Why Fermentable Fiber Is Critical to The Zone Diet

Why Fermentable Fiber Is Critical to The Zone Diet
As discussed in the last chapter, following the Zone Diet you will consume a lot of non-starchy vegetables.  I made this recommendation several decades ago based on the hormonal benefits of using very low glycemic load carbohydrates to stabilize blood sugar levels by controlling the balance of hormones in the blood.

At the time of my initial carbohydrate recommendations, very little was known about the molecular biology of the gut. Now more 20 years since the publication of The Zone, we know both the gut as an organ and the bacteria that residue in the gut operate together in a very complex interplay that has a significant impact on keeping inflammation under control.  Outside of the brain, our gut may be the most complex organ in the body that I describe in greater detail in Appendix G.    What controls this complex interaction between the trillions of bacteria in the gut and the gut itself is the levels of fermentable fiber in your diet.  That’s why in this chapter I want to outline how the Zone Diet also reduces the potential of bacterial fragments from generating gut-induced inflammation.  

There has been a lot of talk about gut health recently, but most people do not know what that means exactly. A healthy gut, in short, requires a unique source of nutrition, which is called fermentable fiber.  Fermentable fiber is the key dietary component to maintain an incredibly thin barrier that acts as a defense between you and the trillions of “friendly” bacteria in your gut waiting for the opportunity to invade the blood and cause significant inflammatory damage. 

Make no mistake about it, you are in a constant battle with bacteria for your survival. It is estimated that there are 5,000 different species of mammals, more than 40,000 species of fish, approximately 5,000,000 species of insects and potentially 1,000,000,000,000 (1 trillion) species of bacteria. Bacteria have been around for more than 3 billion years, whereas humans have been in existence for less than 200,000 years.

Furthermore, relatively few bacteria found in the gut have been cultured in laboratories, so they represent a biological black hole that we know very little about. One of the few things we do know is that bacteria are more successful as a species (in terms of longevity) than humans and are more likely to kill us before we kill them. They can mutate their genetic code rapidly, we can’t. They can reproduce in 20 minutes. It’s doesn’t seem like a fair fight.

The primary weapon we have at our disposal to maintain our biological co-existence with bacteria are the barriers in the gut that separates their world from ours.  Consider these biological barriers in the gut an inner skin that lines your digestive tract as your primary defense system against constant bacterial invasion. But it is not a static wall. It also must allow digested nutrients (amino acids, carbohydrates, and fatty acids as well as vitamins and minerals) into the body so we can survive. This inner skin is also constantly moving ingested food through the gut, allowing the nutrients from digested food into the blood, sending information on nutrient status to your primary brain via hormones, while at the same time protecting you from pathogenic microbes (including fungi, parasites, viruses, as well as other “unfriendly” bacteria) just waiting for the opportunity to invade our bodies. Finally, it is an incredibly effective barrier that separates two seemingly alien worlds. One world consists of your human cells that requires oxygen to survive, whereas gut bacteria thrive best in a world without oxygen. If that inner skin is breached, these two worlds collide. The common name for this is called a “leaky gut.” Whatever it is called, the result is a potential constant flow of a new source inflammation from the gut into our world.  Just like diet-induced inflammation, gut-induced inflammation can lead to obesity, diabetes, auto-immune disorders, and a wide range of neurological conditions.

Details of Your Inner Skin
Your inner skin is far more complex than your outer skin.  Your inner skin has three primary defense components to protect you.  The first is your mucus barrier. Mucus is composed of carbohydrate polymers synthesized by the goblet cells located in your gut wall.  The thicker the mucus barrier, the less likely that microbes or large protein fragments can get close to the gut wall to cause a negative immunological response. The second defensive barrier is the quality of the tight junctions of your gut wall. The greater the integrity of these tight junctions at the face of the gut wall, the less leaky the gut becomes. This is explained in greater detail in Appendix G.  Finally, your third and final defense is the vast array of immune cells lined up just behind the gut wall to attack and neutralize any protein or microbial fragments before they can enter into the body to cause significant inflammatory damage leading to systemic cellular inflammation.  It is not the fermentable fiber per se that is important to maintain these defense systems, but the metabolites that are formed by the its digestion by the resident bacteria in your gut.  In particular, it is the very short chain fatty acids (especially butyric acid) that are essential for maintaining gut health.

