© 6/13/17 GreenMedInfo LLC. This work is reproduced and distributed with the permission of GreenMedInfo LLC. Want to learn more from GreenMedInfo? Sign up for the newsletter here http://www.greenmedinfo.com/greenmed/newsletter
Health Begins In the Gut
From a clinical standpoint, insofar as functional medicine is concerned, whether you present with rheumatoid arthritis, multiple sclerosis, ulcerative colitis, or systemic lupus erythematosus---the fundamental objective is the same: heal the gut.
Hippocrates understood the inextricably intertwined relationship between the systemic health of the organism and the nine-meter tube from mouth to anus when he famously uttered, “All disease begins in the gut” over two thousand years ago. The ancient Greek physician also illuminated his understanding of the therapeutic role of nutrition when he championed holistic medicine with his proclamation, “Let food be thy medicine and medicine be thy food”.
After all, covering an average surface area of thirty-two square meters, the size of half a badminton court, the gut represents the second largest interface between the external environment and the internal biochemical milieu of the body (Helander & Fandriks, 2014). Over sixty tons of food will pass through our gastrointestinal tract in our lifetime.
Why is gut health so paramount in prevention and treatment of autoimmune disease? If you are a savvy consumer of holistic health information, you probably already know how important our microbiome---the collection of one hundred trillion commensal bacteria that inhabit our colon, plus their genetic material---is to our health. Although the widely cited 10:1 ratio has been revised, researchers estimate that we have at least as many bacterial cells as human cells, which has led some scientists like Stanford’s Dr. Justin Sonnenberg to hypothesize that humans may merely be elaborate vessels designed for the propagation of bacterial colonies (Sender, Fuchs, & Milo, 2016).
At any single moment, two to six pounds of bacteria resides within us. Even more awe-inspiring is that a single person contains 3.8x10^13 bacteria (38,000,000,000,000 colony forming units)—a number representing more than all the stars in the galaxy (Sender, Fuchs, & Milo, 2016).
Following the advent of germ theory and the discovery of vaccinations, scientists were under the impression that all bacteria were bad bugs, and speculated that specific microbes were the causative agents behind particular disease entities. This led to the reductionist, pill-for-every-ill therapies that predominate in Western medicine, as well as to the maligning of all bacteria as organisms to be feared and eradicated. Thus the age of antibiotics, triclosan-laden anti-bacterial soaps, hand sanitizer, chemical cleaners, and the “there’s a shot for that” mentality was inaugurated.
Ironically, it is rumored that on his death bed, Louis Pasteur, the father of immunization and pasteurization himself, admitted that it is the terrain—the gut ecology and biochemical milieu—that matters, rather than the infecting pathogen (Tracey, 2017). In other words, our bodies, like plants, are more susceptible to pests, or infection, when our ecosystem is in a state of disharmony---when our microbial soil is depleted and our micronutrient status is compromised.
The magic bullet approach initially introduced by Pasteur, however, was misguided, and has the potential to produce dire consequences for immune health. In fact, the hygiene hypothesis, embraced by many scientists, purports that the reason that autoimmune diseases and atopic disorders (eczema, allergies, asthma) are epidemic in the Western world while virtually absent from developing nations is the hyper-sanitized, antibiotic-ridden society in which we live, which has decimated our gut microflora and thus obliterated their beneficial effects on our immune systems (after all, 70% of our immune system resides within our gut) (Vighi et al., 2008).
According to the hygiene hypothesis, the immune system acquires self-tolerance, or the ability to distinguish self from stranger and safety from danger, and thus prevent over-reactions against our own tissue, based on repeated infectious exposures (Eschler, Hasham, & Tomer, 2011). Further, “Some pathogens have the potential to prevent or abrogate rather than induce an autoimmune process,” such that annihilating them with antibiotics results in improper maturation of the immune system and a tendency towards autoimmune reactions (Christen, 2014).
