Leaky Brain, Leaky Gut: The Real Mind-Body Connection

gut brain leaky gut leaky brain

The mind-body connection is real.

This once-fringe concept is now being exposed by scientists researching the gut and its direct connection to the brain.

What happens in the gut affects the brain
Brain-Gut connection. What happens in the gut affects the brain

Many experts still consider this research to be in its infancy,

However, one conclusion seems to be clear.. what happens in the brain directly reflects what is happening in the body.

One of the most glaring examples of this is the phenomenon of leaky brain and its relationship to leaky gut.1Mark E. M. Obrenovich. Leaky Gut, Leaky Brain?, Microorganisms. 2018

Leaky brain research indicates that it is a serious problem.

In fact, it may be at the heart of many mental health disorders.

However, it is encouraging to know that it is possible to heal leaky brain by rebuilding the integrity of your gut.

This means that healing your gut could be a promising method to optimize your mind.

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In this article, I’ll give an overview of what leaky brain is, how it relates directly to problems with the gut, why I believe it to be so prevalent in our modern culture, and steps you can take to optimize your brain by healing your gut.

What Is Leaky Brain

The blood-brain barrier is your brain's security guard
The blood-brain barrier is your brain’s security guard

Leaky brain is the end result of a complex breakdown in the blood-brain barrier commonly referred to as blood-brain barrier permeability.1Souhel Najjar, Daniel M Pearlman, Orrin Devinsky, Amanda Najjar, and David Zagzag. Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence, J Neuroinflammation. 2013

A functional blood-brain barrier is essential to maintaining central nervous system homeostasis.

The Blood-Brain Barrier

The blood-brain barrier (BBB) separates the central nervous system (CNS) from the peripheral tissues of your body.

It’s effectively a security checkpoint that keeps harmful toxins and inflammatory mediators that can negatively affect neural function out of your brain.2N Joan Abbott, Lars Rönnbäck, Elisabeth Hansson. Astrocyte-endothelial interactions at the blood-brain barrier, Nat Rev Neurosci. 2006

When the blood-brain barrier breaks down, the brain becomes exposed to molecules that may be toxic to vulnerable neurons in the hippocampus and elsewhere in the brain.

Conditions Associated With Leaky Brain

Leaky brain connection has been implicated in a number of psychiatric disorders1Hadar Shalev, Yonatan Serlin, Alon Friedman. Breaching the blood-brain barrier as a gate to psychiatric disorder, Cardiovasc Psychiatry Neurol. 2009 including:

Chronic disease numbers courtesy of the CDC
Chronic disease numbers courtesy of the CDC
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    Leaky Gut: The Culprit

    Of all the potential causes of disruptions in the blood-brain barrier, the most notorious might be leaky gut.10Manuela Pennisi, Alessia Bramanti, Mariagiovanna Cantone, et al. Neurophysiology of the “Celiac Brain”: Disentangling Gut-Brain Connections, Front Neurosci. 2017 Sep 5

    If you’ve spent any time sifting through wellness articles online than you’ve probably come across this term.

    Leaky gut, technically referred to as “intestinal permeability” occurs when there is dysfunction in the epithelial lining of the digestive tract.11I Bjarnason, T J Peters, N Veall. A persistent defect in intestinal permeability in coeliac disease demonstrated by a 51Cr-labelled EDTA absorption test, Lancet. 1983

    The lining of your GI tract is very thin and delicate making it susceptible to damage.

    This dysfunction allows for certain proteins, lipopolysaccharide, and antigens to find their way outside of the digestive tract and into the intestinal mucosa where immunoglobulin A (IgA) antibodies are made.12AGerwyn Morris, Michael Berk, André F Carvalho, Javier R Caso, Yolanda Sanz, Michael Maes. The Role of Microbiota and Intestinal Permeability in the Pathophysiology of Autoimmune and Neuroimmune Processes with an Emphasis on Inflammatory Bowel Disease Type 1 Diabetes and Chronic Fatigue Syndrome, Curr Pharm Des. 2016

    The immune system identifies these particles from the gut as foreign invaders and mounts a response.

    This leads to increased inflammation throughout the body which has been tied to a number of chronic and autoimmune diseases.





    How Leaky Gut Leads To Leaky Brain

    The pro-inflammatory cytokines triggered by leaky gut eventually attack the tight junctions of the blood-brain barrier.

