Leaky Gut Syndrome
by Len Saputo, M.D.
The intestinal lining has the paradoxical role of selectively letting into the body those chemicals, which it needs, and keeping out what is toxic. The permeability of this barrier is an especially important factor in maintaining the integrity of these critical functions. The leaky gut syndrome exists when some factor makes the spaces between the small intestinal epithelial cells wider than normal, and allows the transgression of macromolecules, bacteria and bacterial fragments, and other toxic substances through these spaces and into the internal milieu. This surprisingly common problem occurs in a wide variety of clinical situations, and, as one would suspect, has profound negative consequences on the body. The importance of this increase in small intestinal permeability is not to be taken lightly, as it is always associated with two very important and potentially serious pathophysiological processes that pertain to effects on liver detoxification and on the immune system.
The liver is the major detoxifying organ of the human body. All products absorbed across the intestinal barrier, must pass through the liver, before entering the general circulation. There is a homeostatic balance between the size of the toxic load presented to the liver, and the liver’s capacity to metabolize this load. Unless the liver’s detoxification system has sufficient reserve capacity to adjust to an increased toxic load, serious consequences can, and often do, result.
Liver detoxification is a process that occurs in the Kupffer cells of the liver, and involves two separate chemical phases, oxidation and conjugation. The first phase of liver detoxification, which involves the cytochrome p450 oxidative enzyme system, converts some of the toxic load into substances that have free radical activity as well as carcinogenic properties. As long as the second phase of liver detoxification can quickly metabolize this load of free radicals and carcinogens by their chemical conjugation with glycine, glutathione, glucuronide, or sulfate, there is no problem. These inert conjugated products are simply secreted into the bile, which then pass into the stool, and are excreted from the body. However, when the reserve capacity of this phase two system is exhausted, the liver can no longer metabolize this production of free radicals and carcinogens before they overflow and cause damage locally, as well as leak into the general circulation, where they can create profound biochemical damage in distant parts of the body.
The reserve capacity and balance of these liver detoxification phases can be revealed by challenging the system with small doses of aspirin, acetaminophen, and caffeine, and measuring how the liver metabolizes them (called a liver detoxification profile test). The specific biochemical pathways involved in liver detoxification can be isolated and quantitated, allowing for specific therapeutic nutritional support that can improve the capacity of these processes to handle increased toxic loads quickly and safely.
As mentioned earlier in our discussion of dysbiosis, the gastrointestinal tract is the largest immune organ in the human body. It is appropriately strategically positioned at the interface of the external and internal milieu, where it is able to defend the body against invasion by substances foreign to it. In the presence of leaky gut syndrome, wherein intestinal permeability is increased, there is a transgression of macromolecules, translocation of bacteria and bacterial fragments, and passage of many chemicals that normally could not get across the gut lining, into the internal milieu. The immune system responds to this invasion by producing specific antibodies that are designed to neutralize these foreign substances.
This process can result in four problems. First, the immune system’s nutrient supplies and reserve function are taxed. Second, it sets the stage for possible autoimmune complications. If one of the transgressing macromolecules has the same antigenic configuration as some other tissue within the body (i.e. joint, nerve, lung, skin, etc.), the resulting antibody produced and directed against the original macromolecule will not be able to distinguish the difference between them, and will attack and destroy both. Third, when the total antigenic load to the body is substantially increased for a prolonged period, the development of a “hyperimmune state” can follow. Fourth, the antigen antibody reaction within the gut wall itself can create an inflammatory reaction that can further aggravate the leak in the gut, thereby setting the stage for a vicious cycle that is self-perpetuating.
Thus, it becomes crystal clear that the presence of a leaky gut syndrome, with its liver and immune ramifications, always creates a metabolic price for the human body. This pathophysiological process is particularly important in patients with clinical disease, but even in the absence of clinical symptoms, it will tax “wellness reserves,” and can eventually lead to serious clinical sequellae.
There are at least four situations wherein the leaky gut syndrome is self-perpetuating. First, in food allergy induced leaky gut syndrome, the offending food stimulates an allergic reaction in the gut lining that induces increased permeability. The increased permeability allows the passage of additional materials across the intestinal lining that further stimulate the immune system to form antigen- antibody complexes that cause additional aggravation of the leak in the gut lining. Unless the vicious cycle is interrupted by avoiding the offending food or blocking the allergic reaction, the process will self sustain, and continue to tax the hepatic, immune and gastrointestinal system’s nutritional reserves and clinical functions.
Second, in the malabsorption malnutrition induced leaky gut syndrome, there is a lack of nutritional supply to the small intestinal lining that results in atrophic changes in the intestinal epithelium that results in increased permeability. The increase in permeability aggravates the malabsorption by the intestinal cells, and results in worsening of the intestinal atrophy and of the leaky gut syndrome. This cycle can be interrupted by providing proper nutritional support to the small intestinal epithelial cells.
Third, dysbiosis itself can aggravate the leaky gut syndrome. When there is disordered gut ecology, there can be an associated translocation of bacteria and bacterial fragments across the small intestinal lining that can induce an antigen antibody reaction, which can further aggravate intestinal permeability. Clearing the dysbiosis can break the cycle by removing the bacteria that are translocating across the gut lining and thereby stop the immune reaction.
Fourth, in the leaky gut syndrome associated with unbalanced liver detoxification, as previously explained, there is an overflow of free radicals into the bile, forming “toxic bile.” This toxic bile is secreted into the intestinal tract where it causes further direct injury to the small intestinal epithelium and results in worsening of intestinal permeability. In this situation, in order to break the vicious cycle, it is important to control the underlying problem that has caused the leaky gut syndrome in first place.
The widespread frequency and critical importance of the leaky gut syndrome has been largely underrated in clinical medical practice. It has been reported in association with an enormous range of acute and chronic diseases, as well as in asymptomatic persons (see chart). In one study that tested for leaky gut syndrome in an intensive care unit, all patients studied had the leaky gut syndrome, regardless of what was wrong with them. Because of the incredibly high incidence of chronic diseases today, and the high frequency of leaky gut syndrome in chronic diseases, it seems reasonable to test for intestinal permeability at least in these patients routinely. It could be further argued that it is an appropriate general screening test in everyone.
The diagnosis of leaky gut syndrome depends upon how the small intestinal surface epithelial cells respond to an oral challenge with two inert sugars, mannitol and lactulose. This test is simple, sensitive, reliable, inexpensive, and easy for the patient to complete. These non metabolizable sugars are ingested, and urine is collected over the ensuing six hours. Mannitol is a monosaccharide (a simple sugar like glucose) that is actively transported across the small intestinal epithelial surface into the internal milieu. Because it is non metabolizable and is then excreted into the urine, the amount that is present in the urine is a measure of the amount that was transported into the body (a test measuring absorptive capacity, or tendency to malabsorption).
Lactulose is a disaccharide (a larger molecule like sucrose) that cannot pass across the small intestinal epithelial cell membrane, and can only get into the internal milieu by passing between the intestinal epithelial cells. This does not happen normally except in very small amounts. However, when the spaces between these epithelial cells are abnormally wide, these large lactulose molecules can then more easily enter into the internal milieu. Because lactulose, like mannitol, is also non metabolizable, it is excreted into the urine after passing into the body. The amount of lactulose that is collected into the urine is a measure of the size of the leak in the gut. Interpretation of this test depends upon the amounts of mannitol and lactulose that is absorbed into the body, as well as the ratio of lactulose: mannitol that has been excreted.