Mucosal Dysfunction in Inflammatory Bowel Diseases

Source: Microbiome Labs Blog August 15, 2018

The mucosal barrier is a very important part of the human immune system. Not many people think of mucus as being protective, but it is the first line of defense between the human body and the outside world. The mucosal system contains 150 times more surface area than skin, which makes it one of the most important immune barriers in the body.

Furthermore, new studies indicate that the health of the mucosa can actually determine how the body interacts with antigens (1). In this way, the integrity of the intestinal mucosa can dictate overall immune function.

The pathogenesis of inflammatory bowel conditions (IBD) like Crohn’s and ulcerative colitis is multifactorial but research suggests that the mucosal barrier plays a significant role in its initiation and development (2). Some researchers even believe that mucosal damage is the initial injury that ultimately leads to IBD.

Antibiotics, NSAIDs, stress, alcohol, gut infections, and other factors can degrade the intestinal mucosa which can weaken the immune system and allow unwanted toxins to enter circulation and trigger an inflammatory response (3).

One of the most pervasive toxins is an endotoxin known as lipopolysaccharide (LPS). This endotoxin is a component of the outer cell membrane of gram-negative bacteria in the gut. When these bacterials cells die, they release LPS into the intestinal lumen. If the mucosal barrier becomes damaged, LPS can easily enter circulation and trigger the release of inflammatory cytokines, like tumor necrosis factor-alpha (TNF-α).

TNF-α is one of the major cytokines that coordinates the natural inflammatory process by signaling to other immune cells the location of the injury or threat. However, an overabundance of TNF-α can lead to mixed signals that mistakenly tell the immune system to attack its own tissues. This is how chronic inflammation can breed autoimmune responses within the body.

Studies have found that TNF-α is one of the main effectors of intestinal inflammation in inflammatory bowel diseases (4). In Crohn’s and colitis patients, TNF-α appears to modulate the transcription of tight junction proteins that tightly connect intestinal epithelial cells, or enterocytes (5). When tight junctions are functioning properly, they affix enterocytes to one another like super glue, forming a strong intestinal lining.

An overabundance of TNF-α can cause tight junctions to loosen up between enterocytes, creating a more permeable intestinal lining. In some cases, too much TNF-α can even trigger apoptosis, or cell death, of enterocytes, leaving open gaps between intestinal cells (6). The result is a hyperpermeable intestinal lining, otherwise known as leaky gut.

When the gut is hyperpermeable, or leaky, it allows unwanted toxins and even undigested food particles to leak directly into the bloodstream. Once toxins like LPS enter the blood, they can accumulate and induce chronic inflammation just about anywhere in the body, including the brain.

Short-chain fatty acids (SCFAs), like butyrate, are normally responsible for regulating the production of inflammatory cytokines in the intestines. Butyrate can regulate the production of TNF-α by reducing the activity of histone deacetylase (HDAC), an enzyme that promotes the expression of TNF-α in the gut (7). In this way, butyrate has a strong anti-inflammatory effect in the intestines.

In a healthy gut, butyrate comes from butyrate-producing bacteria, like Bifidobacteria and Faecalibacterium prausnitzii. When these bacteria die, from antibiotics or high fat, high calorie diets, the availability of butyrate in the gut begins to fade. Not surprisingly, low levels of Bifidobacteria and F. prausnitzii appear to be common signatures of IBD, along with increased levels of Escherichia coli (8).

Relieving chronic intestinal inflammation is a multi-pronged approach that requires neutralizing toxins in the intestines, rebuilding the intestinal mucosal barrier, and increasing Faecalibacteria in the gut.

Step 1: Neutralize toxins

Secretory immunoglobulin A (sIgA) is the body’s first line of defense against toxins like LPS in the intestinal lumen. Immunoglobulins, also known as antibodies, can reduce the toxic load on the system by binding to antigens and removing them from the system. When sIgA levels are low, the adaptive immune response is weakened.

However, sIgA levels can be revived with the supplementation of Bacillus spores that appear to help by stimulating gut-associated lymphatic tissues (GALT) (9). Additionally, serum-derived bovine immunoglobulins (SBI) can also assist in lightening the toxic load on the body. As a dairy-free alternative to colostrum, SBI powders can bind a variety of pathogens, including bacteria, viruses, and fungi, as well as their toxic by-products and remove them from the body (10).