However, antibiotics are not only harmful in that they prevent infections from instructing development of the immune system. They also disrupt the finely tuned symphony of actions orchestrated by our microbiota, or those friendly bugs that inhabit our gut. The microbiota serve innumerable roles, including competing for attachment sites with potentially pathogenic microbes, reducing their virulence, inhibiting the effects of bacterial toxins, and generating anti-microbial substances such as bacteriocidins and hydrogen peroxide that can selectively suppress pathogenic bacteria and fungi (Corr et al., 2009; Castagliuolo et al., 1999).
Our gut microbes also promote the de-conjugation and detoxification of proliferative, carcinogenic estrogen species and other exogenous toxins, reducing their enterohepatic recirculation (Gorbach, 1984). Commensal bacteria likewise aid in nutrient extraction and assimilation, as the secondary bile acids and short-chain fatty acids they produce from fermentation of indigestible carbohydrates lead to liberation of compounds like peptide YY from cells, which decreases intestinal transit, encourages satiety, maximizes nutrient absorption, and increases energy harvested from food (Boulange et al., 2016).
Critically, gut bacteria reinforce the intestinal barrier, preventing metabolic endotoxemia, a process which contributes to metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), coronary heart disease, stroke, and polycystic ovarian syndrome (PCOS) (Neves et al., 2013; Lindheim et al., 2017). The products of microbial fermentation of prebiotic carbohydrates also increase insulin sensitivity and improve glucose balance, which prevents the pathologic insulin resistance, oxidative stress, and endothelial dysfunction that lead to diabetes and cardiovascular disease (Boulange et al., 2016).
The maintenance of the intestinal lining by the microbiota similarly prevents autoimmune disease. For instance, a decrease in bifidobacteria populations leads to intestinal hyper-permeability, or leaky gut, which in turn leads to the translocation of metabolic byproducts, food antigens, bacteria, and lipopolysaccharide (also known as LPS, an immunogenic cell wall component from Gram-negative bacteria) across the gut barrier into systemic circulation (Rapin & Wiernsperger, 2010). This activates the mesenteric lymph nodes and gut-associated lymphoid tissue (GALT) and instigates a downstream inflammatory cascade.
Medications Compromise Gut Barrier Integrity
A single course of antibiotics can lead to perturbations in microbiota lasting up to 16 months on average, or 18 to 24 months for Clindamycin and up to four years following triple therapy for Helicobacter pylori (Hawrelak & Myers, 2004; Jernberg et al., 2010; Cotter et al., 2012). Even worse, novel molecular analysis techniques using 16S rRNA have demonstrated that antibiotic resistant microbes are present up to four years post-antibiotic (Jernberg et al., 2010; Cotter et al., 2012).
Other commonly used medicinal agents, non-steroidal anti-inflammatory drugs (NSAIDs) such as Motrin, Ibuprofen, and Naproxen, increase concentrations of gram-negative bacteria, which produce lipopolysacchide (LPS), the endotoxin that can traverse the gut barrier and generate a milieu favoring insulin resistance, type 2 diabetes, NAFLD, PCOS, coronary heart disease and stroke (Marlicz et al., 2014).
In addition to inducing gastrointestinal ulcers, increasing risk of myocardial infarction by a third, and doubling risk of congestive heart failure, NSAIDs have also been demonstrated to decrease concentrations of bifidobacteria and lactobacilli---beneficial commensal flora populations in our gut (Bhala et al., 2013; Montenegro et al., 2014). Because bifidobacteria are responsible for butyrate production, the short chain fatty acid that heals and seals the gut lining, a decrease in bifidobacteria can perpetuate leaky gut syndrome.
What’s more, acid-blocking drugs, or proton pump inhibitors (PPIs) such as Prilosec and Nexium, used for gastroesophageal reflux disease (GERD), are associated with a decrease in small bowel beneficial bifidobacteria and a significant decline in microbial diversity within seven days of beginning therapy (Seto et al., 2014; Wallace et al., 2011). PPIs have likewise been shown to increase the risk of small intestinal bacterial overgrowth (SIBO) and the potentially fatal infection, Clostridium difficile (Lo & Chan, 2013; Janarthanan et al., 2012).
