How Your Microbiome Affects Your Mental Health

In this episode we discuss:

• Why the “chemical imbalance” theory of depression falls short
• The immune–cytokine model of depression
• How gut inflammation and intestinal permeability affect the brain
• The role of butyrate in reducing inflammation and increasing BDNF
• New research on probiotics and mental health outcomes
• Why probiotic strain specificity matters
• Bacillus coagulans and its dual gut–brain benefits
• Diet, supplementation, and functional testing strategies
• How gut-focused care can complement—not replace—conventional treatment

Show notes:

• “So depression is an inflammatory disease, but where does the inflammation come from?” by Berk, M., et al.
• “Anxiolytic- and antidepressant-like effects of Bacillus coagulans Unique IS-2 mediate via reshaping of microbiome gut-brain axis in rats” by Satti, S., et al.
• “Immune dysregulation in depression and anxiety: A review of the immune response in disease and treatment” by Hole, C., et al.
• “From gut to glee: Is butyrate a promising antidepressant? A systematic review and mechanistic insights” by Korenblik, V., et al.
• “Impacts of inflammatory cytokines on depression: A cohort study” by Liu, F., et al.
• “Bacillus coagulans MTCC 5856 for the management of major depression with irritable bowel syndrome: A randomised, double-blind, placebo controlled, multi-centre, pilot clinical study” by Majeed, M., et al.
• “Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression” by Miller, A. H., Maletic, V., & Raison, C. L.
• “Acceptability, tolerability, and estimates of putative treatment effects of probiotics as adjunctive treatment in patients with depression: A randomized clinical trial” by Nikolova, V. L., et al.
• “Exploring the mechanisms of action of probiotics in depression: Results from a randomized controlled pilot trial” by Nikolova, V. L., et al.
• “Clinical, gut microbial and neural effects of a probiotic add-on therapy in depressed patients: A randomized controlled trial” by Schaub, A. C., et al.
• “Exploring role of Bacillus coagulans BCP92™ (MTCC 25460) in modulation of depressive-like behavior: Unraveling microbiome gut-brain axis” by Shaikh, S. S., et al.
• “Add-on probiotics for inflammatory depression: A double-blind randomized placebo-controlled trial” by Söderberg Veibäck, G., et al.
• “Association of inflammation cytokines with cognitive function in first-episode major depressive disorder” by Xi, Y. Q., et al.
• “Bacillus coagulans and Clostridium butyricum synergistically alleviate depression in a chronic unpredictable mild stress mouse model through altering gut microbiota and prefrontal cortex gene expression” by Xu, J., et al.
• Learn more about Adapt Naturals Biome Protect, Core Plus bundle, or take our quiz to see which products best suit your needs
• If you’d like to ask a question for Chris to answer in a future episode, submit it here
• Follow Chris on Instagram or Facebook

Hey everybody, Chris Kresser here. Welcome to another episode of Revolution Health Radio. If you’ve struggled with depression or anxiety, you’ve probably been told it’s a chemical imbalance in your brain. Maybe you’ve been prescribed an SSRI or another antidepressant. Maybe it helped, maybe it didn’t, or maybe it came with side effects that made you wonder if there had to be a better way.

What if I told you that your gut health, the trillions of bacteria living in your digestive tract, might be playing a bigger role in your mood than the serotonin levels in your brain? This isn’t just speculation or wishful thinking. We now have robust scientific evidence showing that the gut and the brain are in constant communication with what’s called the microbiota-gut-brain axis, and that disruptions in gut health, particularly inflammation originating in the gut, can directly contribute to depression and anxiety. In fact, a brand new systematic review just published last month in Brain, Behavior, and Immunity examined whether butyrate, a compound produced by beneficial gut bacteria, could work as an antidepressant. The researchers analyzed 32 animal studies and two human trials, and the findings are compelling. I’ve been researching and treating patients with mood disorders for 20 years, and I can tell you both from clinical experience and the growing body of studies that addressing gut health is one of the most powerful interventions we have for mental health. We have a saying in functional medicine– fire in the gut, fire in the brain. When someone comes to me with depression, anxiety, or another mood issue, the first thing I do is test their gut health. I’ve seen hundreds of patients experience dramatic improvements in mood when we fix their digestive issues.