Step 2: Rebuild mucosal barrier

The mucosa is a key barrier that protects LPS from entering into the basolateral layer. When the mucosa suffers from inadequate production of MUC2 mucin and inadequate viscosity, it fails to perform its barrier function and thus allows for the migration of LPS.

MUC2 mucin is a protein that gives the inner mucus layer its thick, gel-like qualities. Increasing MUC2 mucin production can help prevent LPS and other toxins from migrating towards the intestinal epithelial and triggering an innate immune reaction.

Butyrate not only feeds enterocytes, but it is also one of the most potent stimulators of MUC2 mucin production. Bacillus spores have been shown to increase butyrate production by nearly 40%, and butyrate-producing bacteria like Bifidobacteria and Faecalibacterium prausnitzii can also play an important role in rebuilding the mucosa.

However, a healthy mucosal barrier needs more than an ample supply of butyrate, the amino acid building blocks are also essential. These building blocks include L-threonine, L-serine, L-proline, and L-cysteine (11).

Step 3: Increase Faecalibacteria

F. prausnitzii is one of the most abundant and important commensal organisms of the human gut microbiota. In light of recent findings, F. prausnitzii is quickly becoming known as an anti-inflammatory bacteria that regulates human intestinal health. Low levels of this bacteria have become common signatures of intestinal disorders like IBD, IBS, colorectal cancer, obesity, and celiac disease (12).

However, as an anaerobic bacteria, F. prausnitzii is impossible to take as a supplement. And as a result, the only way to increase its abundance is from within – by feeding it the right prebiotics. Bacillus spores have been shown to significantly increase F. prausnitzii populations in the gut, and Precision PrebioticsTM like fructooligosaccharides (FOS) have been shown to increase F. prausnitzii by 100% in as little as 4 weeks.

References

  1. Citi S. Intestinal barriers protect against disease. Science. 2018;359(6380):1097-1098.
  2. Michielan A and D’Inca R. Intestinal Permeability in Inflammatory Bowel Disease: Pathogenesis, Clinical Evaluation, and Therapy of Leaky Gut. Mediators Inflamm. 2015; 2015: 628157.
  3. de Punder K and Pruimboom L. Stress Induces Endotoxemia and Low-Grade Inflammation by Increasing Barrier Permeability. Front Immunol. 2015; 6: 223.
  4. Schmitz H, Fromm M, Bentzel CJ, et al. Tumor necrosis factor alpha (TNFα) regulates the epithelial barrier in the human intestinal cell line HT-29/B6. Journal of Cell Science. 1999;112(1):137–146.
  5. Coskun M. Intestinal epithelium in inflammatory bowel disease. Front Med. 2014;1:24. doi: 10.3389/fmed.2014.00024.
  6. Su L, Nalle SC, Shen L, et al. TNFR2 activates mlck-dependent tight junction dysregulation to cause apoptosis-mediated barrier loss and experimental colitis. Gastroenterology. 2013;145(2):407–415. doi: 10.1053/j.gastro.2013.04.011.
  7. Vinolo MAR, Rodrigues HG, Nachbar RT, and Curi R. Regulation of Inflammation by Short Chain Fatty Acids. Nutrients. 2011; 3(10): 858–876.
  8. Matsuoka K, Kanai T. The gut microbiota and inflammatory bowel disease. Semin Immunopathol. 2015; 37: 47–55.
  9. Huang JM, La Ragione RM, Nunez A, Cutting SM. Immunostimulatory activity of Bacillus spores. FEMS Immun & Med Micro. 2008;53(2):195–203.
  10. Detzel CJ, Horgan A, Henderson AL, Petschow BW, Warner CD, Maas KJ, et al. Bovine immunoglobulin/protein isolate binds pro-inflammatory bacterial compounds and prevents immune activation in an intestinal co-culture model. PloS One. 2015;10(4):e0120278.
  11. Faure M, Mettraux C, Moennoz D, et al. Specific Amino Acids Increase Mucin Synthesis and Microbiota in Dextran Sulfate Sodium–Treated Rats. J Nutr. 2006 Jun;136(6):1558-64.
  12. Martin R, Miquel S, Benevides L, et al. Functional Characterization of Novel Faecalibacterium prausnitzii Strains Isolated from Healthy Volunteers: A Step Forward in the Use of F. prausnitzii as a Next-Generation Probiotic. Front Microbiol. 2017; 8: 1226.

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