Prospects for Nutraceutical Support of Intestinal Barrier Function

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madman

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Perspective: Prospects for Nutraceutical Support of Intestinal Barrier Function
Mark F. McCarty and Aaron Lerner




ABSTRACT

Impairment of intestinal barrier function is linked to certain pathologies and to aging and can be a cause of bacterial infections, systemic and hepatic inflammation, food allergies, and autoimmune disorders. The formation and maintenance of intestinal tight junctions are supported by glucagon-like peptide-2 (GLP-2), which via insulin-like growth factor I activity boosts phosphoinositide 3-kinase/Akt/mammalian target of rapamycin complex 1 (PI3K/Akt/mTORC1) signaling in enterocytes. 5 -AMP-activated protein kinase (AMPK) activity, as well as estrogen receptor-β (ERβ) activity, are also protective in this regard. Conversely, activation of mitogen-activated protein kinases (MAPKs) and cellular Src (c-Src) under inflammatory conditions can induce dissociation of tight junctions. Hence, nutraceuticals that promote GLP-2 secretion from L cells—effective pre/probiotics, glycine, and glutamine—as well as diets rich in soluble fiber or resistant starch, can support intestinal barrier function. AMPK activators—notably berberine and the butyric acid produced by health-promoting microflora—are also beneficial in this regard, as are soy isoflavones, which function as selective agonists for ERβ. The adverse impact of MAPK and c-Src overactivation on the intestinal barrier can be combatted with various antioxidant measures, including phycocyanobilin, phase 2–inducer nutraceuticals, and N-acetylcysteine. These considerations suggest that rationally designed functional foods or complex supplementation programs could have clinical potential for supporting and restoring healthful intestinal barrier function.




Introduction

The enterocyte tight junction


The intestinal epithelial monolayer represents the body’s largest interface with the external environment. It serves dual opposing functions. It selectively absorbs needed nutrients while preventing the absorption of detrimental luminal components, including antigenic peptides, proinflammatory factors, oxidants, toxins, bacteria, yeasts, parasites, microbial components or their secreted mobilome, and various allergens and carcinogens (1). Adjacent intestinal enterocytes form tight junctions that are an integral part of the physical intestinal barrier, regulating the paracellular traffic. The tight junctions represent evolutionarily well-conserved sealing complexes between adjacent enterocytes. Also called occluding junctions or zonulae occludentes, they are composed of a branching network of sealing strands, acting independently from each other. Each one of them is composed of a row of transmembrane proteins embedded in both adjacent enterocytes’ plasma membranes, with extracellular extensions joining one another. There are ≥40 different proteins in the tight junction complex, each containing both cytoplasmic domains and transmembranous elongations. The 3 major ones are occludin, claudins, and junction adhesion molecule proteins. The parallel strands are attached to zona occludens-1 (ZO-1), located in the enterocyte’s cytoplasm, which anchors the strands to the actin component of the cytoskeleton. Thus, tight junctions are fully integrated with the cytoskeletons of adjacent enterocytic cells.

Not surprisingly, the Hippocratic quote “all disease begins in the gut” is proving to be true. Two millennia later, it appears that dysfunction of the tight junctions is associated with numerous pathological conditions. Gastrointestinal infections, allergic, autoimmune, cancerous, and metabolic diseases have been linked to increased intestinal permeability (1–5). Even the elderly’s senescent gut is leaky (6). The term “leaky gut” refers to the failure of tight junctions to execute their multiple homeostatic functions. Loss or impairment of intestinal barrier function owing to a failure to form or maintain tight junctions can lead to infections, an increase in systemic and hepatic inflammation reflecting LPS absorption, and induction of food allergies or autoimmune disorders. Hence, it is pertinent to examine what safe nutraceutical measures might be useful for maintaining an effective intestinal barrier.



