This blog is my second in a 3 part series of important factors that regulate gut health. In a previous blog, I covered how intestinal alkaline phosphatase(IAP) plays a role in regulating the gut. If you didn’t get a chance to check that one out, you can do so here. Anywho, back to the show.
Whether you like Big Pharma or not, their new interest in bowel disorders is going to further the science on gut health. My personal feeling is that many of their solutions may not be great, but they’re helping. Their identification of mechanisms underlying gut pathology is crucial to understanding SIBO, IBS, & IBD.
In my last blog, I covered intestinal alkaline phosphatase and how it regulates gut homeostasis. In this blog, we’ll take a look at the Pregnane X receptor(PXR) and how it plays a complementary role with IAP.
PXR regulates many processes in the body. It’s involved in:
- Biotransformation of steroid hormones
- Detoxification of xenobiotics (BPA, bacteria toxins, pesticides)
- Regulation of the inflammatory response
- Regulation of tight junction proteins
- Metabolism of pharmaceutical drugs
- Regulation of glucose and lipid metabolism.
From a gut perspective, PXR:
- Regulates inflammation and the microbiome
- Maintains the intestinal barrier
- Detoxifies harmful substances and eliminates them from the body.
The primary way that PXR does this by is the biotransformation(aka detoxification) of fat soluble molecules. If you missed my previous blog on this topic, check it out here. It will be extremely helpful for you to understand that blog moving forward.
The Pregnane X receptor
PXR is a nuclear receptor. It basically floats around in the cytoplasm of cells waiting for a ligand to bind to it. Unlike other receptors that bind specific ligands, PXR binds to a host of xenobiotic and endobiotic molecules.
- Xenobiotic-A substance foreign to the body (BPA, pesticides, herbal supplements, pharmaceutical drugs)
- Endobiotic-A substance produced by the body (Steroid hormones, bile acids, etc.)
When one of these molecules binds to PXR, PXR makes its way to the nucleus and regulates gene expression. This induces the expression of genes that regulate the 3 phases of biotransformation.
Biotransformation is the more scientifically accurate term for “detoxification”. PXR also regulates the expression of other genes and vice versa. This 2-way communication defines the way that PXR regulates gut homeostasis. Note: In the figure, “Drug” can be any fat soluble molecule, not just pharmaceuticals
Layman’s breakdown: PXR helps dispose of a number of different things from the body by making them water soluble. This includes hormones, bile acids, and environmental toxins.
Pregnane X receptor in the gut
PXR is highly expressed in the gut and liver where it regulates the powerful detoxification capacity of both organs. The gut gets exposed to a large number of xenobiotics in the food we eat, and PXR metabolizes them. Some of these xenobiotics actually benefit us. Others like BPA and the pesticide glyphosate may have harmful effects.
The contents of the gut are generally water soluble which keeps them in the gut. Water soluble molecules can’t enter cells of the GI tract because the plasma membrane of the cell is made of lipids. They travel through the GI tract and leave in the feces. Fat soluble molecules, on the other hand, can pass through the plasma membrane and cause toxic effects or cell death.
Taken from: http://slideplayer.com/slide/7250675/
When fat soluble molecules enter cells in the GI tract, PXR swoops in and binds to them. This induces PXR expression in the cytosol as well as the production of cytochrome p450 enzymes(CYP450). This starts the first phase of biotransformation which makes it more water soluble.
Next, phase 2 conjugation enzymes get induced and they turn the fat soluble molecule completely water soluble. Phase 3 transporters then spit the molecule back in to the intestinal lumen or in to the portal vein to be further detoxified in the liver. Either way, the molecule eventually leaves the body in either the feces or urine.
The key word here is “eventually”. Certain substances stick around for a long time. BPA and other xenobiotics can gain access to the circulation and alter homeostasis.
PXR also performs the biotransformation of steroid hormones in endocrine glands. BPA binds to PXR in these organs and disrupts hormonal balance. Specifically, BPA mimics estrogens. This can disrupt processes regulated by the estrogen receptor including fertility.
