From Gut to Brain: The Inflammation Connection

When a woman experiences fatigue, brain clouding, flat mood, PMS, and constipation, we call it anxiety or stress and we stick her on an antidepressant that she will likely take for the rest of her life. Where in this protocol have we investigated why she is feeling that way?  How have we personalized the treatment to her unique biochemistry?  What is the plan for side effects including new and different psychiatric symptoms resulting from this prescription?  We haven’t.  We’ve applied a one-size-fits all treatment to mask symptoms without consideration for the cause.

The Immune System and Depression

Psychiatry has known about the role of the immune system in certain presentations of depression for the better part of the last century, and more recently, pioneering thinkers like Maes, Raison, and Miller have written about the role of altered immune set points and inflammation in models of depression. Our immune systems are largely housed in the gut and the interplay between the gut and the brain is a complex and profoundly important relationship to appreciate.

We all recognize that anxiety or nervousness can impact our guts – most of us have had butterflies before a date or even diarrhea with extreme performance anxiety?  We are just learning that this relationship is bidirectional; however, and that the gut can also communicate its state of calm or alarm to the nervous system.  We think that the vagus nerve is a primary conduit of information and that inflammatory markers are the vehicles traveling this highway. Scientists have studied the “protective effects” of severing this nerve when animals are exposed to gut-related toxins that normally cause depressive symptoms.  We are getting ahead of ourselves; however, because we need to better elucidate why inflammation matters, where it comes from, and why it is the universal driver of chronic illness.

How Does Inflammation Start?

When a woman feels foggy, run-down, easily overwhelmed, and flat, we know that  her hormones as messengers between her gut and brain are out of balance. From my perspective; however, hormone derailment is a downstream effect of cellular dysfunction from oxidative stress and inflammation. Inflammation stems from many sources, including, hallmarks of the modern American lifestyle:

  • Sugar. Sugar, particularly in the form of fructose and sucrose, spikes insulin and triggers release of inflammatory cytokines. It forms advanced glycation endproducts when it binds to proteins, and oxidizes lipids which form cell and mitochondrial membranes.
  • Chemicals. Pesticides, environmental pollution from industrial waste, hormonally-modulating plastics, fire retardants, and cosmetic additives all stimulate our immune systems to varying extents and disrupt optimal production of energy on a cellular level, particularly in vulnerable tissues like the thyroid.
  • Pathogens. The aforementioned culprits, and notably herbicides, gluten grains, and genetically modified foods, promote intestinal permeability, changes in our intestinal flora that facilitate growth of pathogenic bacteria, yeast, and fungus which keep our immune systems in a state of alarm,
  • Stress. This catch-all term, broadly defined, represents the ultimate link between hormones and inflammation, because stress, whether it’s psychological or physiologic, triggers the release of cortisol. Cortisol helps to mobilize blood sugar so that you can run effectively and efficiently from that tiger chasing you. It also acts as a systemic immune suppressant, lowering levels of secretory IgA, an important body guard of the gut mucosa.

Cortisol and insulin are like stress-response sisters, and high cortisol states will also contribute to insulin resistance, or high insulin and high sugar while the cells, themselves, are starving.  Insulin protects fat storage (inhibits lypolisis), and fat cells secrete their own inflammatory signals in addition to aromatizing testosterone to estradiol contributing to states of estrogen dominance, while also increasing DHEA and androgens to fuel that process (as well as acne, hair growth, and agitation).

Cortisol also inhibits the conversion of storage thyroid hormone to active hormone leading to states of hypothyroidism even with normal-looking labs.

What Does Inflammation Do?

