In more recent years, the anti-carcinogenic activity of curcumin both in prevention and treatment has been studied in colon, bone marrow, breast (Liu et al., 2013), prostate, and lung cancer (Sharma et al., 2001; Gomez-Bougie et al., 2015; Tieten et al., 2010; Tsai et al., 2015). While curcumin has been established as safe and nontoxic at high doses in humans (Krishnakumar et al., 2015), how curcumin has such a diverse range of medicinal effects is less understood. The liver is the major organ responsible for metabolizing or breaking down substances. When something is ingested, it is normally absorbed into the
Integrity of the Gut
The intestines are the largest mucosal interface between the environment and us. A single layer of epithelial cells is all that separates the bloodstream and the contents of the intestines. The small intestine has the complex and crucial role of allowing nutrients inside the body while keeping bacteria, toxins, and wastes outside. The tight junctions separating the intestinal cells assume some of these functions. The tight junctions aren’t cemented as previously thought but are rather dynamic structures. Research has revealed that tight junctions are made up of a complex meshwork of proteins, the interaction of which dictates their competency. To date, multiple proteins that make up the tight junction strands have been identified: occludin,1 members of the claudin family,2 and the junctional adhesion molecule (JAM), a protein belonging to the immunoglobulin superfamily which has been described as an additional component of tight junction fibrils.3 To meet the diverse physiological challenges to which the intestinal epithelial barrier is subjected, tight junctions must be capable of rapid and coordinated responses that are involved in developmental, physiological, and pathological processes. To achieve such responses, a complex regulatory system orchestrates the assembly and disassembly of the multiprotein tight junction network.Compromised tight junctions cause increased intestinal permeability, commonly referred to as leaky gut, and can result in the absorption of incompletely digested proteins and antigens that overstimulate the immune system through the bloodstream. Emerging research shows that most autoimmune conditions may share a common root hiding in the intestinal linings of individuals with autoimmune diseases, even years before the symptoms manifest.
The Development of Celiac Disease
Celiac is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward. Symptoms can include chronic diarrhea, failure to thrive (in children), and fatigue – but even these may be absent, and symptoms in other organ systems could occur. Increasingly, diagnoses are being made in asymptomatic persons as a result of increased screening;4the condition is thought to affect somewhere between 1 in 1,750 and 1 in 105 people in the United States.5 An immune reaction to a main protein component of gluten, gliadin, found in wheat, and similar proteins found in Triticeae crops (which includes other common grains such as barley and rye) can trigger the development of Celiac disease.6
Upon exposure to gliadin, and specifically to three peptides found in gluten proteins (also known as prolamins), the enzyme known as tissue transglutaminase modifies the protein, and the immune system cross-reacts with the small bowel tissue, causing an inflammatory reaction. That leads to destruction of the villi lining the small intestine (called villous atrophy). This interferes with the absorption of nutrients, because the intestinal villi are responsible for absorption. The simple effective treatment is a lifelong gluten-free diet.6 While the disease is caused by a reaction to wheat proteins, it is not the same as wheat allergy.Early in the development of celiac disease, tight junctions are opened,7,8most likely secondary to zonulin upregulation,9 and severe intestinal damage ensues.8 Zonulin is normally present in the intestines to control the passage of fluids, macromolecules, and leukocytes, but this protein appears to be overexpressed in patients with autoimmune conditions, resulting in increased intestinal permeability. The upregulation of the zonulin innate immunity pathway is directly induced by exposure to the disease’s antigenic trigger, gliadin.10 Gliadin has also been shown to be a potent stimulus for macrophage proinflammatory gene expression and for cytokine release.11Once gluten is removed from the diet, serum zonulin levels decrease, the intestine resumes its baseline barrier function, auto antibody responses are normalized, the autoimmune process shuts off and, consequently, the intestinal damage (which represents the biological outcome of the autoimmune process) heals.
The Autoimmune Triad
Alessio Fasano, MD, a pediatric gastroenterologist, research scientist, and founder of the University of Maryland Center for Celiac Research, believes all autoimmune conditions have three factors in common: a genetic susceptibility, antigen exposure, and increased intestinal permeability.12“Besides celiac disease, several other autoimmune diseases, including type 1 diabetes, multiple sclerosis, and rheumatoid arthritis, are characterized by increased intestinal permeability secondary to non-competent tight junctions that allow the passage of antigens from the intestinal flora, challenging the immune system to produce an immune response that can target any organ or tissue in genetically predisposed individuals,” Fasano wrote in the February 2012 issue of Clinical Reviews in Allergy and Immunology.12 While it was previously believed that the autoimmune process remained ongoing once activated, this recent evidence indicates that the process could be modulated and possibly reversed by interrupting one of the modifiable factors involved in the autoimmune triad.
