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Regenerating the Gut: Intestinal Stem Cells (+ 3 Nutrients to Support Intestinal Stem Cell Pools)

I want to set the stage by giving a quick review of what these intestinal stem cells are and the role they play within the gut’s overall anatomy.

So first, if we were going from the inside of the gut or gut lumen and making our way towards the gut wall—going outward—we would first encounter a layer of mucus. The mucus varies throughout the intestine. In the small intestine, the mucus forms a thin, discontinuous layer, which facilitates the absorption of nutrients, while in the large intestine, it consists of two layers. The two layers consist of an inner layer, where there are no bacteria, and then a layer of external mucus that physically separates the intestinal lumen from the epithelium. The mucus components are water (more than 98%), mucins, and glycoproteins.

Now, in that layer of mucus in the large intestine where we don’t have bacteria, we’ve also got things like secretory immunoglobulin A, antimicrobial products, peptides trefoil (trefoil factor family, TFF), cathelicidins, and ribonucleases, which are responsible for reinforcing the physical separation of the microbiota.

So far, if we were moving from the inside of the gut outward, we have the gut lumen and microbiota, then assuming we are in the large intestines, we’ve got the layer of mucus where microbiota are still present, and then even closer to the epithelium, we have the layer of mucus where microbiota are no longer present.

Now, let’s move through the gut wall a bit more. Just beyond that sterile layer of mucus, we have the intestinal epithelium, with its tight junctions. And of course, this intestinal epithelium is what many would think of as the essential component of the intestinal barrier, separating the microbiota from underlying immune cells.

The intestinal epithelium is composed of a monolayer of specialized epithelial cells which are renewed every 3 to 5 days. Structurally speaking, the surface area of the intestinal epithelium is increased due to tiny folds or finger-like projections called villi. These villi protrude into the intestinal lumen, and the protruding part of the villi is referred to as the villi tip, while the spaces between each protrusion are called crypts. These crypts contain the pluripotent stem cells that continually divide and differentiate themselves as they emigrate towards the tip of the villus, generating the different cell types of the epithelium.

Some of these cell types include enterocytes (our main absorbers), Goblet cells, enteroendocrine cells, and M cells. It's important to note that some of the stem cells differentiate into Paneth cells, which remain in the crypt rather than migrating towards the tip of the villi. So, to summarize: these stem cells in the crypt differentiate into enterocytes, goblet cells, enteroendocrine cells, M cells, and Paneth cells.

If there is an issue with either the function or supply of these pluripotent intestinal stem cells, maintaining the health, structure, and function of the gut lining becomes a significant issue.

Before delving deeper, we need to address one more thing—the immune system. Just beyond the single layer of epithelial cells, we have immune cells in the lamina propria, containing innate and adaptive immune cells. These cells protect against microorganisms that penetrate the epithelium.

Starting from the inside of the gut and moving outward, we’ve gone through the layers of the gut lining—from the gut lumen and microbiota to the mucosa, then to the epithelium, and finally to the immune cells.

Now, there is one last thing that might be helpful to review—the reminder of those tight junctions. For cells to form an epithelium, they need to be attached to the membrane by intercellular junctions, classified into three groups: intercellular junctions, anchor junctions, and communicating junctions. The tight junction proteins must be regulated to avoid any deleterious effects on the integrity of the barrier. Defects in the barrier with the TJs open in a prolonged way can allow the passage of antigens from the diet or bacteria, a situation known as leaky gut syndrome or simply increased intestinal permeability.

Now, to solidify the relationship between tight junction proteins and intestinal stem cells—we need to remember that these cells at the crypt of the villi are responsible for differentiating into cells of the epithelium, thus renewing the single layer of epithelial cells that make up the gut lining. And the enterocyte, in particular, is largely responsible for making the proteins that form tight junctions. So, we need those intestinal stem cells to function properly and be in good supply in order to then differentiate into all those specialized cell types, so that they can maintain the overall integrity of the gut lining (and produce tight junction proteins, for instance).

Factors that affect the intestinal stem cell pool: Aging

A recent study looked at aged intestinal stem cells versus young ones, noting differences in gene activity, which could lead to chronic inflammation (due to an increase in the expression of MHC class II molecules on the surface of these stem cells).

Factors that affect the intestinal stem cell pool: Dysbiosis

Aside from aging, dysbiosis can disrupt the function of regulatory T cells, leading to depletion of the intestinal stem cell pools.

All-in-all, it’s essential to maintain the health and function of these stem cells, as they are crucial for the continuous turnover of epithelial cells in the gut lining.

Therapies & Nutrients

Stem cell therapy shows promise, but it's not yet affordable or well-regulated. In the meantime, protecting mitochondria, reducing oxidative stress, and addressing sources of inflammation like gut dysbiosis are vital for supporting stem cell health and renewal.

Some nutrients and compounds, such as vitamin D, aloe vera, and L-arginine, have been shown to support increase populations of intestinal stem cells as well. More research is needed, but these findings provide insights into potential strategies for maintaining intestinal stem cell function.

In summary, intestinal stem cells are essential for the continuous turnover of epithelial cells in the gut lining. Depletion or dysfunction of these cells can impair intestinal barrier function and increase susceptibility to damage and inflammation, whether due to intrinsic factors like aging or extrinsic factors like dysbiosis.




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