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When it comes to gut health, the gut microbiome is probably the hottest topic right now, but it’s not the only piece of this mammoth jigsaw.
Within your gastrointestinal tract there are many different pieces that all interconnect to help make up the system. And a major one is the intestinal epithelial barrier, also commonly known as the gut lining.
This incredible structure is made up of millions of cells which come together to form a tight barrier. It’s a bit like the security gates between your gut and the rest of your body. Along the barrier are tight junction proteins, these can be thought of as the security guards, that are responsible for allowing things like nutrients through into the body and stopping nasty stuff like pathogens and toxins gaining entry.
You’ll often hear us refer to the epithelial lining in your gut, but what exactly is it and what’s it’s job? Well, come with us to find out.
The gut lining is made up of several important components that help to support its structure and function. They are:
The mucus layer is the first line of defence between the gut and the rest of the body. Along the epithelial layer are mucin proteins that help to form a gel across the top. The thick gel acts like a sieve, absorbing and transporting nutrients, keeping tissues moist, and protecting the body from invading pathogens, toxins, and other foreign debris[i].
In the colon, there are two layers, an inner and outer layer. The outer layer is where you’ll find all of the friendly bacteria in your gut, while the inner layer has no bacteria present. This dense inner layer, under normal circumstances is impenetrable to bacteria. The most abundant mucus protein in the mucosal layer is mucin 2 (MUC2).
MUC2 is important because it not only acts as an attachment site, contributing to the composition of the microbiome, but it’s also a nutrient of choice for some species, particularly Akkermansia muciniphila[ii].
A. muciniphilaloves a munch on the mucins in your gut because they are a great energy source but it also gives them an ecological advantage. That’s because the bacteria can thrive on the mucins produced by the cells in your gut even if there are no nutrients available. Plus, by eating the mucins in your gut, A.muciniphilahelps to thicken it, which improves its function.
This ultimately means that the colonic mucus layer can affect the composition of the gut microbiome as well as the overall properties of the mucosal layer[iii].
The next layer is the epithelial layer, a single, continuous layer of intestinal epithelial cells or IECs that are tightly attached to one another at junction proteins. The junctions are responsible for allowing the transport of molecules, ions and nutrients and separate the internal space of the gut from the lamina propria.
The epithelium is a dynamic structure which renews every four to seven days. Alongside the mucus layer, the epithelial cell layer makes up the physical barrier within the gut[iv].
The next layer of the intestinal barrier is the lamina propria, a type of connective tissue that’s often found below a thin layer of cells covering a mucous membrane[v]. In the gut, the lamina propria is where the immune cells of both the adaptive and innate systems can be found, so they can easily participate in defence activities.
The gut lining is a semi-permeable structure which has a major role in allowing the transportation of nutrients into the body while, at the same time, preventing pathogens from entering it, a process called intestinal permeabilityiii.
Under normal conditions, the millions of cells that make up the gut barrier join together to create a tight barrier between the gut lumen and the rest of the body. However, if your gut is unhealthy, it is possible for these tight junctions to weaken, causing ‘gaps’ to develop, sometimes referred to as ‘leaky gut’.
If this happens, the risk of toxins, undigested food particles, and pathogens entering the bloodstream increases, triggering an inflammatory response and initiating a cascade of symptoms, such as:
But that’s not all. The intestinal epithelial barrier also has in important role in implementing an immune response with the gut-associated lymphoid tissue (GALT), through the initiation of pro- and anti-inflammatory signals[vi].
For example, epithelial cells are strongly associated with innate immunity. Some intestinal epithelial cells have specific functions such as enterocytes, goblet cells, and Paneth cells.
Goblet cells produce mucin which keeps the intestinal surface well lubricated and protected, contributing to the intestinal mucosal layer. Whereas, enterocytes and Paneth cells are responsible for producing antimicrobial peptides, strings of amino acids responsible for keeping pathogens in check[vii].
The constant turnover of IECs every week also helps to protect the body from invaders because it stops them from attaching to the intestinal wall and setting up camp in your gut, clever stuff, right?
There are several factors that play a part in regulating the integrity and permeability of your gut lining, including growth factors, cytokines, and of course, microbial metabolites such as short chain fatty acids (SCFAs).
Your gut microbiome is a unique ecosystem that has a huge influence on your overall health and wellbeing. The symbiotic bacteria that occupy it are responsible for supplying your body with essential nutrients and SCFAs that help to curb inflammation, improve your mood, and prevent many chronic diseases.
Butyrate is an example of an SCFA produced by your gut microbiota and is the main energy source for the cells that line your gut called colonocytes. With enough fuel, these cells can carry out their roles optimally, including ensuring the gut isn’t leaky.
For example, when healthy, the gut barrier opens to allow nutrients to pass through, it does this because the tight junctions that usually keep it closed relax to allow them through. Yet, bad habits such as frequent snacking, drinking too much alcohol, or just not getting enough exercise can mean that these tight junctions do not fully close between meals. This makes it easier for pathogens and undigested food to defect into the body, where they should not be. But butyrate helps to preserve and strengthen the gut lining, reducing the risk of leaky gut from occurring.