With antibiotics in particular, however, there is evidence of localized permanent extinction---in other words, some species of microorganisms never recover post-antibiotic, and cannot be "reinoculated" unless you undergo the arduous and expensive process of fecal microbiota transplant (FMT).
Furthermore, even food preparation and processing can influence intestinal permeability. When food is browned or caramelized as part of the Maillard reaction, reducing sugars spontaneously react with lipids, nucleic acids, and aminopeptides, creating advanced glycation end products (AGEs) in a process that generates free radicals, inflammation, and ensuing intestinal permeability (Vlassara & Uribarri, 2004; Bengmark, 2007).
The Leaky Gut - Autoimmune Connection
The intestinal barrier is a mucosal surface wherein epithelial cells known as enterocytes are separated by tight junction proteins, desmosomes, and adherens junctions that function as architectural scaffolding and selective gates, opening and closing to allow fluid and nutrients to be absorbed and waste products to be excreted (Groschwitz & Hogan, 2009). According to Turner (2009), epithelial cells “establish a barrier between sometimes hostile external environments and the internal milieu” (p. 799). This barrier is critical because “The mucosa is directly exposed to the external environment and taxed with antigenic loads…at far greater quantities on a daily basis than the systemic immune system sees in a lifetime” (Mayer, 2003).
Tight junctions, regulated by a molecule called zonulin, as well as by conformational changes in the proteins occludin and claudin, are dynamic intercellular structures that modulate the trafficking or passage of macromolecules from the intestinal lumen to the submucosa and into systemic circulation (Fasano, 2012). According to Rapin and Wiernsperger (2010), “Tight junctions play a major role in regulating the paracellular passage of luminal elements” (p. 635).
Under normal circumstances, solutes exceeding a certain size, or molecular radius, are prohibited from absorption across the gut barrier by competent tight junctions (Fasano, 2012). However, when insults such as gluten, dysbiosis, pathogens, toxins, over-exercising, chemotherapy, radiation, and medications such as NSAIDs and steroids disrupt the tight junctions, microbial products and intact food proteins that have not been degraded into their constituent parts translocate across the paracellular space into the body (Fasano, 2012).
Macrophages embedded in the GALT are part of the innate immune system, or the non-specific, first line of defense against infection (Fasano, 2011; Yu & Yang, 2009). These cells, along with dendritic cells, recognize the incoming undigested food particles, toxic agents, and bacterial components as foreign invaders, and present them to cells of the adaptive immune system called T and B lymphocytes, leading to clonal expansion (proliferation or multiplication of specific subsets of T and B cells) and recruitment of more pro-inflammatory immune cells to the gut through a process called leukocyte homing.
The release of inflammatory cytokines, or intercellular signaling molecules such as interleukin-1 (IL-1), interleukin-2 (IL-6), and tumor necrosis factor alpha (TNF-α) at the site of immune activation causes other immune cells migrating throughout the lymphatic vessels of the body to express more cell adhesion molecules (CAMs). CAMS enable white blood cells to stick to and roll along blood vessels and extravasate, or navigate across, the blood vessels made leaky by histamine and other local vasodilators, into the inflamed intestinal tissue. Cytokines contribute to this vicious process of leaky gut syndrome, as they also play a prominent role in compromising tight junction integrity (Watson, Duckworth, Guan, & Montrose, 2009). This culminates in a massive inflammatory response that can become systemic and lead to autoimmunity.
When the amino acid sequence is homologous between the target antigen, such as gluten, against which the immune system is mounting a response, and tissue proteins, such as the thyroid tissue, a case of mistaken identity occurs, and the immune response can become directed against self tissues, manifesting as autoimmune disease (Hashimoto’s thyroiditis in this instance). Summarized by Suzuki (2013), “Disruption of the intestinal tight junction barrier, followed by permeation of luminal noxious molecules, induces a perturbation of the mucosal immune system and inflammation, and can act as a trigger for the development of intestinal and systemic diseases” (p. 631).
A protein called zonulin is responsible for induction of tolerance and orchestration of immune responses by modulating intercellular tight junctions in the gastrointestinal epithelium in a rapid, reversible, and reproducible fashion (Fasano, 2011). Zonulin evolved as an adaptive mechanism to flush out microorganisms as part of the innate immune response against bacterial colonization of the small intestine (Fasano, 2011).
