The gastrointestinal mucosal barrier is an effective and powerful defense and repair mechanism, which allows for the proper absorption of energy, nutrients and water when we eat. The functioning of the digestive system with its balanced gut microbiota depends on the function of the mucosal barrier. The intestinal barrier has to be permeable to allow the passage of nutrients, however, when this permeability increases beyond what is necessary, it can lead to a variety of issues, in some instances, even causing disease.
Intestinal barrier dysfunction has been determined in a variety of gastrointestinal diseases, or GI diseases, such as inflammatory bowel disease, or IBD. It has now become more accepted that proper gastrointestinal mucosal barrier function plays a major role in the pathophysiology of inflammatory bowel disease. However, further understanding as well as research data is required to determine treatment and therapy options for such gastrointestinal diseases, particularly IBD.
Changes to intestinal permeability generally manifest early in the development of intestinal inflammation due to Crohn’s disease and other gastrointestinal diseases. Several risk factors, including the conditions themselves, may even exacerbate intestinal inflammation through increased intestinal permeability. According to recent research studies, nonsteroidal anti-inflammatory drugs, or NSAIDs, and stress can also induce symptoms of inflammation through increased gastrointestinal, or GI, mucosal permeability and the release of corticotropin-released factors. Additionally, changes to intestinal permeability can determine a patient’s risk of relapsing Crohn’s disease. Patients who’ve had an altered lactulose/mannitol test, or L/M test, are often 8 times more at risk of relapsing, even when asymptomatic and results demonstrate normal biochemical indices.
The lactulose/mannitol test is specifically used to evaluate small intestinal permeability by measuring urinary excretion after oral administration of these sugars. Lactulose is a large sized oligosaccharide that generally doesn’t carry out paracellular transport and can be adsorbed in the instance of leaky intercellular junctions while mannitol is a smaller molecule that can freely move across the intestinal epithelium. Both probes are equally affected by gastrointestinal dilution, motility, bacterial degradation, and renal function; consequently, the ratio allows for the correction of possible confounding factors. The lactulose/mannitol test is utilized in clinical practice because of its noninvasiveness, its high sensitivity in detecting active inflammatory bowel disease, or IBD, and its ability to distinguish functional versus organic GI disease, or gastrointestinal disease. An altered L/M test has been reported in approximately 50 percent of patients with Crohn’s disease. Other sugars have also been routinely used to evaluate the upper gastrointestinal tract, for instance, sucrose which has been degraded by duodenal sucrase, may indicate the permeability of the stomach and the proximal duodenum. Accordingly, multisugar tests have been developed, with the latest inclusion of sucralose, which can be barely absorbed through the human intestine, allowing a functional assessment of the entire gastrointestinal tract, extending its use for ulcerative colitis as well.
Other functional tests, such as 51Cr-EDTA or the Ussing chambers, have demonstrated great precision in diagnosing gastrointestinal disease, however, their invasiveness and complex detection methods make their use impossible in humans. Whereas promising results have been demonstrated by novel imaging techniques, particularly confocal laser endomicroscopy. This endoscopic technique allows an in vivo evaluation of the epithelial lining and vasculature with the use of intravenous fluorescein as a molecular contrast agent, which generally doesn’t carry out paracellular transport. Confocal laser endomicroscopy is currently widely utilized to identify and classify gastrointestinal tumors but it has also been used in nonneoplastic conditions, such as celiac disease, collagenous colitis, and irritable bowel syndrome, or IBS. Discovering cellular and subcellular changes, such as cell shedding, is possible through this procedure, which makes it a highly effective technique for the imaging of intestinal barrier dysfunction in inflammatory bowel disease, or IBD. Confocal laser endomicroscopy demonstrated increased density of mucosal gaps after cell shedding in the small intestine of patients with Crohn’s disease as well as in macroscopically normal duodenum in both Crohn’s disease and ulcerative colitis. These alterations could represent impairment of intestinal permeability possibly predicting subsequent clinical relapse. Recently, confocal laser endomicroscopy has been utilized in patients with ulcerative colitis, demonstrating that the occurrence of crypt architectural abnormalities may predict disease relapse in patients with noticeable endoscopic remission, as seen on Figure 1.
Agents routinely used in the therapeutic armamentarium of inflammatory bowel disease, or IBD, may cause and maintain mucosal remission not only for their immunomodulating effect, but also through the recovery of epithelial integrity and permeability, as was demonstrated for anti-TNF-α drugs and medications in Crohn’s disease. Since similar effects are obtained using elemental diets for Crohn’s disease, raising interest is based on dietary strategies with the use of immunomodulatory nutrients and probiotics.
