definition intestinal permeability leaky gut syndrome

definition intestinal permeability leaky gut syndrome

In the past few years, the interest in changes to gut permeability has risen as the association among intestinal inflammation, increased permeability, and autoimmune disease has become well established. The penetration of the intestinal mucosal barrier appears to correlate with clinical disease manifested as infection, food allergy, Crohn’s disease, coeliac disease, dermatologic conditions, colitis, or autoimmune diseases (such as rheumatoid arthritis, ankylosing spondylitis, Reiter’s syndrome, eczema, and other allergy disorders). Decreased permeability appears as a fundamental cause of malnutrition, malabsorption, and failure to thrive.

The small intestine has the paradoxical, dual function of being a digestive and absorptive organ as well as a barrier to the penetration of toxic compounds and macromolecules. The mucosal membranes accomplish this barrier function through a combination of intestinal immune function and mechanical exclusion. Elaborate immunologic and mechanical processes for excluding harmful dietary antigens, bacterial products, and viable microbial organisms are present at the mucosal level.

The distal intestine contains numerous dietary and bacterial products with toxic properties, including actual bacterial cell wall polymers, chemotactic peptides, bacterial antigens capable of inducing antibodies that cross react with host antigens, and bacterial and dietary antigens that can form systemic immune complexes.

Abnormalities of the immune system or mechanical barriers lead to enhanced uptake of inflammatory mediators and pathogenic bacteria. With clinical intestinal injury, mucosal absorption of substances that are normally excluded increases dramatically. Intestinal inflammation enhances the uptake and systemic distribution of potentially injurious macromolecules.

Peters and Bjarnason, in an excellent review of uses of permeability testing noted, “Measurement of intestinal permeability will play an increasing role in clinical investigation and monitoring of intestinal disease.”

The measurement of passive permeability using the dual sugar technique (lactulose and mannitol) may be the most useful and precise noninvasive method for assessing mucosal integrity in the small bowel. Mannitol (a monosaccharide) and lactulose (a disaccharide) are water-soluble molecules that are not metabolized by the body. Mannitol (molecular weight 182) is readily absorbed, and lactulose (molecular weight 360) is only slightly absorbed. An oral dose containing 5 g lactulose and 3 g mannitol in 10 g of glycerol is given and a timed urine sample is analyzed for the ratio of the percentage recovery of lactulose and mannitol.

Clinical Significance Studies on a wide range of illnesses have demonstrated alterations in the uptake of monosaccharides, disaccharides, or both and have correlated these changes with clinical and pathologic conditions. These illnesses, which disrupt the structural barrier of the GI tract, often result in pathologic changes in distant organs and tissues.

The clinical conditions associated with altered intestinal permeability include IBD, irritable bowel disease, malnutrition and malabsorption, accelerated aging, Crohn’s disease, intestinal infections, ulcerative colitis, endotoxemia, autism, nonsteroidal antiinflammatory drug (NSAID) enteropathy, celiac disease, chemotherapy, inflammatory joint disease, giardiasis, food allergy, trauma, alcoholism, and human immunodeficiency virus (HIV) positive status.

Some of the symptoms associated with increased intestinal permeability include abdominal pain, arthralgias, cognitive and memory deficits, diarrhea, fatigue and malaise, fevers of unknown origin, food intolerances, myalgias, poor exercise tolerance, shortness of breath, skin rashes, and toxic feelings.

The permeation of water-soluble molecules through the intestinal mucosa can occur either through cells (transcellular uptake) or between cells (paracellular uptake).

Small molecules (mannitol) readily penetrate cells and passively diffuse through them. Larger molecules such as disaccharides (lactulose) normally are excluded by cells. The rate-limiting barrier in this case is the tight junction between cells, which help maintain epithelial integrity.

The intestinal permeability test directly measures the ability of two nonmetabolized
sugar molecules, mannitol and lactulose, to permeate the intestinal mucosa. Lactulose is only slightly absorbed and serves as a marker for mucosal integrity. Mannitol is readily absorbed and serves as a marker for transcellular uptake. Low levels of mannitol and lactulose indicate malabsorption.

Elevated levels of mannitol and lactulose are indicative of general increased permeability and leaky gut. Permeability to mannitol may decrease, which is indicative of malabsorption of small molecules.

The lactulose/mannitol ratio is a useful parameter. An elevated ratio indicates that the effective pore size of the gut mucosa has increased, allowing access (to the body) of larger, possibly antigenic, molecules. One should consider the possibility of mild IBD or gluten enteropathy in these cases.

Clinical Therapeutics Treatment of altered intestinal permeability is very important for several reasons. Increased permeability can contribute to, or cause, a wide range of systemic reactions. Decreased permeability can cause malabsorption and
malnutrition, leading to a wide range of systemic effects. Correcting the altered permeability can have an immediate effect on relief of symptoms and a gradual improvement on the underlying condition. Eliminating the cause can often stop the pathologic process, allowing the body to heal and return to homeostasis.

One of the first considerations is to identify and eliminate the cause of altered permeability. Some of the most common causes of increased permeability are NSAID use, intestinal infection, dysbiosis, parasites, maldigestion, deficient immunoglobulins, allergenic foods, alcoholism, toxic chemicals, trauma, and endotoxemia. Decreased permeability may be caused by chemotherapy, gastroenteritis, IBS, food allergy, and ulcerative colitis. Identifying the cause is an important first step in reversing altered permeability.

There are a number of therapeutic substances, such as L-glutamine; zinc; vitamins A, E, and C; pantothenic acid; folic acid; glycyrrhiza; gamma oryzanol; slippery elm; aloe vera; cat’s claw; selenium; carotenoids; N-acetyl cysteine; bioflavonoids; and EFAs, which can be used for mucosal support to lower intestinal permeability. In determining which substance to use, it is helpful to understand the proposed mechanism of action. Administration of therapeutic substances must be carried out under the supervision of a medical practitioner. Application of this test to children between the ages of 2 to 12 must be conducted under the supervision of a medical practitioner, as well.