How A Healthy Gut Protects Your Future Brain
The relationship between gut health now and brain health years from now
The last couple of weeks have seen an explosion of new research in areas relating to the body and embodiment. (In some cases, it’s more like new viewpoints on innovative old research.)
In the next few columns, I’m going to unpack a few of these findings and highlight the implications for our lives.
The first has to do with the enteric nervous system, sometimes also referred to as our “second brain.” (I’m not wild about that term, because it’s super brain-centric, and the body has much more primacy than neuroscience traditionally accords it. For example, bioplasticity exists alongside and in equal value to neuroplasticity. Just saying.)
On April 11, I taught a Masterclass on the enteric nervous system, or ENS. One component of the class included the relationship between intestinal permeability and Parkinson’s Disease. The very next day, the Michael J. Fox Parkinson’s Foundation announced a groundbreaking finding that relates directly to the topic of the class. (Don’t you love that kind of synergy?)
My reading of this research: It’s not just about Parkinson’s, but about gut imbalance as an early (sometimes, by dozens of years) biomarker for “brain” diseases like Alzheimer’s and dementia.
My take: these “brain diseases” will, I believe, someday be renamed gut-brain diseases.
Today’s column will focus on one aspect of this gut-brain system: intestinal permeability, also known as Leaky Gut.
Let’s dive in.
The Gut-Brain Connection
Intestinal permeability is at the nexus of an exciting body of research. Yet despite a trove of evidence that corroborates it, some mainstream medical professionals still contest its existence.
The concept isn’t new: Long ago, before the medical community understood the factors that cause disease, doctors believed that many ailments resulted from stomach imbalances. They called these imbalances hypochondriasis, from the Greek root hypo, meaning “under,” and khondros, referring to the soft parts of the abdomen under the breastbone. Although the medical and psychiatric fields later imbued the term “hypochondriasis” with unflattering connotations, this early view proved more spot-on than early doctors may have imagined. The devaluation and rewriting of “old knowledge” also occurs with other bodies of epistemic knowledge. It may not surprise you to know, then, that many indigenous systems also focused on the role of the gut in disease. (See the references below this article for more.)
Intestinal permeability is in many ways “silent,” which is to say that most of us don’t know it’s happening.
However, it can play host to a wide array of symptoms, which happen also to be manifestations of chronic inflammation. Leaky gut can cause or occur with the following:
chronic diarrhea
constipation
bloating
fatigue
headaches
confusion or difficulty concentrating
inflammatory skin issues
autoimmune issues
joint pain
hormonal imbalances
mood disorders
chronic fatigue syndrome and fibromyalgia.
How do you know if you have it? There currently exists one or two accepted medical tests for leaky gut. The first measures (in urine) the ratio of lactulose to mannitol. The second measures (in blood or stool) zonulin, a family of proteins that regulate the junctions between cells. (Zonulin antibodies can also be assessed.) There are a few other correlative measures, but none has been validated yet.
Understanding the basic workings of intestinal permeability is important. It points to the ways we can regulate permeability and lower inflammation.
There’s an even more critical benefit, however: This understanding gives us the chance to time-travel decades into the future—specifically, to our future self—and improve the long-term health of our brains, years and even decades, from now.
It’s a powerful, even exciting possibility: What what you do for your enteric nervous system today can boost the well-being of your mind, brain, and body.
Please bear with a little science as we take a trip into the enteric nervous system, where permeability begins.
What Intestinal Permeability Is + Why It Matters
First, I’d like to highlight that the enteric nervous system (ENS) comprises 75-80% of our immunity. It is therefore an archetypal boundary-negotiator. It decides what is us and what is not us. When something enters the field that is not us, the ENS launches an inflammatory response, which in turn also reverberates in our immune system and throughout our bodies, brains, and minds. (Remarkably, mental rumination isn’t just something that happens in the mind; it correlates with sensations, brain connectivity patterns, and gut disorders such as IBS.)
Intestinal permeability refers to enterocytes, epithelial cells that line our digestive tract. The job of enterocytes is to exchange nutrients with the intestine and the bloodstream. But this is a tightrope walk of sorts: The intestinal lining needs to be open to nutrients and, at the same time, impermeable (not open) to destructive pathogens.
Permeability occurs when the normally tight junctions between enterocytes open up. This causes pathogens to leak into the gut lumen (space), igniting an inflammatory response which includes the release of cytokines and other inflammatory molecules. Chronic exposure to these molecules causes inflammation in the gut.
But permeability isn’t confined to the gut alone. Inflammatory pathogens can also enter the bloodstream, where they circulate throughout the body.