Specific gliadin-permeating peptides can initiate intestinal permeability via MyD88-dependent release of zonulin, which causes conformational changes in tight junction architecture and cytoskeletal assembly that leads to paracellular entry of gliadin (a gluten sub-fraction) into the intestinal submucosa (Thomas, Fasano, & Vogel, 2006). Signaling through the CXCR3-mediated, MyD88-dependent pathway generates a Th1-dominant, pro-inflammatory cytokine milieu that recruits mononuclear cells into the submucosa (Fasano, 2011). After gliadin infiltrates the lamina propria, the barrier function can be further disrupted by the persistence of inflammatory mediators such as TNF-α and interferon-gamma (IFN-γ) (Fasano, 2011).
In those individuals predisposed to celiac disease, gliadin is presented by HLA-DQ and HLA-DR major histocompatibility complex (MHC) molecules, leading to abrogation of oral tolerance and a transition to a Th1/Th17 response (Fasano, 2011). Dendritic cells home to pancreatic and mesenteric lymph nodes and present gliadin, leading to “migration of CD4−CD8−γδ and CD4−CD8+ αβ T cells to the target organ (gut and/or pancreas) where they cause inflammation” (Fasano, 2011). This results in the interaction between T cells and antigen-presenting cells, producing the adaptive immune response that causes profound villous atrophy in celiac disease (Fasano, 2011). Celiac disease patients have higher concentrations of serum zonulin during the acute phase of disease compared with their healthy counterparts, and also have over-expressed CXCR3, the intestinal receptor for gliadin (Fasano, 2011).
However, even in healthy individuals, biopsies reveal a transient zonulin release upon gluten ingestion accompanied by an increase in intestinal permeability that does not reach the level observed in celiac disease (Drago et al., 2006). The authors of the in vitro study state, “Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules” (Drago et al., 2006, p. 408). Furthermore, when intestinal biopsies were examined from celiac patients with active disease, celiac patients in remission, non-celiac gluten-sensitive patients, and non-celiac controls, intestinal permeability was found to occur after gliadin exposure in all individuals (Hollon et al., 2015).
The same mechanism is implicated in all autoimmune diseases—leaky gut leading to molecular mimicry and/or the bystander effect—biochemical processes that could be characterized as "friendly fire" that are responsible for the resultant tissue damage and symptom expression (Fasano, 2012). Thus, compromised gut integrity, or dysfunctional intestinal permeability, is a precursor and essential trigger for all autoimmune disease, including celiac disease, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, Crohn’s disease, ulcerative colitis, and ankylosing spondylitis, and can also appear in allergic syndromes such as asthma (Fasano, 2012; Drago et al., 2006; Westall, 2007; Edwards, 2008; Yacyshyn & Meddings, 1995; Martinez-Gonzalez et al., 1994; Schmitz et al., 1999; Hijazi et al., 2004).
Moreover, intestinal permeability, as assessed by a lactulose-mannitol test, may predispose a patient to the development of food reactions, as increased intestinal permeability is associated with food allergy (Laudat et al., 1994; Andre, 1986). However, food allergy itself may inflict “mucosal damage caused by local hypersensitivity reactions to food antigens,” creating a pattern in which an individual becomes sensitive to more and more foods (Tatsuno, 1989).
An Ounce of Prevention is Worth a Pound of Cure
For people resistant to dietary and lifestyle modifications to resolve intestinal permeability, I will share that I am a living testament to the consequences of dysfunctional intestinal permeability, which leads to a domino scenario where autoimmune conditions are developed one after another. This scenario is far from uncommon, as a fourth of patients with autoimmune disease tend to develop additional autoimmune diseases, leading to multiple autoimmune syndrome. It is often cited that an individual is three times as likely to develop another autoimmune disease after acquiring one (Cojocaru, Cojocaru, & Silosi, 2010). Hence, my mission is to save others from the heartache I have endured as a consequence of these devastating chronic illnesses.