SIBO as a Contributor to Inflammation
Small intestinal bacterial overgrowth (SIBO) has recently been recognized as an underlying cause of many cases of inflammatory bowel disease (IBD), clinical relapses of Crohn’s disease, and celiac patients unresponsive to a gluten-free diet.13-15SIBO is a chronic infection of the small intestine, resulting in the excessive fermentation of dietary carbohydrates and the accompanying flatulence, bloating, abdominal pain, diarrhea, and constipation. SIBO and autoimmunity are related in several ways. SIBO is common in many autoimmune diseases such as: IBD, scleroderma, celiac disease, and Hashimoto’s hypothyroidism, although the exact nature of these associations isn’t fully known. Increased intestinal permeability, which has been demonstrated in SIBO, is one of the three underlying causes of autoimmunity, as demonstrated by Fasano and his team, along with an environmental trigger and genetic predisposition. SIBO, with its high likelihood of generating leaky gut, needs to be corrected for both prevention and treatment of autoimmunity. SIBO can be successfully treated with antibiotics and possibly by natural means and specific dietary protocols. Rifaximin and neomycin usually are preferred because their poor absorbability into the bloodstream maximizes their efficacy within the digestive tract while minimizing systemic side effects. Elemental diet formulas which are special nutrient drinks that do not contain whole foods, can provide all energy requirements for a period of two to three weeks and is also an alternative treatment option. In summary, the classical paradigm of autoimmune pathogenesis involving a specific genetic makeup and exposure to environmental triggers has been challenged by the addition of a third element: the loss of intestinal barrier function. Genetic predisposition, miscommunication between innate and adaptive immunity, exposure to environmental triggers, and loss of the intestinal barrier function secondary to dysfunction of intercellular tight junctions, seem to all be key ingredients involved in the pathogenesis of autoimmune diseases. This new theory implies that, once the autoimmune process is activated, it is not self-perpetuating; rather, it can be modulated or even reversed by preventing the continuous interplay between genes and environment. As tight junction dysfunction allows this interaction, new therapeutic strategies including the use of dietary supplements aimed at re-establishing the intestinal barrier function offer innovative approaches for the treatment of these devastating diseases.
1. Furuse M, Hirase T, Itoh M et al. Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol. 1993;123: 1777–1788.
2. Furuse M, Fujita K, Takashi H et al. Claudin-1 and -2: Novel integral membrane proteins localizing at tight junctions with no sequence similarity to Occludin. J Cell Biol. 1998;141:1539–1550 .
3. Martin-Padura I, Lostaglio S, Schneemann M et al. Junctional Adhesion Molecule, a novel member of the Immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol. 1998; 142: 117–127.
4. Van Heel D, West J. Recent advances in coeliac disease. Gut. 2006; 55 (7):1037–46.
5. Rewers M. Epidemiology of celiac disease: what are the prevalence, incidence, and progression of celiac disease? NIH Consensus Development Conference on Celiac Disease. 2005; 128 (4 Suppl 1):S47–51.
6. Di Sabatino A, Corazza GR. Coeliac disease. Lancet. 2009; 373 (9673):1480–93.
7. Madara JL, Trier JS. Structural abnormalities of jejunal epithelial cell membranes in celiac sprue. Lab Invest. 1980;43: 254–261.
8. Schulzke JD, Bentzel CJ, Schulzke I et al. Epithelial tight junction structure in the jejunum of children with acute and treated celiac sprue. Pediatric Research. 1998; 43:435–441.
9. Fasano A, Not T, Wang W. et al. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet. 2000;355:1518–1519.
10. Clemente MG, S De Virgiliis, J S Kang et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut. 2003;52:218–223.
11. Nikulina M Habich C, Flohe SB et al. Wheat gluten causes dendritic cell maturation and chemokine secretion. J Immunol. 2004;173:1925–1933.
12. Fasano A. Leaky gut and autoimmune diseases. Clinic Rev Allerg Immunol. 2012;42(1):71-78.
13. Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlated with symptom improvement in irritable bowel syndrome: a double-blind, randomized, placebo-controlled study. Am J Gastroenterol. 2003;98(2):412-419.
14. Klaus J, Spaniol U, Adler G et al. Small intestinal bacterial overgrowth mimicking acute flare as a pitfall in patients with Crohn’s Disease. BMC Gastroenterol. 2009;9:61.
15. Tursi A, Brandimarte G, Giorgetti G. High prevalence of small intestinal bacterial overgrowth in celiac patients with persistence of gastrointestinal symptoms after gluten withdrawal. Am J Gastroenterol. 2003;98(4):839-843.