By the end of this episode, you’ll understand how your gut microbiome communicates with your brain, why inflammation is the critical link between gut dysfunction and depression, what the latest research tells us about butyrate and probiotics for mental health, and most importantly, what you can do about it. Let’s dive in.

Chemical Imbalance Theory vs Immune–Cytokine Model

Let’s start with a question that challenges everything we’ve been told about depression. What if depression isn’t primarily a disease of neurotransmitter deficiency, but rather a symptom of chronic inflammation? The chemical imbalance theory, the idea that depression is caused by low serotonin or norepinephrine, has dominated psychiatry for decades. It’s what justifies prescribing SSRIs to millions of people. But here’s the problem with that theory. When researchers reduce levels of serotonin and norepinephrine in humans, it doesn’t produce depression. Only about 25 percent of depressed patients have low levels of these neurotransmitters, and some people with no history of depression have low levels of them. Even more confusingly, some depressed patients have abnormally high levels of serotonin and norepinephrine. What does reliably correlate with depression is inflammation. Back in the early 80s, researchers discovered that inflammatory cytokines, these signaling molecules your immune system produces, create all of the characteristic symptoms of depression when administered to healthy people. A paper published in the Journal of Affective Disorders found that administering endotoxins that provoke inflammation to healthy volunteers triggers classic depressive symptoms. About one-quarter of patients taking interferon, a medication used to treat hepatitis C that causes significant inflammation, developed major depression during treatment. This led to what’s called the immune cytokine model of depression, which holds that depression is not a disease itself, but a multi-faceted sign of chronic immune system activation. To put it plainly, depression may be a symptom of chronic inflammation.

A 2024 cohort study published in BMC Psychiatry tracked 82 depressed patients for three months and found that those with high levels of interleukin-1 beta, one of these inflammatory cytokines, had significantly more severe depressive symptoms at months two and three. Patients with high levels of tumor necrosis factor alpha, or TNF-alpha, had more than double the risk of suicidal ideation and behavior. A 2025 study in Frontiers in Psychiatry examined patients with first-episode major depressive disorder, and found elevated levels of IL-6 and TNF-alpha compared to healthy controls. These aren’t obscure findings from fringe journals. This is mainstream psychiatry research showing us that inflammation and depression are intimately connected.

The Gut as Your “Second Brain”

Okay, so if inflammation drives depression, where is that inflammation coming from? This is where the gut comes into play. Many researchers and clinicians consider the gut the second brain. It’s an extension of the nervous system and thus directly influences mood and cognition. Your gut is home to trillions of bacteria, fungi, and other microorganisms that produce compounds affecting everything from immune function to neurotransmitter production. When this ecosystem is disrupted through things like poor diet, chronic stress, antibiotics, or other factors, it can trigger a cascade of inflammatory responses that reach your brain. Think of inflammatory cytokines like messengers carrying urgent warnings throughout your body. When your gut barrier becomes permeable, also known as leaky gut, bacterial endotoxins like lipopolysaccharide escape into your bloodstream. Your immune system detects these invaders and responds by releasing cytokines like TNF-alpha, interleukin-1 beta and interleukin-6. These molecules travel through your bloodstream and can cross into your brain, where they alter neurotransmitter function, reduce the production of brain-derived neurotrophic factor, or BDNF, which is critical for neuroplasticity, and dysregulate your stress response system.

Studies have consistently shown that people with depression have higher intestinal permeability compared to healthy individuals. A review in PMC documented that patients with major depressive disorder show elevated gut barrier dysfunction markers, and numerous studies have linked unfavorable changes in gut bacteria composition with major depressive disorder. The connection isn’t theoretical. It’s measurable and reproducible across multiple research groups.

I have my own personal experience with this. When I got very sick in my 20s with a digestive illness after traveling in Indonesia, I struggled with depression and mood issues for the first time in my life. It was profound and frightening. Since healing from those GI problems, I haven’t struggled with depression again. That personal experience, combined with treating hundreds of patients with both GI and mood issues and watching their mood improve when we fix their gut, has reinforced my confidence in this approach.