And that’s not all. Butyrate stimulates the production of mucins in the mucous layer[viii], which not only further strengthens the intestinal lining, but also helps to nourish the A. muciniphilacolonies.
Don’t forget you can boost your microbiome through human milk oligosaccharide (HMO) supplements from Layer Origin. HMOs provide vital sustenance to your gut microbes as well as supporting your immune system and shielding the body from inflammation. Plus, HMOs such as 2’-fucosyllactose specifically nourish the Bifidobacteriacommunities, which in turn, feed your butyrate producers such as Faecalibacterium prausnitzii, further improving the integrity of your intestinal barrier[ix].
The tight junctions in the gut barrier are critical to maintaining integrity and facilitating the selective permeability this structure is renowned for. These tight junction structures include a range of different proteins including claudins and occludins. These are important for transporting the good stuff into the body and prevent pathogens from crossing the epithelial barrier.
These proteins are regulated through a variety of signalling pathways as well as cytokines such as interleukin-13 and tumour necrosis factor – α (TNF). For example, research has shown that inhibition of the proinflammatory cytokine, TNF, lowers gut inflammation and can almost restore the gut barrier in Crohn’s disease patients[x].
You may not have thought much about the barrier between the inside of your colon and the rest of your body much before, but it is a fundamental part of you. If your gut barrier becomes compromised, then it can lead to many chronic diseases, including inflammatory bowel disease (IBD).
At present, the best therapy for treating or repairing the epithelial barrier is through the treatment of underlying disease. That’s because a ‘leaky gut’ or weakened tight junction proteins are likely to be both a cause and effect of chronic disease. The success of this has been demonstrated through the use of anti-TNF antibodies to treat IBD.
Therefore, there is growing interest in targeting the gut barrier to restore its function. Some studies have investigated the use of stem cells to treat gastrointestinal diseases. For example, mice with induced epithelial damage were treated with either an enema or mock enema cultured in intestinal stem cells during recovery. Although the stem cells were able to graft where ulceration had occurred, there was no long-term improvement after the damaging stimulus was removed[xi].
Alternative proposals include focusing on tight junction regulation to prevent the onset of IBD. For example, some studies have inhibited myosin light chain kinase (MLCK) to treat colitis but this had other off-target effects. While claudin-2 could offer potential therapy by directly targeting the opening and closing of the tight junctions or regulating claudin-2 mobilityiv. However, further research is needed.
It’s clear that the intestinal epithelial barrier is a fundamental structure within your gastrointestinal tract, and that the importance of looking after it is clear. Here’s the key points we learned in this article:
Remember, you can help to support your gut health with human milk oligosaccharide supplementation. Browse our range here.
Written by: Leanne Edermaniger, M.Sc. Leanne is a professional science writer who specializes in human health and enjoys writing about all things related to the gut microbiome.
[i] Kong S, Zhang YH, Zhang W. Regulation of Intestinal Epithelial Cells Properties and Functions by Amino Acids. Biomed Res Int. 2018 May 9;2018:2819154. doi: 10.1155/2018/2819154. PMID: 29854738; PMCID: PMC5966675.
[ii] Earley H, Lennon G, Balfe Á, Coffey JC, Winter DC, O’Connell PR. The abundance of akkermansia muciniphila and its relationship with sulphated colonic mucins in health and ulcerative colitis. Scientific Reports. 2019;9(1). doi:10.1038/s41598-019-51878-3
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[v] NCI Dictionary of Cancer terms [Internet]. [cited 2023 Jun 12]. Available from: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/lamina-propria
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[vii] Takiishi T, Fenero CIM, Câmara NOS. Intestinal barrier and gut microbiota: Shaping our immune responses throughout life. Tissue Barriers. 2017 Oct 2;5(4):e1373208. doi: 10.1080/21688370.2017.1373208. Epub 2017 Sep 28. PMID: 28956703; PMCID: PMC5788425.
[viii] Willemsen LE, Koetsier MA, van Deventer SJ, van Tol EA. Short chain fatty acids stimulate epithelial mucin 2 expression through differential effects on prostaglandin E(1) and E(2) production by intestinal myofibroblasts. Gut. 2003 Oct;52(10):1442-7. doi: 10.1136/gut.52.10.1442. PMID: 12970137; PMCID: PMC1773837.
[ix] Šuligoj T, Vigsnæs LK, Abbeele PV, Apostolou A, Karalis K, Savva GM, et al. Effects of human milk oligosaccharides on the adult gut microbiota and barrier function. Nutrients. 2020;12(9):2808.
[x] Suenaert P, Bulteel V, Lemmens L, Noman M, Geypens B, Van Assche G, Geboes K, Ceuppens JL, Rutgeerts P. Anti-tumor necrosis factor treatment restores the gut barrier in Crohn's disease. Am J Gastroenterol. 2002 Aug;97(8):2000-4. doi: 10.1111/j.1572-0241.2002.05914.x. PMID: 12190167.
[xi] Yui S, Nakamura T, Sato T, Nemoto Y, Mizutani T, Zheng X, Ichinose S, Nagaishi T, Okamoto R, Tsuchiya K, Clevers H, Watanabe M. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5⁺ stem cell. Nat Med. 2012 Mar 11;18(4):618-23. doi: 10.1038/nm.2695. PMID: 22406745.