Once inflammation is active, it is highly self-perpetuating. These inflammatory cytokines travel throughout the body causing oxidating stress to the fragile machinery of the tissues and mitochondria, specifically.  In the brain, inflammation serves to shunt the use of tryptophan toward production of anxiety-provoking chemicals like quinolinate, instead of toward serotonin and melatonin. They produce a replicable collection of symptoms called “sickness syndrome”, noted for it’s overlap with “depressive” symptoms: lethargy, sleep disturbance, decreased social activity, mobility, libido, learning, anorexia, and andhedonia. Psychiatric researchers have observed that patients with higher levels of inflammatory markers (like CRP) are less likely to respond to antidepressants, and more likely to respond to anti-inflammatories.

Where Do We Begin to Heal?

How is any of this good news? This approach to chronic illnesses like depression views it as a complex, non-specific symptom reflecting a state of bodily disharmony.  It isn’t that you were born with bad genes or low serotonin.  It is far more likely that you are experiencing an unhealthy inflammatory balance, driven by cortisol dysfunction, and stemming from a sick gut.  We can come at modifying your system from many angles, but here is a basic starter kit:

  • Exercise – Burst exercise is my primary recommendation.  It is the most bang for your buck in terms of cardiovascular benefit and specifically enhancing mitochondrial health because it puts a special kind of stress on the body when you move to your max for 30 seconds that then recover for 90.  I recommend 8 intervals 1-3x/week.
  • Meditation – The effects of stimulating the relaxation nervous system, even through listening to a 20 minute guided meditation, can be far-reaching.  Enhanced genomic expression of anti-inflammatory genes and suppression of inflammatory ones was demonstrated in this study.
  • Diet – I recommend a diet that controls for glycemic fluctuations through elimination of refined carbs and grains, and through high levels of natural fats to push the body to relearn how to use fats for fuel.  This is the brain’s preferred source.  I discuss some therapeutic foods here.
  • Strategic supplementation – Natural anti-inflammatories like polyunsaturated fats (evening primrose oil and fish oil), curcumin (the active component of turmeric), and probiotics to name a few, can help promote a synergy of beneficial effects from the above interventions.

In my practice, despite some suggestion that antidepressants may actually be having their effect through an anti-inflammatory mechanism, these medications have become obsolete.  An appreciation of the role of inflammation and immunity in driving hormonal imbalance which directly impacts mood, energy, and wellness, is at the core of personalizing the definition of “depression”. Don’t be lured into the simplicity of a one disease-one drug model.  There’s no room for you in that equation.


Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Miller et al Biol Psychiatry. 2009 May 1; 65(9): 732–741.

Cytokines and cognition – The case for a head to toe inflammatory paradigm. Wilson et al. JAGS 50:2041–2056, 2002.

A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 70:31–41.

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Kelly Brogan MD

Kelly Brogan, M.D. is a holistic women’s health psychiatrist on faculty at George Washington University and in private practice in Manhattan. She completed her psychiatric training and fellowship at NYU Medical Center after graduating from Cornell University Medical College, and has a B.S. from MIT in Brain and Cognitive Science/Systems Neuroscience. View full bio


  1. Wendy said on

    This article hits the nail on the head for me. I just had my second thermoscan and the results were that I have tons of inflammation throughout my body, especially in my female organs and breasts. Thank you for posting this, not to mention I was just recently diagnosed with hypothyroidism and although I am on synthroid, I am gaining weight….Now I understand what I have been trying to find out about inflammation…Thank you again!!!

  2. Deb said on

    I’d add in viruses, bacterial infections, mold and fungal reactions. These impact the immune system and also affect the central nervous system. New research relating to some Strep infections has found a relationship between early age onset of depression/OCD having a link to drug resistant strep, (PANDAS).

  3. April said on

    What brand of cur cumin should I try? I think it’s really interesting that inflammation and the immune system has to do with depression. Thank for for the awareness!