Fortunately, there are mechanisms to prevent this from happening. When a molecule binds to PXR in cells of the gut, the induction of PXR also regulates other genes. This seals up the gut so anything spit back in to the lumen stays there. The goal here is to prevent the detoxified substance from gaining access to the blood.
Layman’s breakdown: Most people have heard of the 3 phases of detoxification. This is sort of a misonomer. The processes known as detoxification are actually biotransformation.
The same processes that change toxins also change hormones and bile acids, so detoxification is inaccurate. They change fat soluble molecules in to water soluble molecules so that they can be excreted via the urine or feces, not just toxins.
These molecules can become more or less toxic depending on which pathways are induced. PXR is one of the receptors in cells responsible for identifying things that need to be biotransformed.
One of the major problems with xenobiotics is that PXR is found in many tissues including endocrine organs. If a xenobiotic makes it past the gut and liver, it can bind to PXR in an organ like the adrenal glands and disrupt hormone synthesis, secretion and signaling.
PXR, inflammation, and leaky gut
Imagine you’re bailing water out of a boat with a bucket, but the bucket has a hole in it. As you begin filling up your bucket with water from the the boat, some of the water in the bucket falls back in to the boat. This will never be an efficient process, the efficiency is dictated by how water tight the bucket is.
If we take this analogy to the gut, having a barrier is crucial to preventing leakage. Cells with a fatty plasma membrane keep water soluble compounds in the gut. Of course, if this border of cells has a bunch of holes in it, stuff cane leak in. The process of turning a fat soluble molecule in to a water soluble molecule and spitting it back in to the gut only works if the cells are tightly packed. Otherwise, you have a bucket with a hole in it.
Besides regulating the biotransformation of fat soluble molecules, PXR also increases the expression of tight junction proteins. Tight junction proteins form a water-tight barrier between enterocytes. By inducing tight junction protein expression, PXR makes sure your bucket doesn’t have any holes in it.
But it gets better…
In addition to increasing tight junction proteins, PXR regulates inflammation. Inflammation reduces tight junction proteins, but PXR blocks inflammation. This keeps holes out of the bucket. Unfortunately, this is a 2 way street and increased inflammation blocks PXR and biotransformation. A hallmark of IBD is dysregulation of this axis. Chronic inflammation blocks xenobiotic and drug metabolism via inhibition of PXR(1).
Layman’s breakdown: When something binds to PXR, it not only induces the 3 phases of biotransformation, it also seals up a leaky gut. It does this by increasing tight junction proteins and reducing inflammation.
On the flipside, chronic inflammation increases a leaky gut by decreasing the amount of PXR floating around in the cytoplasm and decreasing tight junction protein synthesis. A reduction in PXR and detoxification enzymes is a hallmark of IBD and may contribute to the leaky gut associated with the disease.
Send out the commensals
It would be nice to believe that our body is on top of this stuff and we don’t need any help. But that couldn’t be further from the truth. Another reason I’m not a fan of the term “detoxification” is that commensal bacteria use PXR. Metabolites generated by commensal bacteria bind to PXR and regulate the integrity of the intestinal barrier by decreasing inflammation and increasing tight junction proteins(2).
Commensals also use PXR in other ways to stake a gastrointestinal claim. Toll-like receptors(TLRs) are xenobiotic sensors of bacterial components and noxious stimuli. The best example is a component of the cell wall of gram-negative bacteria called lipopolysaccharide(LPS). When LPS binds to a specific TLR known as TLR4, it causes rampant inflammation. For more on this check out this blog here.
Taken from: https://www.uwyo.edu/vetsci/undergraduates/courses/patb_4130/microorganisms_bacteria_extracellular…
Indole-3-propionic acid(IPA) is one of the metabolites commensals use to communicate with PXR. When IPA binds to PXR, it downregulates TLR-4 signaling(3).
