Leaky Gut: Gateway To Chronic Disease Robert J. Silver DVM, MS Introduction It is considered axiomatic that good nutrition is essential for optimal

Transcription

1 Leaky Gut: Gateway To Chronic Disease Robert J. Silver DVM, MS Introduction It is considered axiomatic that good nutrition is essential for optimal health. Yet without a healthy digestive system that is capable of extracting and assimilating the valuable nutrients contained in food, the best diets in the world are worthless. With every bite of food ingested, comes not only nourishment, but also potential threats from pathogens, antigens and toxins (PAT) that are in the food. Yet only seldom are we made ill from our food. The gastrointestinal tract (GIT) therefore has a protective function in addition to its nourishing function When the bowel fails to breakdown and absorb food, it has a mal-absorption/maldigestion problem. Depending upon the severity and duration of bowel dysfunction, this digestive malfunction can lead to chronic malnourishment and chronic disease. Similarly, when the bowel fails in its protective functions, the body s burden of PAT increases, and chronic disease can result. When we eat a meal, we want the GIT to absorb all the good stuff, but we also want it to exclude all of the potentially PAT materials in the food. How can the bowel have the innate intelligence to exclude noxious materials, but allow for the entry of nutrients? At the same time, how does the GIT immune system know which substances require it to mount an inflammatory response and which substances are safe? Intestinal permeability is a double-edged sword. The GIT has the paradoxical double role of both needing to optimally absorb necessary nutrients, while at the same time being able to exclude PAT. This seminar today discusses the role that the dysfunction of the protective mechanisms of the bowel play in the genesis of chronic disease. The syndrome of problems associated with increased intestinal permeability is commonly known as Leaky Gut Syndrome (LGS). Healthy diets and specialized supplements can contribute substantially to restoring and maintaining the integrity of bowel function. Barrier Function Of The Gut Three systems provide protection from the external environment s potential threats: 1) The Integumentary System, 2) The Respiratory System and 3) The Gastrointestinal System. To use the adult human as an example (which has a more consistent size than the many breeds and species of animals), the epidermis has less than 10 square meters of surface area. The mucosal lining of the lungs have about 140 square meters of exposed surface area. But the largest exposed surface area is found in the gastrointestinal tract, which in humans, has 200 square meters in contact with the environment. These surface area relationships are comparable to those found in our animal species as well. Specialized structures and cells that comprise the bowel wall provide for some of the mechanical barrier function of the gut. The gastrointestinal immune system (also known as the Gut Associated Lymphoid Tissue or GALT provides for both a cellular and humorally mediated immune response which is the second part of the barrier function of the bowel. Digestion, Detoxification and The Intestinal Barrier. In addition to the protective value of the mechanical mucosal and mucous barrier, and the immunological barrier provided by the siga and GALT, the gastrointestinal tract is also protected by its own digestive functions such as peristalsis, gastric acid, bile acids, gastric transit time, and digestive enzymes.

2 Further protection to the body is provided by the liver (an integral part of the GIT), which receives in its portal circulation all of the material that has made it through the mucosal barrier of the bowel. This material may be a mixture of nutrients, toxins, pathogens and antigens. The biliary system of the liver secretes bile which helps to digest fats, stimulates peristalsis, and helps to eliminate toxins via the enterohepatic circulation. The liver also provides defensive activity both in terms of its phagocytic Kupffer cells, and in terms of its detoxification enzyme systems. Hepatic enzymes decontaminate toxins and metabolic toxic by-products as well as help to degrade antigens and antigen/antibody complexes. Kupffer cells are the sessile hepatic macrophages that are found in hepatic sinusoids and play an important role in the GI immune system by removing bacteria, particulate matter and toxins. Leaky Gut Syndrome. Leaky Gut, has been well-documented in both the human and veterinary literature. It has been demonstrated that not only do symptoms of food allergies align with leaky gut, but a pathologic mechanism called Bacterial Translocation occurs in which commensal or pathogenic bacteria from the gut can migrate to other organs where they are not commonly found. Once in these distal target organs these foreign bacteria stimulate an inflammatory response, which is first localized to the organ system and then becomes systemic. Appropriately enough, this systemic post-bacterial translocation phase is called: SIRS or systemic inflammatory response syndrome. An example of SIRS is the polyarthritis associated in some patients with enteric salmonellosis infections. In the conventional model, SIRS is initiated by infection or tissue injury and then further exacerbated by bacterial translocation, which provides for the release of endotoxin, which stimulates pro-inflammatory cytokine and leukotriene release (TNF-α, IL-1, IL-6) which, with activation of PMNs and the production of ROS further amplify the inflammatory response. (19) Have you ever wondered why we see so commonly in clinical practice, patients that present with diarrhea who will then develop (either concurrently or following the first infection) a urinary tract infection? Anatomically, the urinary bladder is contiguous to the rectum. They share some venous drainage and lymphatic vessels. When the bowel s barrier system is functioning within normal limits, an acute infection stays within the bowel lumen or within the bladder. But either due to the pathogenesis of the infectious diarrhea or when the bowel barrier has already been breached, the bacteria will translocate to the bladder, or visa versa. Of course transmission of pathogens can also occur externally from rectum to vulva from licking or contamination with feces of the vulva. Following SIRS, if the condition does not find correction, it then progresses to the final and most serious stage, known as MODS or multiple organ dysfunction syndrome. This is where you have multiple organ involvement and a patient with refractory multiple symptoms. This is the underlying mechanism involved with many chronic and degenerative conditions, including both inflammatory and autoimmune disorders. The first step in the correction of BT, SIRS and/or MODS is to correct Leaky Gut. Impaired intestinal barrier function generates a number of problems within the body in addition to SIRS and MODS. Compromised barrier function increases the production of free oxygen radicals (ROS) and carcinogens by the liver s P-450 cytochrome oxidase system. For instance, it is thought that the release of oxidation by-products by the liver into

