Today I want to write about the mucus layer that lines the gut wall. This often overlooked part of the gastrointestinal tract is of immense importance in preventing metabolic endotoxemia.
Mucins are the primary component of the mucus layer that lines the digestive tract. Mucins are high-molecular weight glycoproteins. Glycoproteins are proteins that contain carbohydrate or oligosaccharide chains. The carbohydrate portion of a glycoprotein is known as a glycan.
There are at least 21 genes in humans that encode for mucins, and these mucins can be further divided into secreted mucins and membrane-bound mucins. (1) Membrane-bound mucins are bound to cellular membranes whereas secreted mucins are not.
The mucins found in the typical human colon are MUC1, MUC2, MUC3A, MUC3B, MUC4, MUC13 and MUC17. MUC1, MUC3A, MUC3B, MUC4, MUC13 and MUC17 are all membrane-bound mucins and are involved in cell signaling and growth as well as immune modulation.
MUC2 is the predominant secreted mucin of the gastrointestinal tract and the mucin I’ll be focusing on today. This mucin is produced by specialized cells known as goblet cells.
Once secreted, MUC2 forms two layers in both the stomach and colon:
This illustrates what the mucus layer in the digestive tract of a rat looks like. This fairly represents what is also true in humans, although mucus layers are typically thicker in us.
In both the stomach and colon, there is an inner layer represented by the letter S. This layer is firmly attached to the epithelial cells lining both digestive organs and is, under normal circumstances, free from all bacteria. This inner layer thus serves a very important barrier function between the epithelial cells and the contents of the lumen.
A second, looser layer known as the outer layer is represented in this illustration by the letter O. This outer layer is where most intestinal bacteria in the colon make their home as represented by the red dots.
The small intestine, in contrast, has a patchy mucus layer. Here, goblet cells secrete mucin in the crypts, which are located at the base of the hair-like villi. Mucus travels upwards along the sides of the villi, but may not always cover the tips of these structures.
The fact that mucus is not as prevalent here in contrast to the colon explains why small intestinal bacterial colonization by pathogens is very harmful to the health of this part of the digestive tract. It is also the reason the overwhelming majority of gastrointestinal immune complexes are located here.
This illustrates how MUC2 is generated in goblet cells located in the colon. In the first illustration, MUC2 is represented by the red dot forming in the goblet cell crypt. As it moves upward, it spreads along the base of the inner mucus layer as seen in the second illustration.
After replenishing this inner layer, it extends into the outer layer when exposed to water (3 and 4). Here it will eventually be degraded by bacteria and transported away along with feces.
The looser outer layer is estimated to be twice the thickness of the inner layer, although this thickness is dependent on a number of factors including diet and the bacteria present in this layer. In germ-free mice for example, the outer layer is much thicker due to the fact that these animals contain no mucus-degrading gut bacteria.
Gut flora live and thrive in the outer mucus layer. Inside this mucus gel, gut flora use the large quantities of glycan-degrading enzymes found here to feed on single sugars or monosaccharides.
These glycans are a very important energy source for bacteria, especially in the colon. However, it isn’t just the bacteria that derive energy from this process, so too the host. This helps compensate the host for some of the energy expended to produce this protective mucus coat.
The vital function of this mucin is hinted at by studies conducted in MUC2 knock-out mice. (3) These mice are genetically incapable of secreting MUC2.
Depending on the environmental conditions to which they are exposed, these mice have been found to develop any or all of the following conditions:
- severe gastrointestinal inflammation
- systemic inflammation
- failure to thrive
- rectal prolapses
- colon cancer
In these mice, bacteria that should never come into direct contact with the epithelial cells lining the colon do. Not only that, but these bacteria are often found penetrating these cells and entering systemic circulation provoking chronic inflammatory responses.
A number of causes have been found to increase mucus production by goblet cells. As explained in the previous post, beneficial bacteria like A. muciniphila may increase mucus thickness, although we are still unclear about the mechanisms involved. It is not inconceivable that because A. muciniphila is a gram-negative bacteria, it may provoke mucus secretion due to a biological process known as hormesis.