Emerging research shows inflammation, gut bacteria, and compounds like butyrate play a major role in mood and mental health. In this episode, Chris explains how healing the gut can support the brain—and why probiotics and diet matter more than we’ve been told #ChrisKresser #mentalhealth #guthealth

The Role of Butyrate

And here’s where the story gets even more interesting. Your gut bacteria don’t just sit there. They’re metabolically active, fermenting the fiber you eat and producing short-chain fatty acids. The most important of these is butyrate. Butyrate serves as the primary energy source for the cells lining your colon, but it does far more than that. It strengthens your intestinal barrier, reduces inflammation, and can even cross into your brain where it acts as an epigenetic regulator, meaning it can turn genes on and off. This matters enormously for mental health, because butyrate increases the expression of BDNF particularly in the hippocampus and prefrontal cortex, brain regions central to mood regulation. The systematic review I mentioned earlier, published in December 2025 by Korenblik and colleagues, examined whether direct butyrate supplementation could alleviate depressive symptoms. They analyzed 32 animal studies and found that butyrate consistently reduced depressive and anxiety-like behaviors across diverse rodent models. The mechanisms they identified include anti-inflammatory effects, restoration of gut barrier integrity, increased BDNF expression, and epigenetic modulation through inhibition of histone deacetylases.

The human data is more limited but encouraging. One randomized controlled trial gave patients with ulcerative colitis 600 milligrams of sodium butyrate daily for 12 weeks and found significant reductions in both depression and anxiety scores compared to placebo. Another trial in healthy males found no effects after just one week, which makes sense. You need time for these interventions to work, and healthy people have less room for improvement. The researchers concluded that butyrate shows therapeutic promise as a novel intervention for depression and warrants further clinical investigation. What’s particularly interesting is that people with depression often have reduced levels of butyrate-producing bacteria in their gut. Studies have found lower fecal butyrate in young psychiatric patients with depressive symptoms, and a recent 2025 study reported lower plasma butyrate levels in patients with major depressive disorder. This suggests a vicious cycle where gut dysbiosis reduces butyrate production, which in turn increases inflammation and gut permeability, further disrupting the gut microbiome. If low butyrate and disrupted gut bacteria contribute to depression, the logical question is whether probiotics, the beneficial bacteria we can supplement with, can help. The research here is growing rapidly.

New Research on Probiotics and Why Strain Specificity Matters

A 2022 randomized controlled trial published in Translational Psychiatry gave patients with current depressive episodes either a multi-strain probiotic or placebo for 31 days in addition to their usual treatment. The probiotic group showed greater reductions in Hamilton Depression Rating Scale scores, and when researchers analyzed the gut microbiome, they found that probiotics maintained microbial diversity and increased the abundance of Lactobacillus. This increase in Lactobacillus correlated with a decrease in depressive symptoms. Brain imaging revealed that the probiotic intervention also altered brain activity, specifically decreasing activation in the putamen in response to neutral faces, suggesting altered emotional processing.

A 2023 study in JAMA Psychiatry evaluated probiotics as adjunctive treatment for major depressive disorder and found them tolerable and showing promising effect sizes. And a follow-up study published in 2025 found that probiotics increased gut microbiome richness and normalized diversity compared to placebo. Multiple meta-analyses from 2024 and 2025 have confirmed that specific probiotic strains, particularly those containing Lactobacillus and Bifidobacterium species, produced small but significant reductions in depression scores.

Here’s something critical to understand. Not all probiotics are created equal. Strain matters enormously. A 2024 meta analysis in gut pathogens analyzed 12 randomized controlled trials and found that probiotics containing specific strains like Lactobacillus acidophilus, Bifidobacterium bifidum and Bacillus coagulans showed significant decreases in depressive symptoms. When they looked at Lactobacillus alone without other strains, there was no effect. But combinations or single strains like Bacillus coagulans did show benefits. Which brings me to Bacillus coagulans specifically. This is a spore-forming probiotic that’s particularly interesting for mental health. A 2018 pilot clinical trial published in Food and Nutrition Research studied 40 patients with both major depressive disorder and irritable bowel syndrome. They gave half the patients Bacillus coagulans MTCC 5856, which is a specific type of Bacillus coagulans, at a dose of 2 billion CFU daily for 90 days. The results showed significant improvements on every depression measure they used. The Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale and Center for Epidemiologic Studies Depression Scale. Quality of life improved, sleep quality improved, and myeloperoxidase, an inflammatory biomarker, decreased significantly.