    This results in compromised blood-brain barrier integrity and all the cognitive issues that follow.13Gerwyn Morris, Michael Berk. The Neuro-Immune Pathophysiology of Central and Peripheral Fatigue in Systemic Immune-Inflammatory and Neuro-Immune Diseases, Mol Neurobiol. 2016

    Leaky gut has been directly implicated in a number of cognitive disorders14Christopher B Forsyth, Kathleen M Shannon, Jeffrey H Kordower, Robin M Voigt, Maliha Shaikh, Jean A Jaglin, Jacob D Estes, Hemraj B Dodiya, Ali Keshavarzian. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease, PLoS One. 2011 including:

    • Alzheimer’s
    • Dementia
    • Parkinson’s
    • Depression

    Inflammation is the major disruptor of the BBB. Many diseases and physiological stressors that affect the CNS also alter the functional integrity of the BBB15Michael Maes, Marta Kubera, Jean-Claude Leunis. The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression, Neuro Endocrinol Lett. 2008

    Causes of Leaky Gut

    The lining of the human GI tract is very thin and quite vulnerable to damage.

    There are a number of reasons why someone may experience gut permeability including:

    Occasional exposure to one or even a few of these factors may not present such dire consequences.

    However, in modern society, many people are exposed to excessive doses of one or more of these elements on a daily basis.

    Which may be why diseases tied to leaky gut and leaky brain have become so prevalent.22CDC. Chronic Diseases in America, National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP)

    And to make matters worse, the problem may be handed down generationally, leading to increases in childhood disorders and more compounded issues .23Irene Lacal and Rossella Ventura. Epigenetic Inheritance: Concepts, Mechanisms and Perspectives, Front. Mol. Neurosci., 28 September 2018

    Gut-Brain Tight Junctions and Adherent Junctions

    The similar construction of protective barriers in the gut and brain highlights an example of the intricate connection of these 2 organs.

    Tight junctions in the gut mimic tight junctions in the brain
    Tight junctions in the gut mimic tight junctions in the brain

    The gut and brain barriers are the ultimate security system, intelligently built to keep tabs on the flow of cellular information.

    This is done through selective permeability regulated by tight junctions and adherent junctions that make up the endothelial cells of the barrier lining.24Katherine R. Groschwitz, BS and Simon P. Hogan, PhD. Intestinal Barrier Function: Molecular Regulation and Disease Pathogenesis, J Allergy Clin Immunol. 2009

    These junctions are joined by a number of specialized transporters, pumps, and receptors which aid in the flow of substances across the linings.25Paula Grammas, Joseph Martinez, Bradley Miller. Cerebral microvascular endothelium and the pathogenesis of neurodegenerative diseases, Expert Rev Mol Med. 2011

    In the brain, selective transport proteins allow nutrients, oxygen, amino acids, some drugs, and glucose to enter the cerebrospinal fluid for metabolism in the brain.26Chris Greene, Matthew Campbell. Tight junction modulation of the blood brain barrier: CNS delivery of small molecules, Tissue Barriers. 2016

    In the gut, tight junctions once thought to be static, are in fact dynamic and readily adapt to a variety of developmental, physiological, and pathological circumstances.27Daniel R Clayburgh, Le Shen, Jerrold R Turner. A porous defense: the leaky epithelial barrier in intestinal disease, Lab Invest. 2004

    When these tight and adherent junctions are working correctly, nutrients are better absorbed by the gut and brain which will optimize the function of both.

    When these junctions are not working correctly you experience both leaky gut and leaky brain.


    Circulating, serum zonulin is the main marker of gut permeability.28Agnieszka Zak-Gołąb , Piotr Kocełak, Małgorzata Aptekorz, Maria Zientara, Lukasz Juszczyk, Gayane Martirosian, Jerzy Chudek, Magdalena Olszanecka-Glinianowicz. Gut microbiota, microinflammation, metabolic profile, and zonulin concentration in obese and normal weight subjects, Int J Endocrinol. 2013

    Zonulin is a protein that acts as an endogenous modulator of epithelial tight junctions.

    If tight junctions are the security guard, zonulin is the supervisor giving the orders.

    It serves a number of functions including regulating the movement of fluid, macromolecules, and leukocytes between the bloodstream and the small intestine, and vice versa.29Alessio Fasano, M.D. Physiological, Pathological, and Therapeutic Implications of Zonulin-Mediated Intestinal Barrier Modulation, Am J Pathol. 2008

    Zonulin also protects against microorganism colonization of the proximal intestine.30Ramzi El Asmar, Pinaki Panigrahi, Penelope Bamford, Irene Berti, Tarcisio Not, Giovanni V Coppa, Carlo Catassi, Alessio Fasano. Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure, Gastroenterology. 2002

    While acute low levels of zonulin are natural in a healthy gut, it seems that prolonged chronic exposure can be problematic.31Zejun Zhou, Chuanxiu Bian, et al. Progesterone decreases gut permeability through upregulating occludin expression in primary human gut tissues and Caco-2 cells, Sci Rep. 2019

    Prolonged zonulin exposure is one of the main drivers of leaky gut and ultimately all the disorders that follow.

