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Gastrointestinal: Leaky gut, molecular mimicry, microchimerism, and autoimmunity

by Paul Bergner

Medical Herbalism 9(4):14-17

Most autoimmune diseases are official conditions “of unknown etiology” according to conventional medical science.  Genetic factors appear to predispose individuals to autoimmune diseases, yet factors in the modern lifestyle must contribute to the conditions — autoimmune diseases are rare or nonexistent in primitive humans following a traditional diet and lifestyle. The cutting edge of research into the cause or trigger for these diseases focuses on loss of the integrity of natural barriers within the organism. The most important of these is the gut barrier, which, when it becomes pathologically permeable, becomes the key to the development of “leaky gut syndrome.” Factors in the modern environment that damage the gut and other physiological barriers, such as vitamin and mineral malnutrition and injurious pharmaceutical drugs, may be responsible for the onset of autoimmunity.

Leaky gut syndrome

The gut barrier is paradoxical in that it must allow the passage of nutrients while keeping out offending antigenic substances and microorganisms in the gut. The gut is typically partly “leaky,” allowing particles as large as bacteria and entire undigested proteins to cross it, and it is normal to find gut bacteria in the portal blood, on the “wrong” side of the gut barrier. These and other antigens or pathogens are typically controlled by the extensive gut lymphatic material and by the liver. If gut permeability increases, however, large amounts of antigenic material can overwhelm these systems, and a cascade of inflammatory events may ensue that can trigger or exacerbate autoimmunity. A full discussion of the “leaky gut” syndrome is beyond the scope of this publication. For an excellent and well-referenced review, see Leo Galland’s book chapter (Galland, 1997) or his on-line article (Galland, 1998).  Leaky gut can result in vicious-cycle type pathologies. Gut inflammation can impair absorption of nutrients, and the resulting malnutrition can result in further reduction of the barrier integrity or an increase in inflammation. The hyper permeable gut can allow food antigens across the barrier, initiating allergic reactions that further impair the gut integrity. Toxic overload on the liver’s antioxidant systems can likewise impair the liver’s ability to handle the overload.

The presence of a leaky gut syndrome associated with various illnesses, including autoimmunity, has been a theory of alternative medicine since the mid-1980s, but studies and trials that support the theory now abound in the scientific literature. Research studies indicate that gut permeability may be pathologically increased by antibiotic therapy (Rutgers et al; Whang et al), non-steroidal anti-inflammatory drugs (Jenkins et al; Louis et al;  Nylander et al; Wallace), food allergies (de Boissieu et  al; Louis et al; Troncone et al,1994), alcohol (Bjarnason et al), stress (Saunders et al), and poor nutrition (Rodriguez et al). Research also shows that the gut does not increase in permeability due to normal aging (Saltzman et al), that mother’s milk can protect against permeability-inducing injuries (Crissinger et al.), and that administration of probiotics can restore normal permeability (Salminen et al.). Various researchers have also linked increased intestinal permeability with autoimmune diseases in general (Parke; Zananian), arthritis (Paganelli et al; Parke); ankylosing spondylitis (Martinez-Gonzales et al); collagen autoimmune diseases (Tsutsumi et al), Crohn’s Disease and Ulcerative colitis (Geboes; Ma; Stevens; Zanjanian), and autoimmune skin disorders (Kieffer and Barnetson; Paganelli et al; Parke.)  A key factor in research into intestinal permeability has been the cellobiose/mannitol sugar permeability test, a simple lab test which assesses the absorption of sugars of high and low molecular weights across the intestinal barrier by measuring urine concentrations (Troncone et al, 1995; Bijlsma et al.)
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Molecular mimicry

A second contemporary concept in autoimmunity may explain the devastating effects of compromise of the gut barrier. Molecular mimicry describes a condition in which protein sequences in bacteria, viruses, foods, or other antigens are similar or identical to sequences in human tissues. Thus antibodies to the mimicking substance may attack the corresponding tissue in the body. Molecular mimicry has long been recognized as the cause of autoimmune disease that appears in the aftermath of acute infections, but recent research demonstrates that the phenomenon is much more widespread than previously thought, and that antibodies to gut bacteria and undigested food proteins may also attack various human tissues. Molecular mimicry between the gut bacterium Klebsiella spp and the body’s tissues has been recognized as a probable causative factor in autoimmune ankylosing spondylitis at least since 1977 (Ebringer). For a recent literature review, see Karlsen and Dyrberg (Karlsen and Dyrberg). Antibodies to some of the materials flooding into the system through a leaky gut could thus trigger the onset or an exacerbation of autoimmunity. See Table 1 on the facing page.

