IHSR Laboratory investigations– May 2013
Leaky Gut Syndrome: Intestinal Permeability and Rejuvenation.
Sometime referred to as leaky gut syndrome, increased intestinal permeability (IP) refers to a loss of selective permeability across the paracellular pathway of the small intestine. This has diverse pathological consequences due to the extremely complex role of the intestinal barrier in coordinating digestive, absorptive, motility, neuroendocrine, and immunological/protective functions.
The gastrointestinal (GI) epithelium is the largest mucosal surface in the body, and represents the greatest interface with the external environment. This mucosal barrier must be semi-permeable to absorb nutrients from food; at the same time, it must protect against invasion of microbes and toxins with pathogenic capacities – a dual role sometimes referred to as the “dilemma of opposing functions.” Indeed, unlike other mucosal surfaces which typically have only one of the above functions, the intestinal mucosa must balance the needs for a barrier against a hostile environment with the necessity of active and passive transport. An intact intestinal barrier is, therefore, critical to normal physiological function and prevention of disease.
Given the complexity of this challenge, a number of defence mechanisms have evolved in the gut, including the secretion of toxins known as defensins and mucins, the preference of commensal flora to pathogenic organisms, enhanced sophistication of adaptive immunity, molecules which recognize antigen patterns and can regulate immunological responses, and tight junctions which regulate passage between cells. It is this last mechanism which has received considerable attention, likely because it is the rate-limiting step for paracellular transit, but certainly because tight junction dysfunction has been associated with a number of clinical syndromes and disease. While once viewed as extracellular cement which formed an absolute barrier, it is now apparent that tight junctions are extremely dynamic structures made up of a complex network of proteins; these proteins are involved in several key functions of the intestinal epithelium under both physiological and pathological circumstances.
Consequences of Increased Intestinal Permeability
Perhaps of greatest consequence to abnormal IP is the passage of luminal antigens across the intestinal barrier, which would normally be denied access through functional tight junctions. As a result, immune cells are exposed to intact antigens which disrupt several physiological functions, including immune homeostasis to pathogens (bacteria, viruses, fungi, and parasites), recognition and tolerance of self-antigens, tolerance to commensal flora, and tolerance as well as sensitization and desensitization to foods.
For example, a recent trial found increased IP in all subjects with adverse reactions to food, with the severity of the clinical symptoms correlated with the degree of permeability. One explanation is the loss of tolerance to food antigens, because these intact antigens are allowed to interact more directly with immune cells.
Another of the most significant consequences of IP may be its link with autoimmunity. A recent review described this paradigm shift in thinking about autoimmune disease. The authors note that increased IP seems to precede autoimmune disease, likely because an abnormality in antigen delivery triggers the process which leads to an autoimmune response. This theory also suggests that autoimmune disease may be reversible, if the IP is restored. This is most clearly seen with celiac disease, although it may apply to other autoimmune diseases as well.
Inflammatory bowel disease (IBD), which has a strong association with intestinal integrity, may also be triggered by the same mechanism. Defective function of the mucosal barrier is thought to be a necessary factor in the etiology of IBD; it allows bacterial antigens to come in contact with the innate and adaptive immune cells, which then generate inflammatory responses. Irritable bowel syndrome (IBS) has also been shown to have altered IP.
The effects of IP are not just confined to the gut. Individuals with asthma, atopic dermatitis, fibromyalgia, chronic regional pain syndrome, and possibly autism have also been shown to have an increase in IP. Those with some types of arthritis may be susceptible as well.
Very recently, a connection between chronic heart failure and IP was established. It is unclear if an increase in IP is the primary event that causes systemic inflammation leading to heart disease. However, most likely in patients with pre-existing heart disease, hypoperfusion of the intestinal microcirculation triggers intestinal dysfunction and inflammation, creating a vicious cycle.
Recently, Type I diabetes has been shown to be associated with leaky gut. Even prediabetic normoglycemic individuals with signs of beta cell autoimmunity have been shown to have increased IP and inflammation.
Lastly, those with chronic liver disease have been shown to have increased IP, including some individuals without cirrhosis. While alcohol is a known risk factor for damaged intestinal epithelium, individuals with non-alcoholic steatohepatitis have been shown to have increased permeability in response to aspirin compared to controls, suggesting other risk factors also contribute.
Causes of Increased Intestinal Permeability
There appear to be numerous causes of abnormal IP. Among them are nutritional deficiencies, stress, food allergy/intolerance, any source of increased inflammatory cytokines, noxious environmental toxins, microorganisms, and unknown causes. Certainly in patients with celiac disease increased permeability is caused by gluten consumption, but a recent in vitro study suggests that wheat germ agglutinin (WGA) may have some ability to damage GI epithelium by different mechanisms. Exercise, when accompanied by dehydration, may also increase GI permeability. A small study of twenty runners found that one hour of exercise increases leaky gut if no fluid is consumed during the activity.
Non-steroidal anti-inflammatory drugs (NSAIDs) are a well-known cause of increased IP in both the short and long term, causing significant morbidity and mortality. Aspirin was recently shown to increase the susceptibility to “gut leakiness” in patients with nonalcoholic steatohepatitis (NASH), particularly in the large intestine. Given the important role of microflora in determining GI integrity, antibiotic use is also thought to increase IP by altering the balance between commensal and pathogenic flora.
Lastly, immune dysfunction is an established component of at least some of the cases of intestinal damage. In addition to autoimmune disorders, immune dysregulation may lead to increased intestinal inflammation, which is at least partly mediated by mast cell activation. Mast cells are key regulators of the integrity and function of the gastrointestinal barrier.