High inflammation decreases tight junction protein synthesis and tight junction protein synthesis decreases inflammation(14, 15).  The same process regulates expression of TLR4 in the gut and liver(16).

During this process, LPS-containing bacteria enter the circulation, hit the liver, increase TLR4 expression there, and cause liver inflammation(17).  Any LPS that the liver is unable to deal with hits the circulation and interacts with immune cells, causing further inflammation.

There are other routes for causing leaky gut.  Gluten causes minor, transient leaky gut in normal individuals and major, chronic leaky gut in people with Celiac disease and non-celiac gluten sensitivity(18).  This happens because the protein zonulin is released in response to gluten and decreases tight junction protein synthesis.  Resolution of tight junction protein synthesis takes longer in those sensitive to gluten.

Alcohol also increases gut and liver inflammation and causes a “leaky gut”  Again, this is transient and subsides in most people save for chronic alcoholics.

I don’t think either of these routes are major contributors to chronic inflammation for most people.  They may cause severe responses in people with pre-existing gut pathology as we’ll see in a bit.

If I were to venture a guess, the most common route for leaky gut is excessive, chronic gut inflammation.  Inflammation induces a leaky gut by inhibiting tight junction proteins that keep things like bacteria out of the blood.

I don’t believe this is due to gluten exposure as seems to be the case with the gluten-free craze.  It seems that the problem may lie in the way TLR4 is expressed and the way inflammation and tight junction proteins are regulated together.

IBD, tight junctions, and detoxification

A great model for this is inflammatory bowel disease.  People with IBD have greater levels of TLR4 in their gut(19, 20, 21).  This, coupled with a nearly endless supply of LPS spells trouble for the integrity of your intestinal barrier.

At the same time, there is a loss of expression of the pregnane X receptor(PXR)  PXR is important because it’s the cellular component that ties together inflammation, tight junction proteins, and cellular detoxification.  Loss of PXR expression increases TLR4 expression, increases inflammation, decreases tight junction proteins, and decreases cellular detoxification(22, 23).

All of these factors change the way the gut behaves.  It sensitizes the gut to LPS which sets off a firestorm on inflammation.  This could also be the smoking gun that leads to the increased inflammatory response to gluten and delayed tight junction protein resynthesis.

LPS and the enterohepatic circulation

If this isn’t the first blog of mine that you’ve read, you know that I think a major cause of gut problems lies with bile and the enterohepatic circulation.  If you’ve read this blog, you know that the portal vein and bile duct connect the entero- and -hepatic arms of this circulation.

LPS does undergo enterohepatic circulation and this is a good thing.  There are enzymes in the gut and liver that detoxify LPS and remove its inflammatory effects.  There is/are component(s) of bile that render LPS non-toxic, bile salts being one of them(24).

The problem is that there are many lines of evidence indicating that the enterohepatic circulation of LPS decreases bile salt production and delivery in to the gallbladder(25, 26, 27).  These changes may precede stoppages in bile flow depending on the severity of the LPS load(27).

In turn, this could cause LPS to continually circulate through the enterohepatic circulation without one of its checks and balances.  As TLR4 expression increases in the gut, the inflammatory response amplifies and the result will be a “leaky gut”.

But wait…Somewhere lost up there in all of the bile and LPS talk I mentioned an enzyme that detoxifies LPS.  Interestingly enough, people with IBD have defects in this enzyme, specifically in areas of the gut with active IBD.  We’ll be taking a look at this in a 2 blog series available to members of the private facebook group.  If you want in, just send me a request here.  I’ll be posting the first one Monday and second one on Wednesday. The password to each will be in the comment section on the facebook group page.  The next public blog will be on how the gut regulates thyroid signaling.

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