Molecular mimicry and cross reactivity between gluten protein and human tissues has recently been documented. Gluten has long been known to produce celiac disease in some individuals. Celiac disease is accompanied by the autoimmune destruction of the intestinal wall as antibodies to gluten attack the epithelial cells of the intestine (Tuckova et al). It has recently been recognized that the antibodies to gluten may not significantly affect the intestine, but instead attack other tissues throughout the body (Kamaeva et al.) Kamaeva et all suggest that molecular mimicry of the gluten protein has been identified in autoimmune thyroid disease, systemic lupus, autoimmune nephritis, psoriasis, juvenile rheumatoid arthritis, and other autoimmune  diseases. Cross reactive anti-gluten antibodies were found in 19 of sixty patients with various autoimmune disease, including 4 of 16 cases of rheumatoid arthritis and 1 of 8 cases of systemic lupus evaluated in the study. The study implies that removal of gluten from the diet may improve these other conditions just as it does for celiac disease.. Milk protein has been implicated in similar pathologies, with one study finding a direct proportion between circulating autoandibodies and the antibody to the casein protein in cow’s milk. The researchers also found that 10% of the subjects they measured in the general population had cross reactive autoantibodies between cow’s milk protein and body tissues (Cunningham-Rundles et al.). Soy protein has also been implicated in autoimmune diseases, especially autoimmune thyroiditis (Fort et al 1990; Fort et al 1986).
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Other barriers

The gut barrier is not the only one implicated in autoimmune disease. Researchers have theorized that autoimmune pathologies may involve imperfections of  the blood-brain barrier (Claudio et al. 1995), the blood-nerve barrier (Brosnan et al; Yu et al), the blood-retina barrier (Claudio et al, 1994), the bladder epithelial barrier (Bullock et al; Neal et al.), the arterial-endothelial barrier (Wisser), and the placental barrier (Nelson).


The association between pregnancy and the onset of several autoimmune diseases, including SLE, is well-established. A mechanism called “microchimerism” may explain the phenomena. Microchimerism describes a condition in which fetal cells, including components of the immune system, can enter maternal blood and remain there, for decades sometimes. Maternal immune cells can also enter the  fetal blood, reproduce there, and linger into later life. Male fetal DNA has been found in mother’s blood as long as twenty-seven years after birth, and as many as 4% of the white blood cells in infants have been found to have originated in the mother’s blood. White blood cells may remain in the foreign blood, replicating and producing antibodies, for long periods of time. Both situations are implicated by association with autoimmune disease such as scleroderma and lupus. For a review, see Nelson, who first proposed the connection between microchimerism and autoimmunity in 1996 (Nelson)..

The pathologies described above may explain why autoimmunity is a modern disease, and rarely seen in primitive societies following traditional dietary and lifestyle patterns. The malnutrition in key vitamins and minerals common with the modern diet may injure barrier integrity. Modern anti-inflammatory drugs, available over-the-counter and widely consumed either through medical prescription or self-medication, as well as other prescription drugs, may induce leaky gut. In general, conventional medicine can do little for autoimmunity other than turning off the inflammatory mechanisms with drugs. This may be important in life threatening situations, but,  if  leaky gut and accompanying molecular mimicry are not corrected, the disease can be expected to progress, now complicated by drug side effects. Ironically, some of the drugs used to treat autoimmune diseases themselves can produce leaky gut syndrome.

Implications for natural medicine

Natural medicine, on the other hand, may present possibilities for preventing and treating the underlying pathologies. The following strategies might be considered in any case of autoimmunity.

1) Maintain or restore barrier integrity through optimal nutrition.

2) Balance fats and oils in the diet to promote sufficient levels and balance in the anti-inflammatory prostaglandins.

3) Withdraw and/or avoid non-essential pharmaceutical drugs that can induce leaky gut, especially antibiotics, non-steroidal anti-inflammatory drugs, and corticosteroids.
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4)  Screen for and eliminate food allergens.

5) Recommend avoidance of alcohol or treatment for alcoholism

6) Counsel or make referrals for stress reduction. Consider spa therapy for rest during acute attacks.

7) Prescribe gut-healing anti-inflammatory, demulcent, and/or carminative herbs.

One consideration when seeking to apply the principles of traditional herbal systems such as traditional Chinese medicine, Ayurveda, or Unani Tibb is to bear in mind that autoimmunity itself is a disease of modern society, especially of the twentieth century. Leaky gut syndrome and the related issues above were probably rare as the above systems were being developed, and preexisting protocols do  not exist in those systems for autoimmune diseases. Assessment of the clinical picture and the history for the development of and presence of leaky gut syndrome, and treatments to reduce gut permeability might be prudent first steps to take in the treatment of autoimmunity, regardless of the traditional system being used.


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