When the Gut Malfunctions
You hear a lot about a leaky gut, but what does that really mean?  The most likely suspect for a leaky gut is a reduction in the width of the mucus barrier. The mucus barrier is essentially a “no-man’s land” that not only keeps bacteria but also prevents proteins or large fragments of proteins from coming near the surface of gut wall. If they come in direct contact with the outer cells of the gut wall and the immune cells directly behind those cells, they will generate an immunological response.  This is why most of the major food allergens are proteins. These are known as the Big 8 and includes milk, eggs, fish, shellfish, nuts, peanuts, wheat, and soy. We can now add another protein to the traditional Big 8: gluten. A strong case can be made that “gluten sensitivity” is really a consequence of a leaky gut. A functional and robust mucus barrier would prevent the protein fragments from those foods from getting near the immunological cells located just inside your inner skin.

Perhaps the primary bacterial player for maintaining the mucus barrier is a recently discovered microbe known as Akkermansia muciniphila. It also appears that the more Akkermansia you have in your gut, the fewer inflammatory attacks you will be exposed to since its increased presence is associated with a decreased leaky gut. So, what’s the connection?

Although there are 1,000 to 1,500 distinct bacteria species (these are considered your friendly bacteria) that reside in the gut, it appears that Akkermansia muciniphila may be the “best of the best.” This is because this particular bacteria resides mainly in the outer layer of the mucus barrier and prevents more  pathological microbes from getting close to the gut wall.  Unfortunately, you don’t provide the gut with enough dietary fermentable fiber, Akkermansia gets hungry and its primary alternative food source now becomes the carbohydrate polymers that make up the mucus barrier. This degrades your primary barrier to prevent entry of microbes or large protein fragments from reaching the gut wall where they can cause an immunological response.

So, how do you make more of Akkermansia and keep that bacterial species nourished so they don’t start digesting your mucus barrier? First you have to eat adequate amounts of fermentable fiber to nourish the bacteria in your gut. Next you have to consume optimal amounts of polyphenols as the “fertilizer” to enhance their growth.  The primary dietary source of polyphenols are low-glycemic carbohydrates like non-starchy vegetables.  What the polyphenols do is to activate AMP kinase in the gut wall to increase the production of mucus.  Finally, you have to reduce the levels of oxygen in the gut allowing Akkermansia can survive because oxygen is toxic for these anaerobic bacteria. This reduction of oxygen in the gut is achieved with an adequate intake of omega-3 fatty acids that will activate another gene transcription factor (PPARa) that causes the gut cells to increase the oxidization of fatty acids consuming any residual oxygen in the gut thus maintaining an oxygen-free gut environment. The best indication that you have adequate levels of all three dietary components needed to maintain a healthy gut is to be in the Zone.

Besides maintaining a functional mucus barrier, you also have to maintain a tight barrier between the cells that line the gut wall. These are called tight junctions because they contain high levels of specialized proteins (occludins) that hold these surface cells together. The synthesis of occludins are also stimulated by the short-chain fatty acids that are the primary metabolites coming from the metabolism of the fermentable fiber in your diet. However, the assembly of the occludins into the gut wall is under the direction of AMP kinase. 

These occludin proteins are not only important in maintaining the integrity of the gut wall, but also in other organs like the brain. In the brain, these cells form a tight blood-brain-barrier (BBB) that keeps virtually everything circulating in the blood out of the brain.  As bad as a leaky gut is, a leaky brain is even worse.  Unfortunately, these barriers in the gut, the brain, lungs, etc. can be disrupted very easily by the overproduction of pro-inflammatory eicosanoids (especially leukotrienes) derived from AA.  Therefore, keeping your levels of pro-inflammatory eicosanoids low as well as consuming adequate levels of fermentable fiber necessary to product short-chain fatty acids is one of your best ways to prevent a leaky gut as well as a leaky brain.  Following the Zone Diet accomplishes both tasks.

Other Causes of Leaky Gut
Obviously, the primary dietary contributor to a leaky gut is the lack of fermentable fiber as outlined above.  As the amounts and diversity of fermentable fiber in your diet decreases, so does the diversity of the bacteria in your gut.  Eventually, certain species of your gut bacteria go extinct.  But lack of fermentable fiber is not the only factor that lead to a leaky gut. There are a wide number of other factors include other components in your diet like alcohol and food additives as well as drugs and stress.

