The pathogenesis of inflammatory bowel disease, or IBD, suggests that interrupted interactions between the gastrointestinal tract, or GI tract, and the gut microbiota can often be the cause behind the development of the disease. A damaged or unhealthy gastric mucosal barrier may result in increased intestinal permeability which can cause an immunological reaction and result in symptoms of inflammation. Individuals diagnosed with inflammatory bowel disease present several defects in the many specialized components of mucosal barrier function, from the mucous coating makeup to the adhesion molecules that regulate paracellular permeability. These alterations may represent a primary dysfunction in Crohn's disease, but they may also cause chronic mucosal inflammation in ulcerative colitis.
How does inflammatory bowel disease affect intestinal permeability?
In clinical practice as well as experimental testings, many research studies have reported that changes in intestinal permeability can predict the development of inflammatory bowel disease, or IBD. Functional evaluations, such as the sugar absorption test or the novel imaging technique using confocal laser endomicroscopy, allow an in vivo assessment of intestinal barrier integrity. Antitumor necrosis factor-α (TNF-α) therapy reduces mucosal inflammation and soothes intestinal permeability from IBD patients. Butyrate, zinc, and some probiotics also ameliorate mucosal barrier dysfunction but their use is still limited and further research is required before suggesting permeability manipulation as a therapeutic goal in inflammatory bowel disease.
The gut plays a major role in food digestion and absorption of nutrients as well as in maintaining the overall homeostasis. It is estimated that the entire bacterial count in our entire body exceeds ten times the entire amount of individual cells in it, with more than one million species found in the gastrointestinal tract. The gut microbiota, whose genome includes 100 times more genes in relation to the entire human genome, also plays an important role in nutrition, energy metabolism, host defense, and immune system development. However, modified microbiota has been connected to, not just gastrointestinal disorders, but also to the pathogenesis of systemic conditions, such as obesity and metabolic syndrome. Therefore, the expression "mucosal barrier" seems to properly highlight the critical role of the gut and its interaction with microbiota: it is not a static shield but an active apparatus with specialized components. According to Bischoff et al. "permeability" is described as a functional feature of this barrier which allows the coexistence of bacteria required by our organism and prevents luminal penetration of macromolecules and pathogens. Altered intestinal permeability was documented during several diseases, including, acute pancreatitis, multiple organ failure, major surgery, and severe trauma, and may also explain the high incidence of Gram-negative sepsis and related mortality in critically ill patients. Furthermore, perturbation of the complex mechanism of permeability has been connected to the development of irritable bowel syndrome and steatohepatitis, or NASH.
The pathogenesis of inflammatory bowel disease, or IBD, remains unclear but it most likely is multifactorial and driven by an exaggerated immune response towards the gastrointestinal microbiome in a genetically susceptible host. Increasing evidence suggests that intestinal permeability may be critical and some authors even considered inflammatory bowel disease, or IBD, as a disease, primarily caused by intestinal barrier dysfunction.
Intestinal Barrier Dysfunction in Inflammatory Bowel Disease
The main component of the mucosal barrier is represented by the intestinal epithelium, which is made up of one layer of various subtypes of cells, including the enterocytes, goblet cells, Paneth cells, and enteroendocrine cells, as well as immune cells, such as intraepithelial lymphocytes and dendritic cells, as seen on Figure 1. The regulation of paracellular permeability of ions and tiny molecules is provided by three kinds of junctional complexes: the tight junctions, or TJs, adherence junctions, and desmosomes.
Figure 1
Individuals with IBD present enhanced paracellular permeability with TJ abnormalities, according to several research studies. These are complex multiprotein structures with an extracellular portion, a transmembrane domain and an intracellular association with the cytoskeleton, referenced from Figure 1. A decreased expression and redistribution of the components, such as occludins, claudins, and junctional adhesion molecules, abbreviated as JAM, have all been demonstrated in IBD, where a current experiment found that eliminating claudin-7 can cause colonic inflammation. In addition, tumour necrosis factor-α (TNF-α), one of the main factors behind IBD inflammation, may regulate the transcription of TJ proteins whereas its antagonists, anti-TNF-α, can ameliorate intestinal permeability. However, TNF-α may contribute to altered intestinal permeability as well, inducing apoptosis of enterocytes, increasing their rate of shedding and preventing the redistribution of TJs which should seal the remaining gaps.
