If you’re dealing with gastrointestinal issues, you’ve been through the ringer with different doctors and treatments.
You’ve also scoured the internet and books looking for information that may help you get relief from your symptoms. You know what leaky gut, the microbiome, and motility are, but do you know them well enough to do anything? Probably not.
You may have found a diet that fits your needs and helps manage your symptoms, and that’s great. But is your goal to be on some restrictive diet for the rest of your life? Do you consider that a cure?
If it were me, I’d be trying to figure out what went wrong. What caused the train to go off the tracks? How do you go from eating everything perfectly fine to a rapid decline where most of what you put in your mouth causes some weird type of reaction?
Go to 5 different blogs and you’ll find 5 different diets, 30 different supplements, or 10 different lifestyle factors you can use to help with your issues. I’m a big fan of blogs, bloggers, and the blogosphere. The problem is, relying on this information may help manage symptoms but it doesn’t get to the root cause of your problem. While symptom management can make you feel great, it only takes one slip up to go right back to ground zero.
Enter Big Pharma
Despite spending decades ignoring things like IBS, SIBO, or “leaky gut”, conventional medicine is catching up. Truth be told, there’s a lot of money to be had in the gastrointestinal disorder arena. And luckily they have money to put behind finding answers. While I’m no fan of their solutions which typically involve antibiotics or prokinetics, their research is knocking it out of the park when it comes to identifying mechanism.
Naturally, their end goal is to find a pharmaceutical drug that will lead to a cure or total symptom management. But that doesn’t mean you can’t use their mechanistic studies now and apply those principles to your diet, lifestyle or supplement regimen. Right now there are many big mechanisms that are ripe for exploitation. Big Pharma is dumping a lot of money in trying to develop drugs to manipulate these mechanisms. They include:
- Intestinal alkaline phosphatase(IAP)
- Pregnane x receptor(PXR)
- The Farnesoid x receptor(FXR)
These are 3 major players in the immune system and work overtime in the gut. They work together to regulate inflammation, intestinal permeability, detoxification, and the microbiome. Sound intriguing? Well let’s get started today by looking at intestinal alkaline phosphatase.
Intestinal Alkaline Phosphatase
Alkaline phosphatase is an enzyme that performs many functions throughout the body by breaking down proteins. There are 3 forms of alkaline phosphatase found in different tissues. One form is in the liver/bone/kidney, one in the placenta, and another in the intestine. It’s major function is in dephosphorylating proteins. Basically, it removes a phosphate, thus changing the protein.
Intestinal alkaline phosphatase(IAP) gets secreted at the brush border and travels through the digestive tract, primarily with meals. It was recently identified as a major player in mucosal defense helping maintain a healthy gut. It maintains a healthy gastrointestinal environment through regulating pH, dampening inflammation, regulating the microbiome, and maintaining intestinal barrier integrity.
Intestinal alkaline phosphatase and pH regulation
Most people have the wrong view of pH in the digestive tract. The prevailing thought is that pH is lowest in the stomach, increases through the small intestine, drops in the cecum, and continues a small rise throughout the colon.
Taken from: https://www.philrichardsperformance.co.uk/blog/part-2-improving-digestion-for-muscle-gain-fat-loss-health/
While this image is correct, it fails to show that pH in each segment changes as you get closer to the intestinal wall.
Taken from: https://en.wikipedia.org/wiki/Hydrochloric_acid
There is a change in pH as you move from the lumen(A), through the mucus(B), to the brush border(B/C). The pH in the lumen tends to be more acidic and gets more alkaline as you get closer to the brush border.
Acidity is damaging to enterocytes, so this protects them from damage. It also brings the pH at the brush border in to the range that maximizes brush border enzyme activity. So besides protecting against damage, it also optimizes digestion, particularly of proteins.
When you eat, food enters your stomach, mixes with gastric acid, and enters the duodenum. When this happens, bicarbonate gets secreted to neutralize the pH. This is done through the release of ATP. As the name suggests, alkaline phosphatase is more active at an alkaline pH. As the pH rises, IAP begins dephosphorylating ATP and bicarbonate secretion slows bringing pH to where it should be(1).
Without regulation by IAP, bicarbonate secretion would increase brush border pH beyond the pH optimum for brush border enzymes and cause a severe amount of bloating. Think baking soda/vinegar volcano. Other evidence indicates that bicarbonate secretion is also dependent on IAP. Mice bred to lack IAP don’t release ATP which prevents bicarbonate secretion(2). This could cause acid damage to enterocytes.
Taken from: https://www.researchgate.net/figure/261604211_fig1_Fig-8-Gut-microbiota-live-in-symbiosis-with-the-host…
Intestinal alkaline phosphatase and the microbiome
The dephoshorylation of ATP also plays a role in regulating the microbiome. Mice bred to lack IAP(IAP-KO mice) experience significant dysbiosis that’s corrected by administering IAP(3). Reduction of ATP and other triphosphates are involved in this process, probably by altering pH.
A study looking at the same mice found lower abundance and diversity of bacteria in the gut of KO mice when compared with wild type. Supplementing these mice with IAP restored their microbiome to that of the wild type(4).
