In this episode, Neutrophil, Normal Cell and NK Cell visit the large intestine. They notice that the large intestine smells bad due to toxic gases being released by harmful bacteria. Normal Cell leaves Neutrophil and NK Cell to seek the place where the last Lactic Acid Bacterium lives. Normal Cell visits the gut epithelium, where Intestinal Epithelial Cell and Goblet Cell work desperately to keep the gut epithelium strong despite persistent attacks by harmful bacteria. Despite their efforts; though, the gut epithelium breaks, forcing the cells to run away as harmful bacteria enter through the broken epithelium.
As discussed in my introductory blog post on the gut microbiota, the gut microbiota serves a variety of functions that are essential to optimal human health. One of the main functions of the gut microbiota is to maintain the integrity of the gut epithelium. In this blog post, I will talk about how the gut epithelium serves as an important physical barrier to prevent gut contents and bacteria from entering the human body before explaining how its integrity is maintained. I will then explain how the breakdown of the gut epithelium can lead to inflammatory bowel disease (IBD).
The gut epithelium as a physical barrier
The gut epithelium is a physical barrier that separates the contents of the gut from the internal environment of the human body and prevents gut bacteria from entering the human body to cause infection. The gut epithelium consists of a single layer of epithelial cells that is continuously renewed by intestinal epithelial stem cells proliferating at the bottom of crypts. As intestinal epithelial stem cells move up the crypt, they differentiate into different epithelial cell types. Most stem cells become intestinal epithelial cells that absorb water and nutrients from the large intestine into the body, but some can differentiate into secretory epithelial cells that produce and release proteins. The most notable of these are goblet cells that produce mucin proteins. Mucin combines with each other and carbohydrates to form mucuswhich covers the gut epithelium, forming an additional barrier where gut bacteria get stuck to prevent their invasion into the body.
The gut epithelium is held together by tight and adherens junctions, proteins that join epithelial cells together. These proteins are essential in creating an impermeable barrier that prevents gut contents and bacteria from entering the human body. Supplementing the gut epithelium is the mucosal immune system that continuously samples gut contents. It maintains a basal level of activity to be responsive to harmful bacteria, but it is also heavily regulated to prevent it from damaging the gut epithelium.
The role of SCFAs in maintaining gut epithelium integrity
There are many chemicals that can maintain and enhance the integrity of the gut epithelium. The most notable of these are short-chain fatty acids (SCFAs), short carboxylic acids produced by fermenting indigestible dietary fibres such as pectin, inulin and b-glucans. Anaerobic bacteria such as Firmicutes, Bacteroidetes and Actinobacteria in the gut microbiota ferment dietary fibre in the large intestine, producing SCFAs such as acetate, propionate and butyratewhich have two, three and four carbons respectively.
SCFAs serve a variety of functions to promote gut epithelium integrity and regulate inflammation, exerting their effects in two ways. Firstly, SCFAs can bind to receptors on the cell surface, stimulating a series of signalling pathways that limit inflammation and protect the epithelium from infection. For example, acetate and butyrate can act on GPR43 on intestinal epithelial cells to activate the NLRP3 inflammasome, a protein complex that cleaves and activates IL-18. IL-18 in turn will act on the intestinal epithelial cells to promote gut epithelium repair, maintaining the integrity of the epithelium which is important for limiting the severity of inflammatory bowel disease. Butyrate can also interact with GPR43 on regulatory T cells to maintain its proliferation and function, allowing them to control immune and inflammatory responses to prevent excessive inflammation in the large intestine. Secondly, SCFAs can enter cells to promote or inhibit the expression and production of certain proteins. For example, butyrate can enter intestinal epithelial cells, macrophages and dendritic cells to inhibit the release of cytokines that stimulate inflammation such as IL-1ß, IL-6, IL-8 and TNF-a. SCFAs, particularly butyrate, can also enter intestinal epithelial cells to promote the expression of tight junction proteins such as claudin-1, ZO-1 and occludin. This maintains epithelial integrity by keeping gut epithelial cells together.
Did you know? SCFAs can also regulate different metabolic pathways, particularly those relating to glucose and fatty acids, in the human body. This is important in maintaining a healthy weight and metabolism in the human body.
Inflammatory bowel disease and the gut epithelium
Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gut, where inflammation in some or all layers of the gut results in inflamed intestines. There are two types of IBD depending on which parts of the gut are affected: Crohn’s disease where inflammation occurs on all layers of the gut (mainly the small and large intestines) and ulcerative colitis where inflammation only occurs in the inner lining of the large intestine. Symptoms of IBD include abdominal pain, diarrhoea, constipation, weight loss, malnutrition and fatigue, though these symptoms can range in severity over time.
There are a variety of genetic, environmental and immune factors that contribute to the development of IBD. Although the exact cause of IBD is currently unknown, it is hypothesised that IBD is caused by dysbiosis, an imbalanced gut microbiota, promoting abnormal immune and inflammatory responses that damage the gut epithelium. Various lifestyle factors such as long-term oral antibiotic use and high-fat, high-sugar diet consumption can lead to dysbiosis which is associated with reduced bacterial diversity and increased prevalence in harmful or pro-inflammatory bacteria.
Did you know? Dysbiosis is also a potential contributor to the development of inflammatory diseases such as cardiovascular disease, type 2 diabetes and fatty liver disease.
The prevalence of harmful bacteria in dysbiosis allows bacterial toxins leads to enhanced immune activity and increased gut permeability. Dysbiosis also promotes the release of pro-inflammatory cytokines such as TNF-a IFN-y and IL-13. These cytokines can not only promote inflammation but also reduce the expression and production of tight and adherens junction proteins between epithelial cells. As epithelial cells disassociate from one another, the gut epithelium becomes more permeable, allowing bacteria and bacterial products such as LPS to enter the body. This drives a positive feedback loop as the mucosal immune system becomes activated in response to gut bacteria, promoting inflammation which further damages the gut epithelium and increases its permeability to allow more bacteria to enter the body.
There is currently no cure for IBD, but fibre and SCFAs can play a role in reducing IBD severity. It is found that people who consume a high fibre diet have a reduced risk of developing IBD compared to those consuming a low fibre diet. In addition, administering SCFAs into the colon via the anus can reduce the severity of IBD by reducing inflammation and stimulating gut epithelium repair. These results show the potential of fibre and SCFAs in reducing IBD severity. Further studies, particularly randomised controlled trials, will need to be conducted to further highlight the treatment potential of fibre and SCFAs in IBD.
Conclusion
The gut epithelium serves as a physical barrier to prevent gut bacteria and contents from entering the human body. The gut epithelium is held together by tight and adherens junction proteins that hold epithelial cells together and is further protected by mucus that covers the epithelium. The breakdown of gut epithelium integrity can lead to the development of IBD, where inflammation in the intestines is driven by dysbiosis and enhanced by abnormal immune and inflammatory responses. Nevertheless, SCFAs, produced by fermenting indigestible dietary fibres, can help in maintaining gut epithelium integrity and regulating inflammation which might be important in limiting the severity of IBD.
In the next blog post, I will be going back to cancer, starting off with some emerging hallmarks that can promote the growth and spread of cancers. See you then!