The succession of autoimmune diseases I developed due to a confluence of environmental triggers, genetic susceptibilities, and compromised gut barrier speak to the importance of preserving tight junction integrity and acting as a guardian of your gut epithelium. The gravity of leaky gut syndrome is illustrated by Brandtzaeg (2013), who states, “Increased epithelial permeability for antigens is a crucial primary or secondary event in the pathogenesis of several disorders” (p. 67).
In my case, a multitude of factors converged to produce autoimmunity—intestinal hyper-permeability, dysbiosis, food sensitivities, mitochondrial dysfunction, genetic polymorphisms, histamine intolerance, mycotoxins, adrenal dysfunction, heavy metal toxicity, micronutrient deficiencies, hormonal imbalances, and a host of recalcitrant and stealth infections. Reversing an autoimmune disease is magnitudes of order more complex than preventing one, which is why educating the public at large about how intestinal permeability serves as a prelude to autoimmunity is of the utmost importance.
However, if you go to a conventional physician complaining of a leaky gut, your concerns are likely to be dismissed and more often than not, you will leave with a recommendation to spend less time on the internet---or even worse, your symptoms will be branded psychosomatic and your doctor will label you a hypochondriac, as almost half of autoimmune patients experience in the subclinical stages of their disease (AARDA, 2017).
Despite the litany of peer-reviewed studies in the scientific literature on pathologic paracellular intestinal hyper-permeability, the biomedical establishment is by and large ignorant to this condition and its implications. Ironically, although Western medicine relegates leaky gut syndrome to the realm of fanciful fairy tales, the pharmaceutical industry is actively investigating drugs to reverse it (Kato et al., 2017). Only when there is a financial incentive and a pharmaceutical approach developed for a disorder is it anointed with legitimacy in the eyes of the allopathic physician.
If health is your objective, however, restoration of gut barrier integrity should be prioritized, since, “The autoimmune process can be arrested if the interplay between genes and environmental triggers is preventing by re-establishing intestinal barrier function” (Fasano & Shea-Donohue, 2005). Because gluten is pivotally implicated in intestinal hyper-permeability, its exclusion from the diet, along with an oligoantigenic elimination-provocation diet, should be a first line of treatment in any patient on the autoimmune spectrum.
American Autoimmune and Related Diseases Association. (2017). Autoimmune Statistics: Autoimmune Disease Fact Sheet. Retrieved from https://www.aarda.org/autoimmune-information/autoimmune-statistics/
Bengmark, S. (2007). Advanced glycation and lipoxidation end products--amplifiers of inflammation: the role of food. JPEN Journal of Parenteral and Enteral Nutrition, 31, 430–440.
Bhala, N., Emberson, J., Merhi, A., Abramson, S., Arber, N.,Baron, J.A.,…Baigent, C. (2013). Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. The Lancet, 382(9894), 769-779.
Boulange et al. (2016). Impact of the gut microbiota on inflammation, obesity, and metabolic disease. Genome Medicine, 8, 42.
Brandtzaeg, P. (2013). Gate-keeper function of the intestinal epithelium. Beneficial microbes, 4(1), 67-82.
Castagliuolo et al. (1999). Saccharomyces boulardii protease inhibits the effects of Clostridium difficile toxins A and B in human colonic mucosa. Infectious Immunology, 67(1), 302-307.
Christen, U. (2014). Editorial: pathogen infection and autoimmunity. International reviews of immunology, 33, 261-265.
Cojocaru, M., Cojocaru, I.M., & Silosi, I. (2010). Multiple autoimmune syndrome. Maedica, 5(2), 132-134.
Corr et al. (2009). Understanding the mechanisms by which probiotics inhibit gastrointestinal pathogens. Advances in Food Nutrition Research, 56, 1-15.
Cotter, P.D., Stanton, C., Ross, R.P., & Hill, C. (2012). The impact of antibiotics on the gut microbiota as revealed by high throughput DNA sequencing. Discovery Medicine, 13(70), 193-199.