Other Dietary Factors
One dietary factor leading to a leaky gut is alcohol intake. Increased alcohol consumption will speed the development for developing both a leaky gut and eventually a leaky brain. Another new potential dietary culprit are artificial sweeteners. This occurs because of the greater genetic diversity of gut bacteria which are able to produce unique enzymes that can breakdown the artificial sweeteners (especially sucralose commonly known as Splenda) into toxic compounds that can decrease the levels of the necessary friendly bacterial diversity in the gut just like an antibiotic. Finally, a high-fat diet (especially if it rich in saturated fats like the Atkins diet or a ketogenic diet) can accelerate the transport agent of bacterial fragments (primary lipopolysaccharides or LPS) through the gut wall that generate inflammatory responses in the blood.

Cancer chemotherapy drugs are among the most potent agents for inducing a leaky gut because they can’t distinguish between killing a rapidly dividing cancer cell or killing a rapidly dividing cell that lines the interior of the gut.

Likewise, consistent use of standard antibiotics in even small amounts will also decrease diversity of the bacterial colonies in the gut and result in an increased permeability of the gut wall. This is because current antibiotics are broad-spectrum, indiscriminate killers of bacteria. In nature, bacteria will secrete specific antibiotics to protect their space from other bacterial intruders.  On the other hand, broad-spectrum antibiotics usually come from a completely different microbial kingdom. As a result, their toxins are meant to destroy bacterial competitors, but not attack themselves or other members of their kingdom. As an example, penicillin is derived from a fungus to destroy other bacteria without much specificity but with no adverse effects on other fungi.  Although it is possible to make specific narrow-spectrum antibiotics directed at only one type of offending bacteria, the cost for such targeted antibiotics is incredibly high as would be their cost for their drug approval. That’s why we continue with using broad-spectrum antibiotics. 

Anti-inflammatory drugs also provide a problem for gut health. Besides inhibiting resolution of inflammation (as explained in more detail in Appendix D), anti-inflammatory drugs can ironically produce more inflammation in the body by inducing a leaky gut.

The role of physiological stress through the activation of stress-induced hormones such as corticotropin-releasing hormone (CRH) is another factor that can impact gut permeability.  The more stress you are under, the more CRH is produced in the brain that can travel via the vagus nerve to the gut and accelerate the formation of a leaky gut.  The vagus nerve is a bi-directional transport highway between the brain and the gut.  This is why many mind-body disorders that have neurological effects appear to start in the gut as I will explain later in the book.

The Role of The Zone Pro-Resolution Nutrition System To Repair a Leaky Gut
Fortunately, there are number of dietary factors that can restore a functional gut barrier.  All of these dietary factors are inherent in the Zone Pro-Resolution Nutrition system.  As usual, it starts with the Zone Diet.  The Zone Diet is rich in non-starchy vegetables as its primary carbohydrate source, thus it supplies adequate levels of a wide variety of dietary fermentable fibers critical for gut health.   In addition, the Zone Diet reduces the production of pro-inflammatory eicosanoids (such as leukotrienes) that promote a leaky gut.  The Zone Diet is also rich in polyphenols that promote the growth of key bacteria such as Akkermansia as well as reduce the likelihood of the development of a leaky gut.  Another component of the Zone Pro-Resolution Nutrition system is the supplementation with high-dose omega-3 fatty acids that will not only reduce inflammation in the gut wall, but also activate the fatty acid oxidation in the gut cells to remove residual oxygen in the interior of the gut to promote the growth of Akkermansia.  Finally, the Zone Pro-Resolution Nutrition uses supplemental polyphenols to further activate AMP kinase in the gut wall that is critical to preventing the formation of a leaky gut wall.

Metabolic Endotoxemia
Your body has a unique way of recognizing the invasion of microbes from the gut.  These are sensors known as toll-like receptors (TLR) that are located on every living cell and explained in greater detail in Appendix C.  If a microbial fragment interacts with any of these TLR receptors on the surface of a cell, then a signal is immediately transferred to the gene transcription factor NF-kB inside the cell, which in turn causes the increased production of inflammatory proteins (cytokines) to combat the invasion.  If the breach is significant, then a leaky gut becomes a superhighway for microbes from the gut to enter into the body and cause the equivalent of a five-alarm inflammatory fire. This condition is called sepsis and the mortality rates are about 50 percent. At lesser levels of increased gut permeability, the number of bacteria or their fragments (both will activate TLRs) that enter the blood is much lower and now they simply make you fat and far more likely to develop chronic metabolic diseases (such as obesity and diabetes) at an earlier age because of increased inflammation mediated by their interaction with TLR system. This is called metabolic endotoxemia.  The reason metabolic endotoxemia is so insidious is because you can’t feel it and it is very difficult to measure. Nonetheless, you simply won’t feel right in both the gut and the brain, as well as causing the accumulation of excess body fat.