Goblet cells are specialized in the secretion of mucus that covers the surface of the intestinal epithelium. Mucus is made up of carbohydrates, proteins, lipids, and a high amount of water while it also has antimicrobial properties because of antimicrobial peptides, mainly defensins produced by Paneth cells, and secretory IgA. Individuals with ulcerative colitis demonstrate a lesser variety of goblet cells, a reduced thickness of the mucus layer, and an altered mucus composition regarding mucins, phosphatidylcholine, and glycosylation. Moreover, modified Paneth cell distribution and function has been reported in IBD: these cells are typically limited to the small intestines, within the crypts of Lieberkühn, but in IBD, metaplastic Paneth cells may be found in colonic mucosa, together with subsequent secretion of defensins also from the large intestine. The role of Paneth cells may differ in the two disease phenotypes because the expression of defensins is caused by colonic inflammation in UC but is reduced in patients with colonic Crohn's disease, or CD. The decreased Paneth cell antimicrobial function might be a main pathogenic component in Crohn's disease, or CD, particularly ileal CD, although the greater secretion of defensins in UC could be a physiological response to mucosal damage.
Etiology of Intestinal Permeability in Inflammatory Bowel Disease
Whether mucosal barrier dysfunction is a result of the inflammatory response or a primary defect that prompts mucosal inflammation, still remains under debate. However, several research studies suggest that altered intestinal permeability may be an early event in Crohn's disease pathogenesis. Increased paracellular permeability was found in patients with quiescent IBD and was connected to intestinal symptoms even when endoscopic activity was absent. Furthermore, an ex vivo study with Ussing chambers on colonic biopsies from CD patients revealed a spatially uniform increase in transepithelial conductivity regardless of the presence of minimal mucosal erosions. This finding was attributed to the downregulation of TJ proteins. Lastly, animal models of CD, particularly, IL-10 knockout mice and SAMP1/YitFc mice, also declared that increased permeability can be determined before the onset of mucosal inflammation.
Genes involved in intestinal barrier homeostasis have also been associated with IBD susceptibility, demonstrating a genetic predisposition that's further supported by the observation that up to 40 percent of first-degree relatives of CD patients have altered small intestinal permeability, with a significant connection to familial CD and NOD2/CARD15 variations. This gene, which is involved in bacterial recognition, regulates both innate and adaptive immune responses and is the main susceptibility locus for the development of Crohn's disease. Other research studies have not found a correlation between permeability and hereditary polymorphisms but it's noteworthy they've mostly involved sporadic CD instances. However, environmental factors are also principal contributors in determining mucosal permeability because permeability is raised even in a percentage of CD spouses. Additionally, a recent research highlighted the value of age and smoking status rather than genotype in family. There is only one reported instance of CD development predicted by an abnormal permeability test in a healthy relative.
Independently from being genetically determined or caused by environmental factors, intestinal permeability leads to the disruption of the physiological equilibrium between mucosal barrier and luminal challenge which cannot be properly counteracted by inherent resistance of IBD patients, which on the opposite reacts with an underactive immune trigger. As a matter of fact, many defects in bacterial recognition and processing have been documented in CD patients taking certain genetic polymorphisms, mainly of pattern-recognition receptors, such as NOD2/CARD15 and genes involved in autophagy, like ATG16L1 and IRGM. In intestinal mucosa, the absence of feedback between mutated NOD2/CARD15 expression and gut luminal microbiota may result in the breakdown of tolerance. Interestingly, a recent research study by Nighot et al. revealed that autophagy is also involved with the regulation of the TJs by degradation of a pore-forming claudin, connecting autophagy with permeability.
Finally, intestinal microbiota may become altered in IBD, especially in its relative diversity and composition. This could represent a consequence of chronic mucosal inflammation however, the influence of host genotype in shaping microbial community cannot be missed in CD and NOD2/CARD15 genotype has been shown to influence the composition of gut microbiota in humans. This dysbiosis can further exacerbate permeability dysfunction from the reduction of the symbiotic connection between the microbiota and the mucosal barrier integrity. Information referenced from the National Center for Biotechnology Information (NCBI) and the National University of Health Sciences.
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By Dr. Alex Jimenez
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