Stopping the Leak: Leaky Gut, Leaky Brain and Beyond

Stopping the Leak: Leaky Gut, Leaky Brain and Beyond

The phrase “leaky gut syndrome,” an unappealing term for “increased intestinal permeability,” has been part of the health-oriented vernacular for more than a decade. While it has been dismissed by many as pseudoscience due to a lack of strong evidence supporting a causative role in human health conditions, animal and human research surrounding this mechanism continues to unfold. Although some researchers have embraced the concept of abnormal permeability and its potential health consequences, confusion and skepticism remain. Gaining a greater understanding requires a deep dive into the science, especially since “leaky gut” has given rise to other “leaky” organ systems, including brain and blood vessels.

The Diligent Digestive Tract
The digestive tract is solely responsible for harvesting nutrients from the food we eat, and nutrient status certainly depends on digestive health. But the digestive tract is far more than just a “food tube.” Besides digestion, it also is home to about 70 percent to 80 percent of the body’s immune cells and more than 100 million neurons — collectively referred to as the gut-associated lymphoid tissue, or GALT, and enteric nervous system, or ENS, respectively. The digestive tract also contains the intestinal microbiome and serves as a protective barrier between everything that exists in our “inner tube” — including microbes, undigested food particles, hormone metabolites and microbial endotoxins — and the rest of the body. It does so through a highly sophisticated mechanism involving an intestinal barrier that is only one cell layer thick, which is meant to let nutrients in and keep almost everything else out. The health and integrity of that intestinal barrier may have profound influences on diverse systems of the body, including the cardiovascular, neurological and immune systems.

Intestinal Permeability and Leaky Gut
Intestinal permeability refers to the ability of relatively large molecules to pass or “leak” through tight junctions into circulation, hence the term “leaky gut.” Both the intestinal epithelial cells, or enterocytes, and the spaces between them serve as gatekeepers, selectively allowing certain molecules (such as vitamins, minerals and other nutrients) to pass through. Cell membranes allow passage of specific molecules via diffusion or receptor sites, and tight junction, or TJ, complexes bind enterocytes together and regulate the space between them, allowing very few molecules to pass.

When TJ complexes misfire and become less tight, the contents of the digestive tract are able to slip between intestinal enterocytes and make their way through the mucosa layer and into the blood stream. A sugar permeability test may be used to measure TJ integrity, which involves consuming mannitol and lactulose dissolved in water. The ratio of the sugars in a person’s urine can indicate that permeability of the intestines has occurred.

Since the mucosa layer is full of immune cells, increased permeability can trigger an immune response. This is the mechanism behind increased intestinal permeability and the inflammation and immune system activation it may cause, collectively referred to as “leaky gut syndrome.” Now, researchers are seeking to shed light on the link between leaky gut syndrome and several diseases and disorders.

Permeability Consequences
Undigested food, bacteria, yeast and their metabolic waste products, known as microbial endotoxins, are examples of molecules that are meant to remain within the digestive tract but can enter the lamina propria mucosal layer (connective tissue where GALT resides) and, ultimately, the blood stream through permeable TJs. When these molecules pass through TJs, they are called antigens, which the body perceives as harmful irritants. “Antigen-presenting” immune cells patrol for invaders in the lamina propria, recognize the antigens and trigger an inflammatory cascade. A steady stream of antigens passing through the TJs keeps that inflammatory cascade going, resulting in chronic low-grade inflammation, which may have a negative effect on overall health. In fact, research has found the inflammatory response itself may increase gut permeability, continuing a vicious cycle.

The migration of antigens from the digestive tract to the blood stream, paired with inflammation and immune system activation, may trigger the development of several health issues. For example, immune activation from gut-derived microbial endotoxins and food antigens have been associated with autoimmune disease and psychiatric disorders, including major depression, bipolar disorder, schizophrenia and autism.

Could There Be Leaky Brain Syndrome?
A growing body of animal and human research suggests the intestinal microbiome interacts with the central nervous system, possibly through the blood-brain barrier, or BBB, and that gut dysbiosis — an imbalance between good and bad microbes — may be a causal factor in many central nervous system, or CNS, conditions. Like the intestinal barrier, the BBB is formed by endothelial cells and tight junctions that line cerebral blood vessels, selectively allowing nutrients in and toxins and metabolites out of the brain to maintain optimal interstitial fluid for the CNS, while also protecting against circulating infections. Inflammation from a variety of causes is known to disrupt the BBB, which can expose the brain and CNS to harmful compounds in circulation. Some research has found a compromised BBB to be a key feature in neurological diseases, especially those that also involve immune activation, including multiple sclerosis, brain cancers, and Parkinson’s and Alzheimer’s diseases.

The connection between the gut microbiome and the BBB is not well understood, but researchers propose it could be mediated by the immune system. Gut bacteria are known to release compounds into the blood stream that can affect the CNS, either by crossing the BBB or interacting with BBB cells. Furthermore, these inflammatory molecules increase both intestinal and BBB permeability, while short-chain fatty acids such as butyrate, made by gut bacteria, have been shown to improve both intestinal and BBB permeability.

Blood Vessel Permeability and Cardiovascular Health
In addition to “leaky gut” and “leaky brain,” there is evidence from human and animal studies that blood vessel endothelium also can become permeable. The endothelial glycocalyx, or eGC, is a layer of hair-like macromolecules on the endothelial cells of blood vessels. It regulates endothelial function, and its dysfunction may be linked with early physiological changes in vascular permeability and clotting cascades that precede conditions including edema, hypertension, sepsis, Type 2 diabetes and atherosclerosis. Microbial endotoxins, free radicals and inflammatory cytokines can damage the eGC.