Drago, S., El Asmar, R., De Pierro, M., Grazia Clemente, M., Tripathi, A., Sapone, A.,…Fasano, A. (2006). Gliadin, zonulin and gut permeability: effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scandanavian Journal of Gastroenterology, 41, 408–419.
Edwards, C.J. (2008) Commensal gut bacteria and the etiopathogenesis of rheumatoid arthritis. Journal of Rheumatology, 35, 1477–1497. doi: 10.1007/s12016-011-8291-x.
Eschler, D.C., Hasham, A., & Tomer, Y. (2011). Cutting edge: the etiology of autoimmune thyroid diseases. Clinical Reviews in Allergy and Immunology, 41, 190-197.
Fasano, A. (2011). Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiology Reviews, 91, 151-175.
Fasano, A. (2012). Leaky gut and autoimmune disease. Clinical Reviews in Allergy and Immunology, 42(1), 71-78.
Fasano, A., & Shea-Donohue, T. (2005). Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. National Clinical Practice in Gastroenterology & Hepatology, 2(9), 416-422.
Gorbach, S.L. (1984). Estrogens, breast cancer, and intestinal flora. Reviews in Infectious Disease, 6(Suppl 1), S85-S90.
Groschwitz, K.R., & Hogan, S.P. (2009). Intestinal barrier function: Molecular regulation and disease pathogenesis. Journal of Allergy and Clinical Immunology, 124(1), 3-22.
Hawrelak, J.A., & Myers, S.P. (2004). The causes of intestinal dysbiosis: A review. Alternative Medicine Review, 9, 180-197.
Helander, H.F., & Fandriks, L. (2014). Surface area of the digestive tract - revisited. Scandinavian Journal of Gastroenterology, 49(6), 681-689.
Hijazi, Z., Molla, A.M., Al-Habashi, H., Muawad, W.M., Molla, A.M., & Sharma, P.N. (2004) Intestinal permeability is increased in bronchial asthma. Archives of Diseases in Children, 89, 227–229.
Hollon, J., Puppa, E.L., Greenwald, B., Goldberg, E., Guerrerio, A., & Fasano, A. (2015). Effect of gliadin on permeability of intestinal biopsy explants from celiac disease patients and patients with non-celiac gluten sensitivity. Nutrients, 7(3), 1565-1576. doi: 10.3390/nu7031565.
Janarthanan, S., Ditah, I., Adler, D.G., & Ehrinpreis, M.N. (2012). Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. American Journal of Gastroenterology, 107(7), 1001-1010.
Jernberg, C., Lofmark, S., Edlund, C., & Jansson, J.K. (2010). Long-term impacts of antibiotic exposure on the human intestinal microbiota. Microbiology, 156(11), 3216-3223.
Kato, T., Honda, Y., Kurita, Y., Iwasaki, A., Sato, T., Kessoku, T.,…Nakajima, A. (2017). Lubiprostone improves intestinal permeability in humans, a novel therapy for the leaky gut: A prospective randomized pilot study in healthy volunteers. PLoS One, 12(4), e0175626.
Laudat, A., Arnaud, P., Napoly, A., & Brion, F. (1994). The intestinal permeability test applied to the diagnosis of food allergy in paediatrics. West Indian Medical Journal, 43(3), 87-88.
Lindheim, L., Bashir, M., Munzker, J., Trummer, C., Zachhuber, V., Leber, B.,…Obermayer-Pietsch, B. (2017). Alterations in gut microbiome composition and barrier function are associated with reproductive and metabolic defects in women with polycystic ovarian syndrome (PCOS): A pilot study. PLoS One, 12(1), e0168390.
Lo, W. K., & Chan, W.W. (2013). Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis. Clinical Gastroenterology and Hepatology, 11(5), 483-490.
Marlicz, W., Loniewski, I., Grimes, D.S., & Quigley, E.M. (2014). Nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and gastrointestinal injury: contrasting interactions in the stomach and small intestine. Mayo Clinic Proceedings, 89(12), 1699-1709.
Martinez-Gonzalez, O., Cantero-Hinojosa, J., Paule-Sastre, P., Gomez-Magan, J.C., & Salvtierra-Rios, D. (1994) Intestinal permeability in patients with ankylosing spondylitis and their healthy relatives. British Journal of Rheumatology, 33, 644–648.