Critically, inflammatory molecules can also cross the blood-brain barrier, an important boundary that protects the brain from inflammation. Put another way, inflammation in the gut often leads to inflammation in the bloodstream and the brain.
The Causes of Intestinal Permeability
What gives rise to gaps between these normally tight cell junctions? Part of this complex picture is genetic. The human gut microbiome alone contains 3.3 million genes, over 150 times the amount in our own genome.
Other permeability-inducing culprits include gluten (and in the U.S. and other countries, the pesticides with which it is cultivated), the standard Western diet (low in fiber and high in processed foods, sugar, and saturated fats), long-term or acute use of antibiotics, alcohol abuse or even use, stress, and trauma.
People with anxiety or trauma are four times likely to develop gut disorders than those without such a history. The prevalence of sexual assault and harassment in the patriarchal system we live in makes the fact that women develop gut disorders at a much higher frequency than men not at all surprising.
The Consequences of Intestinal Permeability
Intestinal permeability has itself been implicated as a cause in many diseases, including:
Type 1 diabetes
Celiac disease and gluten sensitivities
Irritable Bowel Syndrome (IBS), Crohn’s Disease, ulcerative colitis, and other inflammatory bowel diseases
Mood disorders
Alzheimer’s Disease and other dementia-related illnesses
Parkinson’s Disease
How does intestinal permeability influence all these other illnesses, including emotional ones?
Let’s zoom in on a special group of inflammatory molecules called lipopolysaccharides, or LPS. These molecules are so inflammatory that scientists often use them in lab experiments to cause inflammation, also referred to as endotoxicity. Most people can handle them only in low doses.
My take: Lipopolysaccharides increase mildly in response to exercise. This mild increase and return to baseline may actually protect us from chronically elevated levels of LPS. (This mild rise in LPS may be part of the reason why people with Long Covid, who have elevated levels of viral pathogens, often have an inflammatory reaction to exercise.)
Lipopolysaccharides increase cortisol and can cause anxiety and depression. They also induce sickness behaviors (such as social withdrawal and the loss of interest in normally pleasurable activities in depression). They inflame the lungs. (Remember, the lung microbiome influences the gut microbiome, and vice versa.) Researchers think they damage joints and induce autoimmune disease. They also contribute to cardiovascular disease, Type 1 and Type 2 Diabetes, and Irritable Bowel Syndrome (IBS).
Lipopolysaccharides also affect the brain. They promote neuroinflammation. They contribute to accumulation of the amyloid and tau brain plaques associated with Alzheimer’s Disease and other dementias. They cause brain fog. In one interesting study, a group of researchers showed this: They used neomycin (an antibiotic!) to induce an inflammatory state in the brain’s microglial cells.
LPS and Brain Inflammation
And now to the connection between LPS and Parkinson’s Disease, a neurodegenerative illness that results in disordered movement, depression, and gastrointestinal illness. Large percentages of people with Parkinson’s have gastrointestinal symptoms, which include dyspepsia (hypokhondria, or pain in the upper abdomen just below the ribs), constipation, nausea, and swallowing difficulties. People with Parkinson’s also have Lewy Bodies, abnormal protein deposits that affect chemicals in the brain (like dopamine) and cause difficulties with cognition, movement, behavior, and mood. (This also occurs with Lewy Body Dementia.)
To recap: In Parkinson’s Disease, the above issues are caused by intestinal permeability, as well as inflammation and changes in the gut microbiome.
The exciting element here: People with Parkinson’s exhibit signs not of acutely elevated lipopolysaccharides (remember, high levels of an endotoxin caused by intestinal permeability), but chronic and prolonged elevated LPS.
This type of non-acute but prolonged LPS elevation, researchers think, contributes to the initiation and aggregation of a protein called a-synuclein at the gut level. Alpha-synuclein is a misfolded protein linked to Parkinson’s Disease.
Damage to the intestinal barrier can allow alpha-synuclein and also microbes, environmental toxins, and other contents of the gut to access the bloodstream and enter systemic circulation, and also to cross the blood-brain barrier.
Remarkably, alpha-synuclein and Lewy bodies don’t originate in the brain; rather, they begin in the enteric nervous system long before they enter the central nervous system.
Enter the Michael J. Fox Foundation + Groundbreaking New Research
Back to the announcement of April 12th. The Michael J. Fox Foundation for Parkinson’s Research announced a new discovery. In a paper published in The Lancet Neurology (the publication is actually dated May of 2023), a cohort of researchers reported that measures of alpha-synuclein detected by a lumbar puncture can be used to determine whether someone has Parkinson’s. (This has historically been difficult to diagnose.)