3 the bile and the reflux of this toxic bile into the pancreatic ducts may be the major cause of chronic pancreatic disease. (1). Impaired barrier function can also lead to diseases of the immune system. For instance, when bowel permeability is increased, classic hypersensitivity to foods and to components of the normal gut flora can result. (2,3) Bacterial endotoxins, cell wall polymers and dietary gluten may cause non-specific activation of pro-inflammatory pathways mediated by complement and cytokines. In experimental animals, chronic low grade endotoxemia has been shown to contribute to the development of auto-immune disorders. (4). The list of clinical disorders associated with Leaky Gut Syndrome (LGS) as reported in the human literature has been studied extensively. Examples include: 1. Inflammatory and infectious bowel diseases (5) 2. Chronic inflammatory arthritis (6) 3. Dermatoses such as acne, psoriasis and dermatitis herpetiformis (7) 4. Conditions triggered by food allergies or specific food intolerance such as eczema, urticaria and irritable bowel syndrome (8) 5. Chronic fatigue syndromes 6. Chronic hepatitis (9) 7. Acute and Chronic pancreatitis (10) (18) 8. Cystic fibrosis (11) 9. Pancreatic carcinoma Increased intestinal permeability may be involved in the course of each disease, or may be a secondary effect of the hyperpermeability leading to immune activation, hepatic dysfunction and pancreatic insufficiency, creating a vicious cycle of disease promotion promoting more disease. Causes Of Leaky Gut. LGS is often caused by the introduction of substances which are capable of damaging the intestinal mucosa s integrity. Commonly these substances damage the tight junctions that bind the epithelial cells together. This increases passive para-cellular absorption of substances. Damage can be caused by infectious agents, ethanol and NSAIDs. Hypoxia of the bowel can also lead to LGS. One study of LGS in dogs found an increase in intestinal permeability in dogs following major trauma, which interfered with bowel perfusion, leading to hypoxia. (12). Reactive oxidative species as well as cytotoxic drugs are also considered causes of increased intestinal permeability. Following exposure to allergenic foods, it has been found that intestinal permeability sharply increases. In studies it has been found that this increase in permeability can be blocked by sodium cromoglycate, which indicates that atopic mediators released from mast cells such as serotonin and histamine are responsible for this increase in permeability. (13) The more damage done to the bowel mucosa by these toxic compounds, the increased hyperpermeability that results, and with it more ingress of toxic compounds leading to increased permeability a vicious cycle. When the epithelial mucosal cells are damaged, leading to increased para-cellular transport of macromolecules, the damaged epithelial cells have reduced trans-cellular transport. Nutrients are usually absorbed through trans-cellular transport. LGS then can lead to malnourishment by means of this mechanism. The malnourishment can lead to increased structural and functional disturbances. This is another vicious cycle associated

