In addition to its very important functions of digestion and absorption, the gastrointestinal tract is also the largest organ of the immune system in the body. The percentage of lymphocytes residing in the GI tract are estimated to range between 60% to 80%.

When we eat, we want the digestive system to absorb all the good stuff while keeping out all the potentially toxic, antigenic and pathogenic materials in food. How can the digestive system possess the innate intelligence to exclude noxious materials while allowing for the entry of nutrients? The answer lies in the four levels of protection provided by the barrier system of the GI mucosal wall:

1. Mucus layer covering the microvilli
2. Tight junctions between epithelial cells
3. GALT-sIgA in the mucus of the glycocalyx
4. Probiotic species

The GIT (gastrointestinal tract) has the greatest amount of surface area exposed to the environment of all three barrier systems in the body. In humans, the skin has less than ten square meters of surface area, whereas the lungs have about 140 square meters. The human gastrointestinal tract, however, has 320 square meters of surface area exposed to the environment. These surface area relationships are comparable in veterinary species as well.

Disturbances to the GI mucosal barrier
The GI mucosal barrier can be disturbed by factors associated with GIT injury, exposure to toxins or infection. Bacterial infections and endotoxins can injure the tight junctions holding intestinal mucosal cells together.

Bacterial overgrowth secondary to inappropriate use of H2 blockers and antacids can lead to proximal gut colonization by pathogenic bacteria that are “attracted” to the more alkaline pH. Immunosuppressed or protein-deficient patients can have decreased sIgA production, which impairs the immunoprotective value of this secretory immunoglobulin. sIgA is embedded in the mucus layer (or glycocalyx) that overlies the mucosal epithelia.
The liver provides defensive activity both in terms of its phagocytic Kupffer cells, and its enzyme detoxification systems. The liver has a dual-phase system of detoxification. Hepatic enzymes decontaminate toxins and metabolic toxic by-products, and help degrade antigens and antigen/antibody complexes. Kupffer cells are the sessile hepatic macrophages found in hepatic sinusoids; they play an important role in the GI immune system by removing bacteria, particulate matter and toxins.
Compromised barrier function increases the total toxic load on the body as a whole by allowing ingested toxins and xenobiotics entry into the systemic circulation, bypassing the portal circulation, thus allowing these foreign substances entry into the body without modification by hepatic detoxification enzymes.
Contrary to the recommendations of folk medicine, prolonged fasting may do more harm than good in patients with challenged immune systems. “Bowel rest” for more than three days has been shown to cause deterioration of the enterocyte population, which can lead to atrophy of the mucosal surface, alterations in bowel permeability and an overall diminution of gastrointestinal immune function. Studies have shown that early enteral feeding can improve splanchnic blood flow and immune system function.
With disrupted barrier function, antigens and pathogens are allowed to gain entrance into the systemic immune system. The first contact of antigens and pathogens is with dendritic cells that then carry the information from those antigens or pathogens to naïve B and T cells, and “activate” them to be specific for those antigens or pathogens.

Following their activation, naïve T and B lymphocytes clone themselves and then migrate to the regional mesenteric lymph node. From the regional lymph nodes, these activated lymphocytes enter the lymphatics, and from there the venous circulation and systemic blood supply, ultimately migrating back to a specific anatomical region of the GI tract.

Increased immune mobilization leads to disease
When allergens and pathogens are prevented from being absorbed into the systemic circulation by healthy mucosal barrier mechanisms, there can be no systemic immunological response (Hamilton, 1985). Disrupted bowel barrier function, however, will lead to inappropriate increases in antigen and toxin loads and will disrupt detoxification mechanisms, thereby creating increased immune system and liver enzyme mobilization. Over time, this can lead to chronic pathology. Disrupted bowel barrier function has three synonyms:

1. Hyperpermeable bowel
2. Increased intestinal permeability
3. Leaky gut

Impaired barrier function can also lead to diseases of the immune system. For instance, when bowel permeability increases, classic hypersensitivity to foods and components of normal gut flora can result (Galland, 1993). Bacterial endotoxins, cell wall polymers and dietary gluten may cause non-specific activation of proinflammatory 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 (Branganza, 1983). Increased intestinal permeability may be either involved in the course of each disease, or may be a secondary effect of the hyperpermeability leading to immune activation and hepatic dysfunction, creating a vicious cycle of disease promotion.