My take: This new connection may be a game-changer, particularly because intestinal permeability and LPS arise decades before symptoms of PD occur. And the same may be true of other brain-involved diseases, such as neurodegenerative disorders, Alzheimer’s Disease, and dementias. (My Dad, who had a progressive neurological illness, popped antacids like candy for several decades before his symptoms manifested.)
Intestinal disorders aren’t just a symptom or consequence of Parkinson’s Disease, but a pathological catalyst for the disease decades before Parkinson’s Disease (or other issues) progress to the central nervous system and brain.
Managing LPS, gut inflammation, enteric nervous system function, and intestinal permeability early may be a way to prevent or at least delay the onset of PD as well as other brain diseases like Alzheimer’s and the dementias.
Redrawing the Intestinal Boundary
In my opinion, ways to address intestinal permeability will become an exciting new area of research. Here’s my take on the possibilities.
Some studies indicate that saturated fat can increase LPS, while omega-3’s can decrease it. Polyphenols, particularly those found in green tea and cocoa, can also help, particularly in older adults. There is also evidence that eating fermented foods increases the diversity of the gut microbiome, which can help to manage inflammation. Also, recent studies out of Stanford University indicate that eating more fiber-rich diets is helpful, but only in the presence of increased microbial diversity (i.e. through pre- and pro-biotics and fermented foods).
Some of these options, particularly the omega-3’s, can become costly, which is yet another way that social inequity impacts BIPOC people, and that our wealth gap does the same. (One of my goals this year is to make my own fermented foods; if you do so already, please share your favorite recipes in the comments.)
All this said, one of the much-overlooked elements of gut health concerns the link between the body, mind, and brain—and in particular, the relationship we have with our bodies.
In a previous column, I talked about the importance of deepening the connection we have with our embodiment, which includes trusting our bodies. In my opinion, it’s no accident that mindfulness, particularly Mindfulness-Based Stress Reduction (MBSR) has been shown to be helpful for Irritable Bowel Syndrome. Or that self-compassion is helpful for gut disorders.
My favorite practices for strengthening and nourishing the enteric nervous system are dynamic rest practices, particularly the ones that offer gentle stimulation to the connective tissue of the belly. (Like Face-Down Burrito Pose, below.) Here’s my “short list” of dynamic rest practices:
formal and informal self-compassion practice
restorative yoga
breathwork, particularly box breathing or nasal breathing
abdominal self-massage
connective tissue work
listening to interoceptive signals earlier in the day but not as much before bed
time in nature
active listening to the body
setting interpersonal boundaries
Sources:
Long ago, before the medical community understood the factors that cause disease: Campos, M. (2017). Leaky gut: What is it, and what does it mean for you? Harvard Health. https://www.health.harvard.edu/blog/leaky-gut-what-is-it-and-what-does-it-mean-for-you-2017092212451
Many indigenous systems also focused on the role of the gut in disease: Ndlela, S. Z., Mkwanazi, M. V., & Chimonyo, M. (2022). Characterisation of the indigenous knowledge used for gastrointestinal nematode control in smallholder farming areas of KwaZulu-Natal Province, South Africa. BMC veterinary research, 18(1), 75. https://doi.org/10.1186/s12917-022-03172-0. See also: Warbrick, I., Heke, D., & Breed, M. (2023). Indigenous Knowledge and the Microbiome-Bridging the Disconnect between Colonized Places, Peoples, and the Unseen Influences That Shape Our Health and Well-Being. mSystems, 8(1), e0087522. https://doi.org/10.1128/msystems.00875-22
The human gut microbiome alone contains 3.3 million genes: Zhu, B., Wang, X., & Li, L. (2010). Human gut microbiome: the second genome of human body. Protein & cell, 1(8), 718–725. https://doi.org/10.1007/s13238-010-0093-z