  4. Denise logue said on

    Found your article very helpful I was diagnosed with hashimotos a year ago and just recently I have been told I have IC. The doctors just want to prescribe drugs I would prefer a more holistic natural way to lower inflamation. Many thanks

  5. Wendie Nelson said on

    I have a question: I have read about and am currently using “Internal Water Therapy” to help clean the gut. The recomendations are 1.5 litres of water every morning to cleanse the gut and colon with one hour of nothing else in the gut,. I have more energy than ever, have had a reduction in my hernia bump, hemmhoroids are clearing up, and my skin has greatly improved. The question is, is this radical therapy harmful to the electrolytic balance in the body when one is eating right, on no medications, and moderately active? PS. I am 60 years old, in great health, and have no preexisting conditions other than previously mentioned, and am a female. Also am on a supplemental regimin of enzymes, organic supplements, and protien. No gmos, sugar or synthetic food or supplements for this girl!

  6. James Cassidy said on

    Dr.Brogan: The Relationship between Leakey Gut and inflammation and the Immune system is profound, have suffered over 45 years from this syndrome i can totally relate to this disturbance. I feel can of let down by many physicians and to a degree we as patients are spoon-feed our delay dose without scientific verification, I feel as a Father it is beyond Gender, or Race or Creed but a connective process how we Feed our Auto-Immune systems for health and not drug ourselves to disability. Change is in the winds.

  7. Lindsay Wilson said on

    Great article. I would also suggest a good quality probiotic or probiotic/prebiotic along with a gut-healing protocol (under the diet category). Also, it would be good for a person in this situation to take an adaptogen (holy basil, reishi, rhodiola, etc) coupled with the appropriate nervine (skullcap, lemon balm, milky oats, passionflower, etc).

  8. Gwen Hill said on

    This is pure genius! I’m going to read and re-read this several times. I recognized a while back that eating sugar triggered swelling, which led to pain in my joints and muscles. Still working on the sugar cravings…

    I’m printing the tips in “basic starter kit” and posting them on my fridge so that I can incorporate them into my lifestyle. I love the idea of burst exercises! Thanks to this brilliant article, I may be poised for a breakthrough. Thank you, Dr. Brogan!

  9. Rick said on

    This is a good thread but why focus on just women? This guy brain link is just as valid for a man add it is a woman. I’m the future “when a person” would be a more inclusive way of opening the topic.

  10. Liz said on

    Rick, the article is about women’s health, as a result of taking the Pill.
    Men will definitely read the article, if they care about the health of women
    in their lives, just as I read articles on men’s health that have a “masculine”
    headline – because I care about the men in my life.
    I don’t see a need for a complex here.

  11. Neurotruth said on

    I developed soul-crushing depression, anxiety and IBS after quitting benzodiazepines last year. Been clean 11 months and still feel terrible, although it’s slowly improving.

    The gut/brain connection is freakishly strong with IBS. When I’m depressed (which is pretty much daily), I’m constipated. When a wave of anxiety hits, I immediately get diarrhea and painful gas. Oral birth control pills have helped my mood and cognition greatly, as well as my debilitating menstrual cramps. Every woman is different in that regard. Some get terrible mood swings and depression from the Pill.

    Strangely enough, my lymphocyte counts are always off the charts when my blood is taken by a doctor. I have no doubt about the inflammation/depression link, as I also suffer from autoimmune-like symptoms (chronic fatigue, joint pain, allergies, etc). These issues have been present since age 12 but got infinitely worse in the last year since quitting the benzos.

    I take ginger root and turmeric to help fight inflammation and ubiquinol to boost energy levels.

  12. nICK aNGELIS, crna, msn said on

    Love this. In anesthesia, we occasionally use Neurontin or antidepressants for chronic pain patients because all these systems work together. Using one approach or method is dangerous (and leaves these patients miserable and constipated from their narcotic dependency.)

  13. Zoloft said on

    I have taken Zoloft for the past 22 years. 100mg once a day. I have asked my doctor to help me stop and she tells me there is no reason to stop. After reading all these articles it really scares me and I need to know how to stop, what to expect and how long will it take? I want to try the holistic method with diet and exercise.

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