The animal research on Bacillus coagulans backs us up. A 2024 study in Frontiers in Pharmacology found that combining Bacillus coagulans with Clostridium butyricum in mice with chronic unpredictable mild stress improved depressive-like behaviors, increased serotonin in the prefrontal cortex, decreased stress hormones and altered gut microbiota composition. A 2025 study published just a few months ago in Behavioral Brain Research showed that Bacillus coagulans reduced inflammatory markers like C-reactive protein, TNF-alpha, and interleukin-1 beta in the brain while increasing BDNF and restoring short-chain fatty acid production including butyrate, acetate, and propionate. What makes Bacillus coagulans particularly useful is that it’s a spore-forming bacterium, which means it can survive stomach acid and reach your intestines intact. It also produces butyrate, which as we discussed, has direct antidepressant effects. This is a case where the probiotic itself is beneficial, and the metabolites it produces are beneficial. You’re getting a two-for-one effect.

I want to be clear about expectations here because I think this is where a lot of people get frustrated with gut health interventions. This is not like taking a benzodiazepine for anxiety, where you feel the effect within an hour. Interventions that improve gut health take time, typically a couple of months, to reduce intestinal permeability, calm inflammation, and restore a healthy microbiome. The clinical trials I mentioned used protocols ranging from four to 12 weeks, and some showed effects earlier than others. In my clinical practice, I generally told patients to commit to a gut health protocol for at least eight to 12 weeks before evaluating whether it’s working. This isn’t instant gratification, but it can produce real and lasting results that address root causes rather than just masking symptoms. It’s also important to understand that not all depression is gut-related. I don’t want to be too reductionist here. There are situational causes of depression, losing a loved one, going through a divorce, experiencing trauma, and there are other biological and physiological factors beyond gut health that can contribute. Some people will need multiple interventions, and addressing situational factors through therapy or other means is often necessary as well. A holistic approach is typically best when it comes to mental health and mood disorders. That said, the research is clear that for many people, particularly those with coexisting digestive issues, addressing gut health can be transformative.

A 2025 study, specifically targeting patients with inflammatory depression, those with major depressive disorder, elevated BMI, and high C-reactive protein, is testing whether Lactobacillus reuteri can improve outcomes. This precision medicine approach, identifying which patients are most likely to respond based on their inflammatory profile, represents where the field is heading.

Let me walk you through what’s happening in your body when gut inflammation triggers depression. This will help you understand why the interventions I’m about to recommend work. Your gut bacteria ferment the fiber you eat and produce short-chain fatty acids, primarily acetate, propionate, and butyrate. These compounds don’t just stay in your gut. Butyrate gets absorbed by your intestinal cells and provides about 70 percent of their energy. Some butyrate enters your bloodstream and can cross the blood-brain barrier. Once in your brain, butyrate inhibits enzymes called histone deacetylases, which changes how tightly your DNA is packaged and makes certain genes more accessible for transcription. One of the key genes that butyrate upregulates is BDNF. Studies from the butyrate systematic review showed that both oral and systemic butyrate administration increased BDNF gene expression in the hippocampus and prefrontal cortex and elevated BDNF protein levels across multiple brain regions. This matters because BDNF is essential for neuroplasticity, the brain’s ability to form new connections and adapt to stress. People with depression often have reduced BDNF and many antidepressants work in part by increasing BDNF signaling. At the same time, butyrate reduces inflammation. The study showed that butyrate reverse stress-induced elevations in pro-inflammatory cytokines like TNF-alpha, interleukin-1 beta, and interleukin-6 in blood, intestinal tissue, and brain regions, including the prefrontal cortex and hippocampus. It also increased anti-inflammatory cytokines like interleukin-4 and interleukin-10. The Bacillus coagulans studies I mentioned found similar effects, reductions in C-reactive protein, TNF-alpha and interleukin-1 beta in brain tissue.