    High levels of zonulin have been correlated to elevated inflammatory markers, obesity, metabolic disorders, and advanced cognitive aging.32YanFei Qi, Ruby Goel. Intestinal Permeability Biomarker Zonulin is Elevated in Healthy Aging, J Am Med Dir Assoc. 2017

    The biggest triggers of excess zonulin production include bacteria and gluten.33Sandro Drago , Ramzi El Asmar, Mariarosaria Di Pierro, et al. Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines, Scand J Gastroenterol. 2006

    LipoPolySaccharide (LPS)

    Lipopolysaccharides are another contributor to inflammation associated with leaky gut.34Sandro Drago, Ramzi El Asmar, Mariarosaria Di Pierro. Lipopolysaccharide-Induced Increase in Intestinal Epithelial Tight Permeability Is Mediated by Toll-Like Receptor 4/Myeloid Differentiation Primary Response 88 (MyD88) Activation of Myosin Light Chain Kinase Expression, Scand J Gastroenterol. 2006

    Lipopolysaccharides are important outer membrane components of gram-negative bacteria that provide integrity to the bacterial cell and contributes to the interaction of these bacteria to other surfaces.35Aisha Farhana; Yusuf S. Khan.. Biochemistry, Lipopolysaccharide, Stat Pearls. 2020

    In a healthy gut, LPS concentrations mostly stay put in the gut lumen which houses many trillions of commensal bacteria.36R Benoit, S Rowe, S C Watkins, P Boyle, M Garrett, S Alber, J Wiener, M I Rowe, H R Ford. Pure endotoxin does not pass across the intestinal epithelium in vitro, Shock. 1998

    In a leaky gut, tight junctions open in the presences of increased zonulin and LPS is released into the bloodstream.

    Once in circulation, LPS elevates inflammatory cytokines and the odds of chronic physical and mental disease.37Perrine André, Fabienne Laugerette, and Catherine Féart. Metabolic Endotoxemia: A Potential Underlying Mechanism of the Relationship between Dietary Fat Intake and Risk for Cognitive Impairments in Humans?, Nutrients. 2019

    Think of your gut like a tire, LPS like the air, and zonulin like a nail.  When your gut tire is pierced by a zonulin nail, the LPS air is let out.  The result is a flat tire and a broken-down car.

    And much like the broken down car, in the presence of elevated LPS your body also begins to break down.

    In fact, studies examining disease-free centenarians show a low presence of LPS and zonulin.38Pedro Carrera-Bastos, Óscar Picazo, Maelán Fontes-Villalba, Helios Pareja-Galeano, Staffan Lindeberg, Manuel Martínez-Selles, Alejandro Lucia, and Enzo Emanuele. Serum Zonulin and Endotoxin Levels in Exceptional Longevity versus Precocious Myocardial Infarction, Aging Dis. 2018

    How Leaky Gut Helps Toxins Cross The Blood-Brain Barrier

    The release of lipopolysaccharide into circulation through a leaky gut produces a cascade of inflammatory cytokines that compromise the integrity of the blood-brain barrier.39Nan Wang, Dan Zhang, Gengyun Sun, Hong Zhang, Qinghai You, Min Shao, Yang Yue. Lipopolysaccharide-induced caveolin-1 phosphorylation-dependent increase in transcellular permeability precedes the increase in paracellular permeability, Drug Des Devel Ther. 2015

    Lipopolysaccharide itself can also induce blood-brain barrier permeability through phosphorylation of the cellular membrane protein, Cav-1.40Nan Wang, Dan Zhang, Gengyun Sun, Hong Zhang, Qinghai You, Min Shao, and Yang Yue. Lipopolysaccharide-induced caveolin-1 phosphorylation-dependent increase in transcellular permeability precedes the increase in paracellular permeability, Drug Des Devel Ther. 2015

    This is yet another example of how important reducing LPS-induced Cav-1 phosphorylation is to protecting the integrity of the blood-brain barrier.

    The best way to reduce LPS-induced Cav-1 phosphorylation is by lowering circulating LPS through healing gut permeability.