Measuring intestinal permeability
The measurement of increased intestinal permeability in veterinary species requires measured urinary collection with a urinary catheter in place. This makes it more difficult to diagnose without hospitalization.

Typically, in the measurement process, different sized, nondigestible long chain sugars are administered orally, and collected in the urine. The ratio of shorter to longer chain sugars defi nes whether the barrier has been breached, which allows increased urinary recovery of longer chain sugars. Thus, unless it is being specifi cally measured, the role of increased intestinal permeability often goes unrecognized. There’s a new and emerging methodology of food sensitivity and intolerance testing that measures food ingredient-specifi c IgA and IgM in the patient’s saliva, serving as a practical, non-invasive screening for increased intestinal permeability. Secretory (mucosal) IgA is lower with a disturbed intestinal barrier mechanism, and this test can help quantitatively measure food-related antibodies directed against IgA and IgM. Preliminary studies suggest this testing methodology yields highly accurate results. The value of the test is not simply as a screen for leaky gut; it will also help substantially with the formulation of hypoallergenic diets (Miller, 2010; Pfaffe, 2011; Swanson, 2003).

The 4Rs
The hyperpermeable bowel can be treated and managed successfully with a four-part treatment program (“The 4Rs”) that uses diet, herbs and nutraceuticals to reverse the causes and risk factors for increased intestinal permeability. Many naturally occurring substances can help repair the intestinal mucosal surface, or help improve hepatic function when it is overwhelmed by an excessive total toxin load (Galland, 1993; Nathens, 1996;

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 hard in processing them. This makes more energy available to direct toward re-establishing healthy patterns. removal can be done 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 and providing opportunity for pathology to develop. The benefi cial bacteria that produce short chain fatty acids (SCFA) from soluble fi ber 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 digesta do not promote healthy microfl oral ecology. An example of this is the small intestinal bacterial overgrowth (SiBo) seen with EPi.

3 REPAIR damaged intestinal mucosal barrier. The use of the free form amino acid l-glutamine reduces bacterial translocation, and increases the protein synthesis of enterocytes, enabling them to increase their rate of selfrepair. The phospholipid-rich compound lecithin, and the omega 3 fatty acids commonly found in fi sh oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are also integral to repairing intestinal mucosa damaged from disease, stress, toxins or diet.

4 REINOCULATE with probiotic cultures and accessory nutrients to create healthy bowel ecology. Endogenous and transient probiotic Gi microbial fl ora are extremely important factors in maintaining a healthy Gi mucosal barrier. Anaerobes are the most numerous bacteria in the bowel. These commensal benefi cial microorganisms compete with potential pathogens for nutrients and attachment sites to the mucosa, thereby inhibiting bacterial overgrowth by pathogenic gram negative bacteria. Antibiotics can upset this balance between good and bad bugs. H2 blockers and hyperosmolar enteral diets can result in bacterial overgrowth.

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Dr. Robert Silver graduated in 1982 from the College of Veterinary Medicine at Colorado State University. He became certified in acupuncture in 1993 by IVAS and developed a passion for herbal and nutritional medicine, leading to the founding of RxVitamins. He established Boulder’s Natural Animal in 1993, and is president of the VBMA. Dr. Silver has become an expert in the veterinary applications of cannabinoid therapies, and authored Medical Marijuana and Your Pet. He is Director of Animal Health for Folium Biosciences, a biotech company that grows and processes hemp into nutraceuticals. He also provides online education to pet owners and veterinarians for CE credit on the use of cannabis in pets (