Western diets, with its high content of fat and refined sugars, is a risk factor for the growth of Crohn’s disease, where they’re believed to induce a low-grade inflammation through gut dysbiosis and increased intestinal permeability. Furthermore, there is increasing concern about the use of industrial food additives towards promoting immune-related diseases. A recent research study demonstrated how additives can increase intestinal permeability by interfering with the tight junctions, or TJs, increasing the passage of immunogenic antigens. In addition, certain fatty acids, such as propionate, acetate, butyrate, omega-3, and conjugated linoleic acid, amino acids, such as glutamine, arginine, tryptophan, and citrulline, and oligoelements, which are essential for intestinal surface integrity, when supplemented to experimental subjects with gastrointestinal diseases, GI diseases, can decrease inflammation and restore gastrointestinal mucosal permeability. However, their therapeutic effectiveness, especially in inflammatory bowel disease, remains debatable: butyrate, zinc, and probiotics have the strongest evidence in this aspect.
Butyrate is a short chain fatty acid produced by intestinal microbial fermentation of dietary fibers, which in experimental versions, stimulate mucus production and expression of tight junctions, or TJs, in vitro but a broader selection of action is anticipated. It’s essential for the overall homeostasis of enterocytes that its lack, measured as faecal concentrations, has been taken as an indirect indicator of altered intestinal barrier function. In clinical practice topical butyrate had demonstrated effectiveness in refractory distal ulcerative colitis. Other fatty acids with similar properties have also been proposed as an adjuvant treatment in inflammatory bowel disease, namely, omega-3 and phosphatidylcholine, but their usage in clinical practice remains limited. Zinc is a trace element essential for cell turnover and repair systems. Inflammatory conditions and malnutrition have been known to be risk factors for zinc deficiency and many research studies demonstrated the effectiveness of its supplementation during acute diarrhoea and experimental colitis. Oral zinc treatment may restore intestinal permeability in patients with Crohn’s disease, perhaps through its capacity to regulate tight junctions, or TJs, both in the small and the large intestines.
The reason for the use of probiotics in inflammatory bowel disease is for the above mentioned dysbiosis that characterizes these GI diseases, or gastrointestinal diseases. Several trials have tested the effectiveness of various species of probiotics in inflammatory bowel disease, or IBD, with contradicting results. Those which have demonstrated to be effective are Escherichia coli Nissle 1917, Bifidobacterium, Lactobacillus rhamnosus GG, or the multispecies VSL#3, which consists of eight unique probiotics. Nevertheless, their use remains confined to ulcerative colitis and are frequently aimed at maintaining remission rather than treating the active disease, as emphasized by the meta evaluation by Jonkers et al.. The mechanisms of their effect in ulcerative colitis have yet to be fully understood but likely, together with direct anti-inflammatory effects, they can restore the intestinal barrier and decrease intestinal permeability, regulating tight junction, or TJ, proteins. The favorable effect of probiotics in pouchitis seems to be about the improvement of gastrointestinal mucosal barrier function. Another potential mechanism of action is the recovery of butyrate-producing bacteria: patients with ulcerative colitis have decreased bacterial species like Faecalibacterium prausnitzii, but supplementation with butyrate-producing species or probiotics together with preformed butyrate demonstrated effectiveness in experimental models.
Finally, vitamin D can also be involved to preserve intestinal barrier function. Polymorphisms of its own receptor have been related to the development of inflammatory bowel disease, or IBD. While the expression of vitamin D receptor on intestinal epithelium prevents inflammation-induced apoptosis, its removal contributes to faulty autophagy that boosts experimental colitis. But, additional data and clinical trials are needed to rationalize vitamin D use in inflammatory bowel disease management.
The impairment of intestinal barrier function is just one of the critical events in the pathogenesis of inflammatory bowel disease, or IBD. Whether it precedes and predisposes disease development remains under analysis, particularly in Crohn’s disease, but it perpetuates and enriches chronic mucosal inflammation by increasing paracellular transport of luminal pathogens. Novel imaging and functional techniques allow us to assess intestinal permeability in vivo and help identify patients at risk of relapse guiding therapeutic management. Manipulation of intestinal permeability is a fascinating therapeutic approach but more research on its effectiveness and safety are required before nutritional immune-modulators may be utilized in clinical practice. Information referenced from the National Center for Biotechnology Information (NCBI) and the National University of Health Sciences. The scope of our information is limited to chiropractic and spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .
By Dr. Alex Jimenez
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Functional & Physical Medicine & Nutritional Specialist*