A high-fat diet can accelerate metabolic endotoxemia for three reasons. First, a typical high-fat diet is also low in fermentable fiber. The second reason is that a high saturated fat diet (like a ketogenic diet) can also speed up the entry rate of bacterial fragments (lipopolysaccharide or LPS) into the blood by piggybacking with other fats (especially saturated fats like palmitic acid) that are assembled into lipoproteins known as chylomicrons that travel directly to the blood.  Finally, the higher the levels of saturated fats (especially palmitic acid) in your diet, the more likely they can bind the TLR receptors and fool them to think you are under bacterial attack.  

How metabolic endotoxemia makes you fat is complex. Once microbial fragments breach both your primary defense barriers (the mucus barrier and an intact gut wall that has become leaky), they can enter the blood then interact with the TLR system on every cell surface to generate inflammatory responses.   Activation of the TLR receptors increases the activity of your genetic master switch of inflammation (i.e. NF-kB) resulting in cellular inflammation and its fellow traveler, insulin resistance, but now via a different molecular pathway.  This is why there is a difference between diet-induced and gut-induced inflammation.  Diet-induced inflammation is the result of an imbalance of nutrients entering the blood via the small intestine to generate an excess of pro-inflammatory eicosanoids that can activate NF-kB, whereas gut-induced inflammation is the result of microbial fragments entering the blood via the large intestine (i.e. colon) to activate NF-kB.  The results are the same, just the pathways are different.  Following the Zone Diet is the most effective way for reducing both types of dietary-induced inflammation.

The TLR receptor system on the surface of human cells is set up as a sensor system to detect microbial fragments. Once any microbial fragment (such as LPS) is detected, there is a rapid activation of NF-κB to increase the production of pro-inflammatory protein products such as inflammatory cytokines and the COX-2 enzyme required for the production of pro-inflammatory eicosanoids. Therefore, any leakage of microbes or microbial fragments into the blood from the gut can represent a significant source of potential systematic inflammation. As the levels of LPS rise in the blood, metabolic endotoxemia begins to increase. This added inflammatory burden appears to be a significant contributing factor to the development of obesity, metabolic syndrome (i.e. pre-diabetes), and diabetes. It should be noted that the levels of microbial fragments in the blood needed to induce metabolic endotoxemia are perhaps 50-100 times lower than the levels associated with the more severe inflammatory conditions (such as sepsis) that can potentially cause death.

Throughout this chapter there has been little mention of probiotics. Probiotics are live bacteria. Most bacteria that exist outside those in the gut are generally pathogenic. However, a few live bacteria have been used for thousands of years to make the first biotechnology products (yogurt and fermented foods). Although these bacteria are not native to our gut, but at least they aren’t trying to kill us.

Probiotics do have some benefits for gut health although far more limited than fermentable fiber and other prebiotics. Although probiotics don’t colonize the gut, they can serve as target practice for the immune cells that line the gut. Just as soldiers in peace continually practice on the firing range to maintain their shooting skills, probiotics serve the same purpose, assuming they get to the gut. This is because like all live microbes they have to pass through the stomach’s vat of acid that kills nearly all bacteria. Even those few that virtually enter into the small intestine and colon, don’t colonize the gut but they provide non-pathological targets for your immune cells to refine their recognition skills to seek out microbes that are persona non-gratia and then destroy them. 

On a scale of 1 to 10 for gut health benefits I give probiotics a 2, whereas I give adequate levels of fermentable fiber an 8. This means making sure you have adequate levels of fermentable fiber in your diet will have a far greater return on your gut health before you should consider adding probiotics to your diet. This might explain why the Federal Trade Commission fined Dannon more than $20 million in 2010 for making false advertising claims on the health benefits of the probiotics in their yogurt products.

As Hippocrates said 2,500 years ago, “all disease begins in the gut.” We now have a far better understanding of why that statement is true if we consider that both diet- and gut-induced inflammation as ultimately coming from the diet.  This is why reducing diet-induced inflammation and maintaining gut health following the Zone Diet is your obligatory first step to reach the Zone.  Our growing knowledge of the molecular biology of the gut has shown us that the fermentable fiber found in the non-starchy vegetables (as well as fruits) plays a critical role in reducing gut-derived inflammation.  These are the primary carbohydrates that you will be consuming on the Zone Diet.  This is why the Zone Diet is the foundation for the Zone Pro-Resolution Nutrition system and is your primary dietary tool to not only reduce the intensity of diet-induced inflammation in the blood, but also reduce gut-induced inflammation at the same time.