Regulation of intestinal tight junctions

Formation of tight junctions requires synthesis and translocation to the enterocyte apical membrane of a range of proteins, including claudins, occludin, junction adhesion molecules, and ZO-1, which integrate to form junctional complexes that, as noted, form tight links to neighboring enterocytes and are linked via actin to the cell’s actomyosin cytoskeleton. Signaling mechanisms that can promote tight junction formation and maintenance have been characterized, though the precise details of this induction require much further clarification. Specifically, as discussed below, the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin complex 1 (PI3K/Akt/mTORC1) pathway, 5 -AMP-activated protein kinase (AMPK), and estrogen receptor-β (ERβ) function to promote tight junction formation. In contrast, inflammatory circumstances that activate the mitogen-activated protein kinases (MAPKs)— c-Jun N-terminal kinase (JNK), p38 MAP kinase (p38), and extracellular signal-related kinases 1 and 2 (ERK1/2)— and cellular Src (c-Src) tend to promote the disaggregation of tight junctions. Hence, nutraceuticals that promote the activity of PI3K, AMPK, or ERβ might be expected to aid intestinal barrier function whereas, when enterocyte MAPKs are activated in pathological conditions, nutraceuticals that inhibit MAPK activation might likewise have a favorable impact in this regard.




*Trophic Impact of Glucagon-Like-Peptide 2 on Enterocytes is Mediated by Insulin-Like Growth Factor I and PI3K/Akt/mTORC1 Signaling

*Pre/Probiotics, Glycine, and Glutamine Can Promote GLP-2 Secretion

*Berberine and SCFA-Induced AMPK Activity Promotes Tight Junction Formation

*Soy Isoflavones Aid Intestinal Barrier Function Via ERβ

*Antioxidants Can Aid Tight Junction Maintenance by Downregulating MAPK Activity

*A Nutraceutical Program for Promoting Intestinal Barrier Function
Figure 1 depicts suggested mechanisms whereby the nutraceuticals glutamine, glycine, berberine, soy isoflavones, PCB, phase 2 inducers (e.g., lipoic or ferulic acids), NAC, and pre- and probiotics could be expected to aid tight junction formation and maintenance in enterocytes, thereby supporting intestinal barrier function. Functional foods or complex supplementation programs incorporating several of these agents can be envisioned as aids in intestinal health.







Conclusions

A failure of intestinal barrier function reflecting inefficient formation or maintenance of the tight junctions linking enterocytes can lead to unregulated absorption of bacteria, yeast, parasites, bacterial toxins, and intact proteins or peptides derived from food or microbes. Such a failure can lead to infections and systemic and hepatic inflammation and is suspected to trigger allergic and autoimmune disorders. Hence, promoting effective intestinal barrier function is an important goal for preventive medicine. An analysis of the enterocyte signaling mechanisms that either promote or oppose effective tight junction function—notably the PI3K/Akt/mTORC1 axis, AMPK, ERβ, the MAPKs, and c-Src—enables us to pinpoint certain nutraceutical and dietary measures that could be expected to aid intestinal barrier function. In particular, effective pre- and probiotics, the amino acids glycine, glutamine, and cysteine (provided as NAC), the herbal compound berberine, soy isoflavones, the spirulina antioxidant PCB, and phase 2–inducing nutrients or phytochemicals such as lipoic acid or ferulic acid, appear to have practical potential in this regard.

It should also be noted that those measures that protect the intestinal barrier by boosting L-cell secretion of GLP-2 could also be expected to boost production of GLP-1, and thereby aid effective β-cell function while acting in multiple other ways to promote leanness and metabolic, vascular, and neurological health (140–144).
 

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madman

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FIGURE 1 Nutraceutical strategies for promoting tight junction formation in enterocytes. Nutraceuticals are highlighted in bold. AMPK, 5 -AMP-activated protein kinase; ERK, extracellular signal-regulated kinase; ERβ, estrogen receptor-β; GLP-2, glucagon-like-peptide-2; HO-1, heme oxygenase-1; IGF-I, insulin-like growth factor I; JNK, c-Jun N-terminal kinase; NAC, N-acetylcysteine; Nrf2, nuclear factor erythroid 2-related factor 2; p38, p38 MAP kinase; PCB, phycocyanobilin; PI3/Akt/mTORC1, phosphoinositde 3-kinase/Akt/mammalian target of rapamycin complex 1
Screenshot (2410).png
 

madman

Super Moderator
*A Nutraceutical Program for Promoting Intestinal Barrier Function

Figure 1 depicts suggested mechanisms whereby the nutraceuticals glutamine, glycine, berberine, soy isoflavones, PCB, phase 2 inducers (e.g., lipoic or ferulic acids), NAC, and pre- and probiotics could be expected to aid tight junction formation and maintenance in enterocytes, thereby supporting intestinal barrier function. Functional foods or complex supplementation programs incorporating several of these agents can be envisioned as aids in intestinal health.
 
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