Mayer, L. (2003). Mucosal immunity. Pediatrics, 111(6 Pt 3), 1595-1600.
Montenegro, L., Losurdo, G., Licinio, R.. Zamparella, M., Giorgio, F., Lerardi, E.,…Principi, M. (2014). Non steroidal anti-inflammatory drug induced damage on lower gastro-intestinal tract: is there an involvement of microbiota? Current Drug Safety, 9(3), 196-204.
Morris, Z.S., Wooding, S., & Grant, J. (2011). The answer is 17 years, what is the question: understanding time lags in translational research. Journal of the Royal Society of Medicine, 104, 510-520.
Neves, A.T., Coelho, J., Cuoto, L., Leite-Moreira, A., & Roncon-Albuquerque Jr., R. (2013). Metabolic endotoxemia: a molecular link between obesity and cardiovascular risk. Journal of Molecular Endocrinology, 51(2), R51-R64.
Rapin, J.R., & Wiernsperger, N. (2010). Possible links between intestinal permeability and food processing: A potential therapeutic niche for glutamine. Clinics (Sao Paulo), 65(6), 235-643.
Schmitz, H., Barmeyer, C., Fromm, M., Runkel, N., Foss, H.D., Bentzel, C.J.,…Schulzke, J.D.(1999) Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis. Gastroenterology, 116, 301–307.
Sender, R., Fuchs, S., & Milo, R. (2016). Revisited estimates for the number of human and bacterial cells in the body. PLOS Biology, 14(6), e1002533.
Seto, C.T., Jeraldo, P., Orenstein, R., Chia, N., & DiBaise, J.K. (2014). Prolonged use of a proton pump inhibitor reduces microbial diversity: implications for Clostridium difficile susceptibility. Microbiome, 2(1), 42.
Suzuki, T. (2013). Regulation of intestinal epithelial permeability by tight junctions. Cellular and Molecular Life Science, 70(4), 631-659.
Tatsuno, K., (1989). Intestinal permeability in children with food allergy. Arerugi, 38(12), 1311-1318.
Thomas, K.E., Fasano, A., & Vogel, S.N. (2006). Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in Celiac disease. Journal of Immunology, 176, 2512–2521.
Tracey, K.J. (2017). The inflammatory reflex. Nature, 420, 853–859.
Turner, J.R. (2009). Intestinal mucosal barrier function in health and disease. National Reviews in Immunology, 9, 799–809.
Vighi, G., Marcucci, F., Sensi, L., Di Cara, G., & Frati, F. (2008). Allergy and the gastrointestinal system. The Journal of Translational Immunology, 153(Suppl 1), 3-6.
Vlassara, H., & Uribarri, J. (2004). Glycoxidation and diabetic complications: modern lessons and a warning? Reviews of Endocrine and Metabolic Disorders, 5, 181–88.
Wallace, J. L., Syer, S., Denou, E., de Palma, G., Vong, L., McKnight, W.,... Ongini, E. (2011). Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis. Gastroenterology, 141(4), 1314-1322.
Watson, A.J., Duckworth, C.A., & Guan, Y, (2009). Montrose MH. Mechanisms of epithelial cell shedding in the Mammalian intestine and maintenance of barrier function. Annals of the New York Academy of Sciences, 1165, 135-142.
Westall, F.C. (2007) Abnormal hormonal control of gut hydrolytic enzymes causes autoimmune attack on the CNS by production of immune-mimic and adjuvant molecules: a comprehensive explanation for the induction of multiple sclerosis. Medical Hypotheses, 68, 364–369.
Yacyshyn, B.R., & Meddings, J.B. (1995) CD45RO expression on circulating CD19+ B cells in Crohn’s disease correlates with intestinal permeability. Gastroenterology, 108, 132–138.
Yu, Q.H., & Yang, Q. (2009). Diversity of tight junctions (TJs) between gastrointestinal epithelial cells and their function in maintaining the mucosal barrier. Cell Biology International, 33, 78-82.