    Cav-1 and the Blood-Brain Barrier

    Cav-1, a well-established major structural protein of caveolae, has demonstrated an important role in the regulation of multiple cellular processes, including cell growth, differentiation, endocytosis, cholesterol trafficking, and cellular senescence.41Kim Cuc Thi Nguyen, Kyung A Cho. Versatile Functions of Caveolin-1 in Aging-related Diseases, Chonnam Med J. 2017

    It’s a part of the Caveolae family of integral membrane proteins and expressed mostly in the endothelial cells of the blood-brain barrier.42Anna R Busija, Hemal H Patel, Paul A Insel. Caveolins and cavins in the trafficking, maturation, and degradation of caveolae: implications for cell physiology, Am J Physiol Cell Physiol. 2017

    Like many other cellular proteins, there seems to be a homeostatic Goldilocks zone of expression.  Not too much and not too little.

    In the brain, cav-1 regulates neuronal signaling and promotes dendritic growth and predominantly regulates BBB permeability through transcellular and paracellular routes.43Creed M Stary, Yasuo M Tsutsumi, Piyush M Patel, Brian P Head, Hemal H Patel, David M Roth. Caveolins: targeting pro-survival signaling in the heart and brain, Front Physiol. 2012

    Changes in cav-1 can sequentially induce a series of alterations in BBB permeability, neuroinflammation, cerebral angiogenesis, apoptosis, and oxidative stress.44Qianyi Huang, Wei Zhong, Zhiping Hu, and Xiangqi Tang. A review of the role of cav-1 in neuropathology and neural recovery after ischemic stroke, J Neuroinflammation. 2018

    One of Cav-1’s most important jobs is inhibiting matrix metalloproteases (MMPs).

    MMP-9 specifically, degrades tight junction proteins and ultimately the blood-brain barrier.45Gary A Rosenberg. Neurological diseases in relation to the blood-brain barrier, J Cereb Blood Flow Metab. 2012

    MMP-9 production is also highly influenced by inflammatory cytokines and LPS.46Chang-Hoon Woo, Jae-Hyang Lim, Jae-Hong Kime. Lipopolysaccharide induces matrix metalloproteinase-9 expression via a mitochondrial reactive oxygen species-p38 kinase-activator protein-1 pathway in Raw 264.7 cells, J Immunol. 2004

    All of this underlines how important reducing LPS-induced Cav-1 phosphorylation is to protect the integrity of the blood-brain barrier.

    The best way to reduce LPS-induced Cav-1 phosphorylation is by lowering circulating LPS through healing gut permeability.

    Leaky Brain, Leaky Gut Functional Tests

    Functional lab testing can help identify problems
    Functional lab testing can help identify problems

    Now that you know what leaky brain is and how it’s connected to leaky gut, it’s time to find out if this is your problem.

    The best way to do this is through functional lab tests that can be ordered through a doctor or health practitioner.

    These tests can give you insight into your levels of relevant issues that may be affecting your gut/brain axis.  Below are some of the tests that may help you in this assessment.

    The Vagus Nerve: The Real Gut/Brain Axis

    Your vagus nerve is the main interface of the gut/brain connection.

    It a mixed nerve with anti-inflammatory properties both through its afferent and efferent fibers and the principal component of the parasympathetic nervous system.47Bruno Bonaz, Valérie Sinniger, Sonia Pellissier. Anti-inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation, J Physiol. 2016

    It literally connects your brain to your gut and thus highly influences the bidirectional connection.

    A full functioning, highly optimized vagus nerve can

    How To Heal Leaky Brain

    The most effective way to heal leaky brain is a multi-pronged approach of gut healing, stress reduction, and detoxification.

    All 3 will help reduce gut permeability and inflammation while strengthening the integrity of the blood-brain barrier.

    Regular movement, exercise, breathing, and mindfulness practices will help lower stress and boost BDNF and neurotransmitter production as well.

    Leaky Gut/Leaky Brain Diet

    A disciplined approach to diet is of the utmost importance when it comes to healing the gut.

    Of course, this is easier said than done.

    For many people, diet is what caused the onset of these conditions.

    The good news is that many people are able to heal their gut and the associated brain issues with the right diet.

    This may take some trial and error, but once you figure out what foods work best for you and which are your problem foods than you are well on your way to success.

    Some diets that are known to help leaky gut/leaky brain include:

    Foods To Avoid To Heal Leaky Gut/Leaky Brain

    To truly heal your gut you must eliminate all the low hanging problem foods that are known gut irritants.  These include:

    Adding in more nutrient-dense whole foods like organic fruits, vegetables, and high-quality animal products will give your body more healing nutrition.

    Supplements That Help Leaky Brain/Leaky Gut

    Supplements help leaky gut/brain healing
    Supplements help leaky gut/brain healing


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