A microbial endotoxin called lipopolysaccharide, or LPS, has been investigated for its potential role in the development of cardiovascular disease. Research suggests LPS from intestinal bacteria may damage endothelial cells, oxidize LDL cholesterol and encourage the release of proinflammatory cytokines, all of which may contribute to atherosclerosis. This could mean intestinal permeability and the translocation of bacteria and their endotoxins may contribute to systemic inflammation, atherosclerosis and cardiovascular disease. Research already exists that links bacterial translocation from oral bacteria with atherosclerotic plaques and coronary artery disease, and the gut microbiome may be another source of bacteria and endotoxins that fuel chronic inflammation.

An Opportunity for Nutrition Intervention
We may not yet know if or which foods influence the tight junctions of the BBB and blood vessel endothelium, but there is limited human and animal research suggesting certain eating patterns, nutrients and lifestyle factors can help support healthy TJ function in the gut, including flavonoids, probiotics, prebiotics, glutamine, curcumin, gluten avoidance by those with celiac disease and non-celiac gluten sensitivity, and zinc supplementation by those with Crohn’s disease. Some research has found certain factors may have the potential to trigger TJ dysfunction and “leakiness” in the gut including food allergies and sensitivities, dysbiosis, alcohol use and Western dietary patterns.

At first glance, it may not be obvious to target digestive health in people with cardiovascular or neurological disease, but research suggests it could be a potential opportunity for nutrition intervention. As research continues to emerge, it likely will uncover major unknowns that could change the way we think about health and the interaction between distant organ systems. While more research in humans is needed to shed light on how to harness the connectivity between the gut microbiome, CNS and immune system to maximize health and healing, existing research gives registered dietitian nutritionists some interesting food for thought.


Al-Asmakh M, Hedin L. Microbiota and the control of blood-tissue barriers. Tissue Barriers. 2015;3(3): e1039691.
Daneman R, Prat A. The blood-brain barrier. Cold Spring Harb Perspect Biol. 2015;7(1):a020412.
Hall H. Leaky Brain, Leaky Gut: Are They Real? Science-based Medicine website. Published November 20, 2018. Accessed June 19, 2019.
Houser MC, Tansey MG. The gut-brain axis: is intestinal inflammation a silent driver of Parkinson’s disease pathogenesis? NPJ Parkinsons Dis. 2017;3:3.
Joneja, JV. The Health Professional’s Guide to Food Allergies and Intolerances. 1st ed. Chicago, IL: Academy of Nutrition and Dietetics;2013.
Leaky Gut Syndrome.” NHS website. Reviewed September 3, 2018. Accessed June 19, 2019.
Lee B, Moon KM, Kim CY. Tight Junction in the Intestinal Epithelium: Its Association with Diseases and Regulation by Phytochemicals. J Immunol Res. 2018:2645465.
Logsdon AF, Erickson MA, Rhea EM, Salameh TS, Banks WA. Gut reactions: How the blood-brain barrier connects the microbiome and the brain. Exp Biol Med. 2018;243(2):159–165.
Ma Y, Yang X, Chatterjee V, Meegan JE, Beard RS Jr, Yuan SY. Role of Neutrophil Extracellular Traps and Vesicles in Regulating Vascular Endothelial Permeability. Front Immunol. 2019;10:1037.
Ma?kiewicz M, Szarmach A, Sabisz A, Cuba?a W, Szurowska E, Winklewski P. Blood-brain barrier permeability and physical exercise. J Neuroinflammation. 2019;16(1).
Manahan B. A brief evidence-based review of two gastrointestinal illnesses: irritable bowel and leaky gut syndrome. Altern Ther Health Med. 2004;10(4):14.
Mu Q, Kirby J, Reilly CM, Luo XM. Leaky Gut As a Danger Signal for Autoimmune Diseases. Front Immunol. 2017;8:598.
Obrenovich MEM. Leaky Gut, Leaky Brain?. Microorganisms. 2018;6(4):107.
Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch. 2007;454(3):345–359.
Rogler G, Rosano G. The heart and the gut. Eur Heart J. 2014;35(7):426-430.
Rudzki L, Szulc A. “Immune Gate” of Psychopathology-The Role of Gut Derived Immune Activation in Major Psychiatric Disorders. Front Psychiatry. 2018;9:205.
Serra e Silva Filho W, Casarin RC, Nicolela EL Jr, Passos HM, Sallum AW, Gon?alves RB. Microbial diversity similarities in periodontal pockets and atheromatous plaques of cardiovascular disease patients PLoS One. 2014;9(10):e109761.
Uchimido R, Schmidt EP, Shapiro NI. The glycocalyx: a novel diagnostic and therapeutic target in sepsis. Crit Care. 2019;23(1):16.
Van Spaendonk H, Ceuleers H, Witters L, et al. Regulation of intestinal permeability: The role of proteases.?World J Gastroenterol. 2017;23(12):2106–2123.
Xhima K, Weber-Adrian D, Silburt J. Glutamate Induces Blood–Brain Barrier Permeability through Activation of N-Methyl-D-Aspartate Receptors. Journal of Neuroscience. December 7, 2016. 36 (49) 12296-12298; DOI:10.1523/JNEUROSCI.2962-16.2016.
Yoo BB, Mazmanian SK. The Enteric Network: Interactions between the Immune and Nervous Systems of the Gut. Immunity. 2017;46(6):910–926.

Robin Foroutan
Robin Foroutan, MS, RDN, is a National Spokesperson for the Academy of Nutrition and Dietetics who specializes in integrative medicine, functional medicine and holistic healing. She practices privately and at the Morrison Center.