Butyrate also strengthens your intestinal barrier by upregulating tight junction proteins like zonulin-1, claudin, and occludin. When your gut barrier is intact, fewer bacterial endotoxins will leak into your bloodstream, which means less systemic inflammation, which in turn, means less neuroinflammation, which means better mood. It’s a positive feedback loop working in your favor. Unfortunately, most people struggling with depression never get this information. The medical system is fragmented in a way that prevents holistic treatment. If you’re experiencing depression or a mood issue, you go to your primary care provider and maybe get a referral to a psychologist or a psychiatrist. It’s almost unheard of for a primary care doctor to refer someone with depression to a gastroenterologist or to order comprehensive stool testing. This fragmentation means a lot of people won’t get the treatment they need. We also have an over reliance on SSRIs, despite their underwhelming results in the scientific literature. About 50 percent of patients with major depressive disorder don’t respond adequately to antidepressant drugs, and many who do experience significant side effects. Between 30 and 40 percent of patients who suffer from major depressive disorder never achieve symptom resolution with standard antidepressant treatment. This all comes back to the lack of root cause investigation. Functional medicine offers something different. We start by asking why someone is depressed rather than just treating the symptom. When we investigate and find gut dysbiosis, SIBO, increased intestinal permeability, or chronic inflammation, we have specific, evidence-based interventions we can use that address those underlying problems.

Diet, Supplementation, and Functional Testing Strategies

So what can you do if you’re struggling with depression or anxiety and want to investigate whether gut health is playing a role? Let me give you a practical hierarchy of interventions. First, focus on your diet. This is foundational. Eliminate or greatly reduce ultra-processed foods and focus on a nutrient-dense whole food diet. The research is clear that ultra-processed foods are associated with cardiovascular disease, diabetes, and many other health conditions, and these foods often trigger inflammation, not because of any single ingredient but because of the combination of additives, sugar, refined carbohydrates, oxidized fats, and overall nutrient profile. Within that whole food framework, prioritize foods that directly support gut health. Fermented foods like kefir, sauerkraut, kimchi, and other traditionally fermented vegetables provide beneficial bacteria and can help restore microbial diversity. Bone broth is rich in glycine and other amino acids that support intestinal barrier integrity. Consume fermentable fibers from vegetables, fruits, nuts, seeds, and properly prepared legumes and whole grains if you tolerate them. These fibers feed your beneficial gut bacteria and support the production of butyrate.

Second, consider targeted supplementation. The research suggests that a comprehensive approach combining prebiotics, probiotics, postbiotics like butyrate, and polyphenols may be the most effective. Prebiotics feed beneficial bacteria and eliminate harmful bacteria. Probiotics introduce new beneficial strains. Postbiotics like butyrate provide direct benefits, and polyphenols from sources like berries, pomegranate, and grapes have anti-inflammatory and gut microbiome modulating effects. This is one of the reasons I formulated Biome Protect with a four-in-one approach. It contains CoreBiome tributyrin, which is a highly bioavailable form of butyrate that maximizes absorption. It includes LactoSpore Bacillus coagulans at 2 billion CFU, the same strain and dose used in the clinical trial I mentioned showing improvements in mood. It also has FortiPhage, a next generation prebiotic that works at a much lower dose than traditional fiber-based prebiotics without the digestive side effects, and a polyphenol blend from cranberry, blueberry, pomegranate, and grape that supports both gut health and cognitive function. The formulation is shelf-stable so you don’t need to refrigerate it, which makes it practical for daily use. If you want to learn more about Biome Protect you can visit AdaptNaturals.com.

Now, if you implement these dietary changes and take targeted supplements for eight to 12 weeks and don’t see improvement in your gut health or mood, then it’s time to consider functional testing. This might include testing for SIBO, small intestinal bacterial overgrowth, comprehensive stool analysis to evaluate your microbiome composition and look for parasites or fungal overgrowth, and organic acids testing to assess metabolic markers related to gut health. Working with a qualified functional medicine practitioner can help you interpret these tests and create a personalized protocol. Sometimes you need more targeted interventions, antimicrobial herbs for SIBO, specific probiotics for particular imbalances, or gut healing protocols for severe intestinal permeability. The testing gives you a roadmap.