4 with LGS.(see Case: Bella). Prolonged fasting can also lead to impaired bowel permeability. (16) LGS has been shown to develop in conditions where there is an imbalance in healthy bowel ecology. This unhealthy bowel microecology is also known as dysbiosis. Dysbiosis is defined as disease or dysfunction induced by organisms of low virulence that can alter the metabolic or immunologic responses of their host. Crohn s disease and Ankylosing Spondylitis in humans are diseases in which the immune system has become sensitized to normal gut flora. Inappropriate sensitivity to bowel flora may be an early complication of altered permeability. The inflammatory enteropathy induced bacterial sensitization further increases the hyperpermeability of the bowel wall, thus creating another vicious cycle associated with LGS. (14) NSAIDs increase para-cellular permeability, due in part to the inhibition of protective prostaglandins. This hyperpermeability is partially blocked with pre-treatment with misoprostol (Cytotec ). When NSAIDs are administered chronically hyperpermeability results which is not reversed by misoprostal, but which is reversed by metronidazole. This reflects the role that bacterial endotoxins play in perpetuating intestinal hyperpermeability. When an intravenous injection of bacterial endotoxin is given to an experimental subject, increased intestinal permeability results. (15) LGS increases the work of the liver. It needs to remove more macromolecules and oxidize more enteric toxins. Cytochrome P-450 activity is induced, and in the process, the liver produces more reactive oxidative species (ROS) in the first step of detoxification. As a result, these toxins and free radicals can damage hepatocytes, and excrete the free radicals into the bile in an attempt to eliminate them from the body. This toxic bile can damage the bile ducts and as mentioned earlier, reflux into the pancreas leading to chronic pancreatic inflammation. The liver uses up its sulfur-based amino acids such as glutathione in its attempt to eliminate these toxins. (16) Summary Of Leaky Gut Syndromes Pathogenesis. 1. An inflamed gut does not absorb nutrients and foods properly. 2. The inappropriate leakage of large food particles promotes food allergies and GI symptoms. 3. With compromised detoxification pathways, chemical sensitivities can arise. The leakage of toxins overburdens the liver so that the body is less able to handle its everyday burden of chemicals that need detoxification. 4. The disruption of the protective mucosal barrier is causes the body to be unable to adequately resist infection by protozoa, bacteria, viruses and yeasts. 5. Intestinal hyperpermeability allows bacteria and yeast to trans-locate. Translocation is the migration of bacteria or yeast from their appropriate organ environment to an inappropriate organ elsewhere in the body where they can set up infection or inflammation. 6. Intestinal hyperpermeability increases the formation of antibodies due to the hypersensitivity of the immune system created by the syndrome. These antibodies can help to setup autoimmune diseases such as rheumatoid that has been linked to LGS. Reversing Leaky Gut Syndrome: The Four R Program To Address Leaky Gut Syndrome.

5 The following 4 step approach to correct this condition has been developed by the Functional Medicine group out of Gig Harbor, Washington. It is called the 4-R Program. I initiate this program in many of my patients, and often will use at least a part of this program for all of my patients. I have clinically seen it benefit these patients, repeatedly. Some patients with long-standing chronic disease issues may need longer exposure to these tools to effect any clinical change at all. Some patients are so stuck in their pathology that it is possible that none of these tools will do any good. The only way to identify these difficult-to-address patients is by offering them these tools and maintaining them on them for at least 6 months before deciding that they are not working and at that point could be discontinued. The 4-R Program For Leaky Gut And Chronic Disease 1: REMOVE pathogens allergens and toxins. By lowering the total load (the body s burden) of these troublesome substances, the immune system and liver do not need to work as much in processing them. This makes more energy available to these systems to direct toward re-establishing healthy patterns. Removal can be by elimination from the diet or environment, or by the use of agents such as antimicrobial agents to reduce the population of pathogenic organisms. 2: REPLACE digestive factors that are inadequate or absent. Inadequate pancreatic or intestinal enzyme production leaves digesta only partially broken down, thus altering the environment in the bowel, providing opportunity for pathology to develop. The beneficial bacteria that produce short chain fatty acids (SCFA) from soluble fiber in the bowel need a narrow range of temperatures and ph, as well as adequate substrate for their activity. When food is only partially digested, the intermediate breakdown products of the ingested food that result is not conducive to the normal function of these probiotic species. 3: REPAIR Damaged Intestinal Mucosal Barrier The use of the free form amino acid l glutamine has been found to reduce bacterial translocation, and to increase the protein synthesis of the enterocytes which enables them to increase their rate of self-repair. The phospholipid-rich compound lecithin, and the omega three fatty acids commonly found in fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are also integral to the repair of intestinal mucosa damaged from disease, stress or diet. Antioxidants reduce ROS damage to intestinal mucosa. Zinc and Vitamin B5 (pantothenic acid) are involved in the mucosal repair process. Soluble fiber promotes SCFA production which provides nourishment for repair of damaged lower bowel mucosal cells Rice protein solids have been found to reduce intestinal secretions and improve reabsorption of water from colonic digesta. This is why the Rice Water Fast has been recommended for treating diarrhea in third world countries by the WHO. (17) 4: REINOCULATE w/probiotic Micro Flora Cultures and accessory nutrients to create a healthy bowel ecology Normal indigenous GI bacterial flora are an extremely important factor in maintaining the healthy GI mucosal barrier. Anaerobes are the most numerous bacteria in the bowel. These commensal beneficial microorganisms compete with potential pathogens for nutrients and for attachment sites to the mucosa, and thereby inhibit bacterial overgrowth by the pathogenic gram negative bacteria. Antibiotics can upset this balance between the good bugs and the bad bugs. H2 blockers, as well as hyperosmolar enteral diets can result in bacterial overgrowth and colonization of the stomach.

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