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Demystifying Leaky Gut: A Comprehensive Guide to Gut Layer Anatomy

Over 2,000 years ago, Hippocrates famously quipped, “All disease starts in the gut.” In this series we will be discussing the common causes of leaky gut and how to break the cycle of inflammation and keep your organs and body vital and maximize your healthspan. Understanding the structure of the gut barrier can also help with formulating precision medicine treatment approaches to leaky gut. Through this process, you’ll learn about nutrients, nutraceuticals, and interventions that can get to the root of inflammation and help repair the gut barrier.

person using medical technology to understand their gut health

What exactly is “Leaky Gut” or Intestinal Hyperpermeability?

The function of the gut is to absorb nutrients, ions, and beneficial molecules. The gut is made up of a one-cell-thick layer of intestinal epithelial cells. These epithelial cells are connected by tight junctions, which are proteins that help the cells adhere together and vet which molecules can pass through and get absorbed into the bloodstream. Not only do tight junctions provide a physical fence, but they also offer a chemical fence—more on that later.[1]

leaky gut or intestinal hyperpermeability diagram

Normally, tight junction proteins line epithelial cells of the gut, keeping the contents of the gut "outside" and the body's internal milieu "inside." However, sometimes molecular signals in the gut (whether from diet, microbes or microbial products, chemical exposures, etc.) can signal those tight junctions to break apart. That causes intestinal epithelial cells to detach, and the contents of the gut are allowed to enter systemic circulation. Once foreign molecules enter the bloodstream, they can potentially access any organ and trigger systemic inflammation.

Healthy functioning of the gut lining is crucial for a well-adapted body—from digestion and absorption to immune function and brain health.

Layers of the Gut Barrier: Anatomy Overview

Mechanisms of leakage: For gut contents to “leak” outside the gut wall into the body, they need to pass through three major layers: the mucus, the intestinal epithelial cell (IEC) layer, and the underlying immune defense mechanisms.[2]

The lumen is the space occupied by food contents and microbes. There is a certain level of defense against leaky gut even at the level of the lumen. Here, bacteria and antigens are degraded by bile, gastric acid, and pancreatic juice. In addition, commensal bacteria inhibit colonization of pathogens by producing antimicrobial substances.

Mucosal Layer

Beneath the lumen is the mucus layer. Mucosa are also present at the airways, oral cavity, digestive tract, genitourinary tract, and skin.[3] Mucus is full of antimicrobial compounds. Mucus itself prevents bacterial adhesion. Gut mucus in particular helps with digestion, nutrient absorption, waste secretion, and keeping the gut relatively alkaline.[4]

The small intestines digest food and absorb nutrients, while the large intestines absorb water and electrolytes. Bacterial density is very high in the large intestines, necessitating a thick inner mucus layer full of antimicrobial compounds and immunoglobulins. This layer is normally impenetrable to bacteria. Compounds in the mucus, like mucins, prevent large particles, including most bacteria, from directly contacting the epithelial cell layer.

Secretory IgA also contributes to barrier function. IgA is made by plasma cells in the lamina propria and is then secreted by B cells into the lumen in collaboration with intestinal epithelial cells (IECs).[5] IgA binds to specific bacteria, bacterial products, invading microorganisms, and toxins and entraps them in a mucus layer, neutralizing them.[2] IgA also helps goblet cells present bacterial antigens to dendritic cells.[6] More on the cell types in just a moment.

Over time the thick mucus layer turns over, just like skin, and it thins out. This thinner mucus can serve as a “nest” for the microbes, while our intestinal epithelial cells are continually working to produce thick mucus near the border.

Intestinal Epithelial Cell Layer

IECs, or enterocytes, comprise the single-cell thick internal lining of the gut.[6] This layer is composed of different types of specialized intestinal epithelial cells.[7] These include absorptive enterocytes, goblet cells, Tuft cells, enteroendocrine cells, Paneth cells, and microfold cells or M cells.[6]

IECs are rapidly renewed and replaced every couple days. These cells work to maintain barrier integrity. IECs form a brush border at their apical surface to keep things moving. Many intestinal epithelial cells adhering together form villi and crypts. Pore size is relatively smaller at the villus tip and larger at the base of the crypt.[2] As a result, size selectivity varies—the permeability is higher in the crypt and lower at the villus.[3]

IECs also serve immune functions. IECs can react to noxious stimuli by secreting chloride and antimicrobial peptides such as β-defensins and Reg3.[2] They recognize prokaryotic-associated molecular patterns (PAMPs) with toll-like receptors (TLRs) on cell surface and nucleotide-binding oligomerization domain (NOD)-like receptors in cytoplasm, which activate defense mechanisms by secretion of anti-microbial peptides.[6] IECs can also phagocytose bacteria and sequester and neutralize bacteria and toxins, and they communicate with underlying immune cells to regulate inflammatory response against bacterial toxins.

Absorptive enterocytes

Absorptive enterocytes are the most abundant epithelial cells. As their name suggests, they absorb nutrients.

Goblet cells

Goblet cells secrete mucins, among which mucin 2 is the most abundant, which prevents adhesion of bacteria on epithelial cells. Goblet cells also secrete molecules that are central to both defense and repair of the epithelial layer, including IgA, mucus, trefoil peptides, and resistin-like molecule-β.[8] Goblet cells depend on commensal bacterial signals to regulate mucus production—germ-free mice have reduced mucus layer thickness; this can be reversed with TLR ligands.[5] Goblet cells can also deliver antigens to the lamina propria.[5] Goblet cells have been reviewed in detail elsewhere.[9]

helminths in the gut activate the ILC2 immune response

Tuft cells

Tuft cells are more rare and less well-characterized, but they are essential for immunity against parasitic helminths. In response to helminth infection, these cells orchestrate the type 2 immune response by producing IL-25, which activates innate lymphoid cell type 2 (ILC2) cells. ILC2 cells can in turn recruit eosinophils to protect the intestinal epithelium.[10]

Enteroendocrine cells

Enteroendocrine cells produce and release hormones into the submucosal space to interact with neurons or immune cells. These hormones include substance P, bradykinin, prostanoids, and, in response to various mechanical, chemical, and nervous stimuli, most of the serotonin in the gut.[11] Serotonin stimulates motility and secretion in response to most injurious substances to move them down towards the less permeable colon. It also secretes glucagon-like peptide 2 (GLP-2) that is trophic to small bowel epithelium and induces healing.[2]

Paneth cells