This muted sensitivity to LPS helps us by reducing inflammation, and it helps them avoid attack by our immune system. It also plays a complementary role with intestinal alkaline phosphatase by keeping the inflammatory response to LPS down.
As an interesting side note, people with IBD have a large increase in TLR4 expression in their gut(4). The result… greater sensitivity to LPS which is unfortunately everywhere in the GI tract. This may be a product of the decrease in PXR seen in IBD(1).
It would be nice to think our commensals are being altruistic, but it helps them just as much as it helps us. A “leaky gut” will completely change the GI landscape while also attracting immune attention. Inflammation increases immune attention as well. That’s not good for commensals.
Some commensals contain LPS in their cell wall, so having a lot of TLR4 in the gut could attract further undo attention. The net effect would change the environment in a way that’s not conducive to their survival. They don’t like that. All in all, it’s a suitable arrangement for both parties.
Layman’s breakdown: Commensal bacteria use PXR to communicate with you and you gut. Metabolites made by commensal bacteria bind to PXR and decrease inflammation and improve a leaky gut.
Metabolites from commensal bacteria also reduce the sensitivity of your gut to LPS, which is found in spades there. Reducing receptors that sound the alarm when LPS is around decreases inflammation and provides a gut environment that benefits you and your commensals.
Xifaxan and PXR
Xifaxan is a pharmaceutical drug used for SIBO, IBS, and IBD. Most people are familiar with the gut specific antibiotic effect of Xifaxan. However, Xifaxan has other beneficial effects that may be more powerful.
Xifaxxan stays in the gut so well(5) because it’s a fat soluble molecule that crosses the plasma membrane and binds to PXR. In fact, it’s one of the strongest inducers of PXR that we know of. It’s parent compound rifampicin being the strongest.
When Xifaxan binds to PXR, it increases PXR expression and causes a massive upregulation of biotransformation pathways(6). The end result puts Xifaxan and its metabolites back in the gut. It also seals up the gut and squashes the hell out of inflammation. In fact, this effect may be as beneficial or more so than the antibiotic effect(7).
Layman’s breakdown: The IBS/SIBO/IBD drug Xifaxan is an antibiotic that also reduces inflammation and helps resolve a leaky gut. It has effects specific to the gut because it induces PXR which also causes these beneficial side effects. I cover this in more detail in another blog found here.
Big Pharma did us a solid
The research on PXR is solid, and gut research has been given a huge head start thanks to Big Pharma. We know so much about this process because PXR regulates the metabolism of pharmaceutical drugs. PXR regulates their absorption, their half-life, and their disposal. Without understanding PXR, we wouldn’t be able to figure out how to dose most pharmaceutical drugs or even how they work.
PXR plays a vital role in maintaining gut health. PXR:
- Seals up the gut
- Tamps down inflammation
- Detoxifies xenobiotics
- Provides a hub for communication with commensal bacteria
- Plays a complementary role with IAP in reducing LPS-induced inflammation
All these factors help regulate your gut to be an environment where commensal bacteria can thrive and help you thrive as well. Just like IAP, there are natural ways to improve PXR expression and function via diet and supplementation. In fact, I think there may be an evolutionary basis for our modern diet/lifestyle throwing this out of whack.
Hopefully this blog has tempted your fancy enough to get you pointed in the right direction. You’re probably thinking, “Well this is all great, but how do I activate PXR?” Well, I have a little secret for you, there’s a very easy way to do it.
In fact, there’s one nutrient in particular that appears to play a large role in mucosal defense, activating intestinal alkaline phosphatase to reduce inflammation from endotoxin while also activating PXR to seal up a leaky gut and improve detoxification/biotransformation.
If I were on a journey to heal my gut, getting enough of this nutrient would be where I start. I wish I had this information when I started trying to heal my issues because not knowing it probably delayed me a couple of years. I’ll be covering this nutrient in my next private blog only available to members of my private facebook group. Click here to join if that’s your thang.