Hormesis is the process whereby good biological outcomes arise from exposing an organism to low levels of a toxin. For example, the lipopolysaccharides (LPSs) residing in the outer membrane of A. muciniphila may provoke the secretion of MUC2, but without exhausting or harming the goblet cells responsible for its production.
We know that mucus production increases in response to intestinal infection. Both LPSs from gram-negative bacteria as well as lipoteichoic acid from gram-positive bacteria are able to up-regulate goblet cell secretion. (4)
Not only would increased mucus production strengthen gut barrier function in such a scenario, it would also help flush away potential pathogens. For example, the production of MUC17 limits the ability of E. coli to adhere to the gut wall thus causing it to be eliminated sooner. (5)
Other bacterial pathogens capable of acutely increasing intestinal mucus production include Campylobacter jejuni, Cyrptosporidium parvum, Entamoeba histolytica, E. coli, Salmonella and Yersinia.
In both Crohn’s disease and ulcerative colitis, colonies of A. muciniphila are greatly depleted and replaced by other mucin-degrading bacteria. In the case of Crohn’s disease, the major bacteria identified in intestinal mucus is Ruminococcus gnavus, and in ulcerative colitis it’s Ruminoccus torques. (6)
Intestinal parasites are also capable of increasing mucus production as a defensive measure. Nippostronglus brasiliensis, Giardia and Trichinella spiralis all provoke its secretion. (7)
This acute increase in mucus production is a healthy response to any bacterial or parasitic infection. However, chronic intestinal infections and the inflammation they provoke would be expected to deplete or damage goblet cells over time. This in turn would expose the epithelial cells to bacteria, further increasing inflammation in a feed-forward manner.
There is also a genetic component to mucin secretion, which is why it is not uncommon for inflammatory bowel diseases to run in families. However, as gut flora is capable of affecting gene expression in epithelial cells, these genetic susceptibilities are no doubt under some influence by the type of bacterial populations residing in the gut lumen.
Now I’ve mentioned in the past that I’m concerned about certain dietary habits that can compromise this very important physical barrier. One such habit is very low-carb or ketogenic diets which I define as eating less than 50 grams of carbohydrates a day, although issues may arise for some on levels below 100 grams a day. While these diets have been proven effective for treating epilepsy, gastrointestinal side effects are also quite common. (8)
I’ve received my fair share of emails from people on these types of diets who complain of gastrointestinal issues. I don’t mean to claim that everyone on these diets suffer with these problems, but many do.
MUC2 mucins are partly composed of sugar molecules and require that these carbohydrates either come from the diet, or are produced by the liver from non-glucose substrates in a process known as gluconeogenesis.
However, I question just how effective gluconeogenesis is in maintaining mucus secretions over time, especially in those who are physically active. Dry mouth, eyes and nasal passages are a common complaint in this population. If those areas are experiencing dryness, I can assure you the same is occurring in the digestive tract. Furthermore, if a person is also battling an ongoing gut infection, the high oxidative stress in the liver that results from this is apt to compromise that organ’s ability to efficiently produce glucose from non-glucose sources.
I often wonder if part of the reason low-carb diets predispose to decreased thyroid function is due to increased endotoxemia as a consequence of a reduction in mucus barrier function. (9) (10) Remember, translocating endotoxins and the activation of the hypothalamic-pituitary-adrenal axis this provokes are quite capable of reducing metabolic rate by increasing cortisol secretion. (11)
Many folks on ketogenic diets who have contacted me complaining of GI issues, and have heeded my advice to increase the consumption of glucose-rich foods, have been pleasantly surprised when they experience full or partial relief from their symptoms. I believe the reason for that has a lot to do with resolving a glucose deficiency.
Now it’s clear that increasing the intake of prebiotics will greatly mitigate the effects of a mucus deficiency, at least in the colon. However, it probably won’t do much for other areas of the digestive or respiratory tract.
While adding in safe sources of glucose-rich foods like gluten-free grains and starchy tubers won’t automatically resolve a gut infection, in some it can go a long way in helping to heal the gut by rebuilding a depleted mucus layer and providing beneficial bacteria the environment they need to thrive in.