A group of researchers studied rats and used neomycin: Püntener, U., Booth, S. G., Perry, V. H., & Teeling, J. L. (2012). Long-term impact of systemic bacterial infection on the cerebral vasculature and microglia. Journal of neuroinflammation, 9, 146. https://doi.org/10.1186/1742-2094-9-146. See also: Lively, S., & Schlichter, L. C. (2018). Microglia Responses to Pro-inflammatory Stimuli (LPS, IFNγ+TNFα) and Reprogramming by Resolving Cytokines (IL-4, IL-10). Frontiers in cellular neuroscience, 12, 215. https://doi.org/10.3389/fncel.2018.00215
In Parkinson’s Disease, the above issues are caused by intestinal permeability: Yang H, Li S, Le W. Intestinal Permeability, Dysbiosis, Inflammation and Enteric Glia Cells: The Intestinal Etiology of Parkinson's Disease. Aging Dis. 2022 Oct 1;13(5):1381-1390. doi: 10.14336/AD.2022.01281. PMID: 36186124; PMCID: PMC9466983. See also: Aho, V. T. E., Houser, M. C., Pereira, P. A. B., Chang, J., Rudi, K., Paulin, L., Hertzberg, V., Auvinen, P., Tansey, M. G., & Scheperjans, F. (2021). Relationships of gut microbiota, short-chain fatty acids, inflammation, and the gut barrier in Parkinson's disease. Molecular neurodegeneration, 16(1), 6. https://doi.org/10.1186/s13024-021-00427-6. See also: Schwiertz, A., Spiegel, J., Dillmann, U., Grundmann, D., Bürmann, J., Faßbender, K., Schäfer, K. H., & Unger, M. M. (2018). Fecal markers of intestinal inflammation and intestinal permeability are elevated in Parkinson's disease. Parkinsonism & related disorders, 50, 104–107. https://doi.org/10.1016/j.parkreldis.2018.02.022. See also: Clairembault, T., Leclair-Visonneau, L., Coron, E., Bourreille, A., Le Dily, S., Vavasseur, F., Heymann, M. F., Neunlist, M., & Derkinderen, P. (2015). Structural alterations of the intestinal epithelial barrier in Parkinson's disease. Acta neuropathologica communications, 3, 12. https://doi.org/10.1186/s40478-015-0196-0
This type of non-acute but prolonged LPS elevation, researchers think: Ryman, S., Vakhtin, A. A., Richardson, S. P., & Lin, H. C. (2023). Microbiome-gut-brain dysfunction in prodromal and symptomatic Lewy body diseases. Journal of neurology, 270(2), 746–758. https://doi.org/10.1007/s00415-022-11461-9
The Michael J. Fox Foundation for Parkinson’s Research announced a new discovery: https://www.statnews.com/2023/04/12/michael-j-fox-parkinsons-biomarker/
In a paper published in The Lancet Neurology: Siderowf, A., Concha-Marambio, L., Lafontant, D. E., Farris, C. M., Ma, Y., Urenia, P. A., Nguyen, H., Alcalay, R. N., Chahine, L. M., Foroud, T., Galasko, D., Kieburtz, K., Merchant, K., Mollenhauer, B., Poston, K. L., Seibyl, J., Simuni, T., Tanner, C. M., Weintraub, D., Videnovic, A., … Parkinson's Progression Markers Initiative (2023). Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study. The Lancet. Neurology, 22(5), 407–417. https://doi.org/10.1016/S1474-4422(23)00109-6
Some studies indicate that saturated fat can increase LPS, while omega-3’s can decrease it: Lyte, J. M., Gabler, N. K., & Hollis, J. H. (2016). Postprandial serum endotoxin in healthy humans is modulated by dietary fat in a randomized, controlled, cross-over study. Lipids in health and disease, 15(1), 186. https://doi.org/10.1186/s12944-016-0357-6
Polyphenols, particularly those found in green tea and cocoa, can also help: Peron, G., Gargari, G., Meroño, T., Miñarro, A., Lozano, E. V., Escuder, P. C., González-Domínguez, R., Hidalgo-Liberona, N., Del Bo', C., Bernardi, S., Kroon, P. A., Carrieri, B., Cherubini, A., Riso, P., Guglielmetti, S., & Andrés-Lacueva, C. (2021). Crosstalk among intestinal barrier, gut microbiota and serum metabolome after a polyphenol-rich diet in older subjects with "leaky gut": The MaPLE trial. Clinical nutrition (Edinburgh, Scotland), 40(10), 5288–5297. https://doi.org/10.1016/j.clnu.2021.08.027
There is also evidence that eating fermented foods increases the diversity of the gut microbiome: Wastyk, H. C., Fragiadakis, G. K., Perelman, D., Dahan, D., Merrill, B. D., Yu, F. B., Topf, M., Gonzalez, C. G., Van Treuren, W., Han, S., Robinson, J. L., Elias, J. E., Sonnenburg, E. D., Gardner, C. D., & Sonnenburg, J. L. (2021). Gut-microbiota-targeted diets modulate human immune status. Cell, 184(16), 4137–4153.e14. https://doi.org/10.1016/j.cell.2021.06.019