Another part of the same study found that IAP restored the microbiota in mice treated with antibiotics. A follow-up study confirmed these results. It showed IAP to protect against antibiotic associated C. difficile infection as well as other pathogens(5).
Another way IAP helps regulate the microbiome is through inhibiting inflammation. This not only alters the microbiome, but it maintains the intestinal barrier and motility. But this effect is separate from altering the microbiome, in a way we’ll discuss next.
The anti-inflammatory effects of intestinal alkaline phosphatase
There are certain components of bacteria that fire up the immune system, causing inflammation. When they’re identified by receptors in the gut, the response will always be inflammation. It doesn’t matter if the bacteria are live or dead, the result is inflammation.
It doesn’t matter how pristine your diet is, whether you eat cooked or raw, or if you thoroughly clean all your food before you prepare it. You will always have dead bacteria on your food, and none of these processes change the dead bacteria in a way that prevents an inflammatory response.
Due to this constant exposure to bacterial components throughout the GI tract, we need a way to prevent them from firing up the immune system. We need a way to alter them so that the immune system doesn’t recognize them. Enter…
Of course I’m joking, IAP does the trick nicely.
Throughout your gut are receptors called toll-like receptors(TLRs). These toll-like receptors sit and monitor the GI tract for troublesome molecules. When a TLR gets triggered by the molecule it recognizes, an inflammatory response gets initiated. This inflammation, in turn, increases the number of TLRs for that particular molecule. This upregulation of TLRs can cause hypersensitivity to that molecule if things get out of hand.
Toll-like receptor 4 is heavily studied as it’s the TLR that responds to lipopolysaccharide(LPS), a component of the cell wall of gram-negative bacteria. LPS is one of the most inflammatory molecules that we come in to contact on a day to day basis. You may have heard of sepsis or septic shock. And more often than not, sepsis is caused by LPS. For a quick rundown on this check out this previous blog on the topic
IAP is co-localized with TLR-4 and dephosphorylates LPS, rendering it harmless(6). It also does this for other bacterial components that fire up inflammation(7). Additonally, IAP reduces the expression of TLR4(8) and likely other TLRs, reducing sensitivity to bacterial components in the gut. But that’s not all…
Inflammation in the gut is bad, but systemic inflammation throughout the body leading to sepsis is even worse. Bacteria and bacterial components become even more inflammatory once they leave the gut and enter the bloodstream.
IAP can reduce the amount of bacteria that make their way from the gut to the bloodstream(6). We all experience minor levels of systemic inflammation on a regular basis, but it’s not enough to send us in to septic shock.
More often than not, it just messes up our blood glucose regulation and increases blood vessel calcification(9, 10, 11). IAP prevents these common issues and alkaline phosphatase in the liver can clean up the balance that makes it out of the gut.
IAP and intestinal barrier integrity
LPS makes its way in to the bloodstream in one of 2 ways. The first way is by hopping a ride on chylomicrons in to the lymphatic system. Fortunately, dephosphorylation of LPS and other bacterial components by IAP prevents this from firing up inflammation. IAP puts the glasses and nose disguise on these components so your immune system doesn’t recognize them.
The next way LPS can enter the circulation is if the cells lining the intestinal wall aren’t packed tight enough. Enterocytes aren’t packed tightly together. But they do have proteins between them called tight junction proteins. Tight junction proteins help provide a seal that prevents unwanted molecules and bacteria from entering the bloodstream via the gut.
When inflammation is present, it reduces the presence of these tight junction proteins. This allows LPS and other unwanted particles to access the bloodstream(12). Again, IAP plays are role in preventing this by reducing inflammation in the gut. However, besides lowering inflammation, IAP plays a direct role in regulating the intestinal barrier. It does this by increasing tight junction protein synthesis directly(13, 14).
As you can see, IAP plays many roles in maintaining a healthy gut. It helps regulate the GI environment by:
- Regulating pH at the brush border
- Modifying the microbiome
- Reducing inflammation
- Maintaining the intestinal barrier.
In children with Inflammatory bowel disease, IAP levels are low in inflamed mucosa samples when compared to healthy ones(15, 16). This holds true whether the healthy sample came from a different child or from an unaffected area of the same child.
An additional finding is that children with IBD have increased expression of TLR-2 and TLR-4 which could lead to hypersensitivity to ligands that bind to these receptors(17). IAP reduces the expression of TLR-4, but there is no evidence that it affects TLR-2.
The heavy research by Big Pharma in this area has identified IAP as a major player in gut homeostasis. In fact, it may be one of the biggest factors you’ve never heard of that deserves your attention. There are many dietary and supplemental factors that can modulate IAP. In a future blog I hope to tell you how to exploit them.
Looking for a nutrient that’s a big player in gut health? One that can increase alkaline phosphatase in the gut AND reduce the expression of TLR4? What if I told you it also improves leaky gut AND detoxification, 2 major issues for people with IBD. Welp, you can find the blog here, but only those in the private facebook group have access. Request to join here.