There are two border walls that can be important to health, we will used these terms:

• increased intestinal permeability or IIP (often called Leaky Gut, but note: “Leaky gut syndrome is a hypothetical condition that’s not currently recognized as a medical diagnosis.”[src])
• blood–brain barrier permeability or BBBP

The first is an indicator of the availability of bacteria, fungi, chemicals, etc. to move from the intestines into the body/blood. The second is the ability of bacteria, fungi, chemicals, etc. to enter the brain. Both are important — the latter with neurological conditions (for example brain fog, autism, etc).

IIP – Increased Intestinal Permeability

This is usually associated with the Zonulin protein.

• Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer [2011]
• Zonulin, regulation of tight junctions, and autoimmune diseases [2012]

Zonulin is a protein modulator of intercellular tight junctions. It has been shown to induce a significant and reversible increase in gastroduodenal and small intestinal permeability and is involved in tolerance/immune response balance. The hybridization of wheat to dramatically increase gluten (gliadin) content and its overconsumption, multiple times a day, every day, in the typical diet, chronically disrupts this tolerance/immune response balance.

Michael T. Murray ND, John Nowicki ND, in Textbook of Natural Medicine (Fifth Edition), 2020

Zonulin is a member of the MASP (mannose‐binding lectin‐associated serine protease) family of proteins, and elevated serum zonulin levels have been reported in a number of neurological conditions such as multiple sclerosis ⁷ and Alzheimer’s disease. ⁸ 

Zonulin and blood-brain barrier permeability are dissociated in humans [2022]

There is a massive number of studies, speculations, and theories on addressing this issue, especially theories on fixing leaky gut. One example:

• Weight loss via a low-carbohydrate diet improved the intestinal permeability marker, zonulin, in prostate cancer patients. [2022]
• “Besides conventional treatments, several nutritional compounds including Colostrum bovinum (8), Apple-Derived Pectin (9), vitamins A and D (10) have been found to modulate the epithelial barrier by reducing serum levels of zonulin.” The Effects of Probiotic/Synbiotic on Serum Level of Zonulin as a Biomarker of Intestinal Permeability: A Systematic Review and Meta-Analysis [2020]

BBBP – blood–brain barrier permeability

First, we need to be aware that they are different: Zonulin and blood-brain barrier permeability are dissociated in humans [2022]. For a general discussion, see A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity [2020]

Some studies that are of special interest:

• Better together? Treating traumatic brain injury with minocycline plus N-acetylcysteine [2022] IMHO, for ME/CFS this is likely a very good combination.
• The molecular weight impacts the ability to cross the barrier ” An increase of the surface area of a drug from 52 A² (e.g., a drug with a MW of 200 Da) to 105 A² (e.g., a drug with a MW of 450 Da) dramatically decrease its BBB permeation [Blood-brain barrier permeation: molecular parameters governing passive diffusion].”

When dealing with neurological issues when there is a choice of several different substances, I have looked up the molecular weight and advocated for the lower molecular weight choice. For illustration,

• Acetylcysteine (N-acetylcysteine) has a weight of 163.19
• Minocycline has a weight of 457.5
• Azithromycin has a weight of 785
• Amoxicillin has a weight of 365.4
• Piracetam has a weight of 142 (this is a fast acting nootropic that clears brain fog in minutes for some people).
• Resveratrol 228, Quercetin 302, Curcumin 368, Aspirin 180

It is an easy way to do quick evaluation— for example, I would expect Resveratrol to have a greater effect on brain function than Curcumin, with Aspirin having a still greater potential effect.

Bottom Line

The purpose of this post is frame questions that may be relevant to you — and not provide general answers.