I want to step back and look at the bigger picture here. What frustrates me most about how mainstream medicine approaches depression is the lack of curiosity about underlying causes. Someone presents with depression, they get an SSRI prescription, and that’s often the end of the investigation. But depression, as we’ve seen, like fever or fatigue, is a symptom. It’s your body telling you something is wrong. Sometimes that something is situational stress or trauma and therapy is the right intervention. But often there are physiological drivers, inflammation, gut dysfunction, nutrient deficiencies, hormonal imbalances, chronic infections that need to be identified and addressed. The research on the gut-brain axis gives us a framework for investigation. We can measure inflammatory markers, we can assess gut barrier function, we can analyze the microbiome composition, we can measure butyrate levels. These aren’t esoteric tests. They’re becoming more available and affordable, and they can guide treatment in a way that the chemical imbalance theory never could because that theory was never based on solid evidence to begin with. A 2025 review in PMC examining immune dysregulation in depression and anxiety concluded that emerging research highlights the significant role of inflammation and psychiatric disorders and that immune dysfunction, cytokine activity, and neurotransmitter interactions all contribute to these conditions. The review emphasized that while current treatments primarily target neurotransmitter imbalances, many patients don’t achieve symptom resolution, highlighting the need for new approaches that address inflammation and immune function.

All right, let’s bring this together. Here’s what I want you to take away from this episode. First, depression is not simply a chemical imbalance that requires lifelong medication to manage. For many people, it’s a symptom of chronic inflammation, and that inflammation often originates in the gut. The research showing that inflammatory cytokines produce depressive symptoms, that people with depression have elevated inflammation markers, and that reducing inflammation improves mood is robust and growing. Second, your gut microbiome produces compounds, particularly butyrate, that directly affect brain function, mood, and stress resilience. New research from December 2025 shows that butyrate supplementation has antidepressant potential through multiple mechanisms including reducing inflammation, increasing BDNF, and strengthening the gut barrier. Specific probiotic strains, including Bacillus coagulans, have shown benefits in human clinical trials for major depressive disorder. Third, you have practical tools you can start using today. Focus on a nutrient-dense whole food diet, eliminate ultra-processed foods, consume fermented foods and bone broth, eat plenty of fermentable fiber, and consider comprehensive supplementation with prebiotics, postbiotics, probiotics, and polyphenols. Give these interventions time to work, at least eight to 12 weeks. If you don’t see results, pursue functional testing to identify specific gut issues that need targeted treatment.

Now I want to be clear, this doesn’t mean you should stop taking antidepressant medication if it’s working for you. Any changes to psychiatric medication should be done under strict medical supervision. There is a significant risk to abruptly stopping SSRIs and other psychiatric drugs, and I’ve seen really bad things happen when patients do this without supervision. So it’s really important to work with your doctor, or even find another doctor that specializes in withdrawing people from antidepressants and psychiatric meds. And the longer you’ve been taking these meds, the more important it is to move slowly, because the brain becomes habituated to these medications and if you take them away quickly, it can lead to rebound depression and even suicidal ideation and suicide. So it’s not something to trifle with. And I want to be very clear that if you make any changes to your antidepressant medication, you should do that with appropriate medical supervision. What we’re talking about here is an additional avenue for investigation and treatment, one that addresses root causes and can work alongside conventional care or, in some cases, reduce or eliminate the need for medication over time.

The fragmented medical system means that most people with mood disorders never have their gut health evaluated. You may need to advocate for yourself, educate your providers, or work with a functional medicine practitioner who understands these connections. But the science is there, the clinical evidence is accumulating, and the interventions are accessible. These are tools you can use to take control of your health.

Thanks for listening. You can find the show notes and links to all the studies I mentioned at ChrisKresser.com. If you have questions about anything we discussed, head over to ChrisKresser.com/podcastquestion, and we’ll try to answer your question on a future episode. You can also visit AdaptNaturals.com for a wide range of supplements that can support your mood and overall health. If you enjoyed this episode, please share it with someone you think would benefit. I’ll talk to you next time.