RHR: Revisiting the Gut-Immune Axis

In this episode we discuss:

• The role of the microbiome in immune regulation
• Intestinal permeability (“leaky gut”) and its systemic effects
• Lipopolysaccharides and chronic inflammation
• The link between gut dysfunction and chronic diseases
• “Inflammaging” and the gut’s role in aging
• How modern life disrupts gut health
• Practical strategies to support the gut-immune axis

Show notes:

• “Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review” by Di Vincenzo, F., et al.
• “Oral supplementation with bovine colostrum decreases intestinal permeability and stool concentrations of zonulin in athletes” by Haląsa, M., et al.
• “Lactoferrin reduces the risk of respiratory tract infections: a meta-analysis of randomized controlled trials” by Ali, A. S., et al.
• “Akkermansia muciniphila and gut immune system: a good friendship that attenuates inflammatory bowel disease, obesity, and diabetes” by Rodrigues, V. F., et al.
• “Aging and inflammation” by Singh, A., et al
• “Beta-glucans: a potential source for maintaining gut microbiota and the immune system” by Singh, R. P., & Bhardwaj, A.
• “The bidirectional gut-lung axis in chronic obstructive pulmonary disease” by Wang, L., et al.
• Learn more about Adapt Naturals Bio-Avail Colostrum+, Biome Protect, 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. Over the last several years, immunity has become one of the most talked about topics in health. COVID-19 forced most people to think seriously about their immune system for the first time, and the conversation hasn’t let up since. Autoimmune disease rates are climbing. Allergies and asthma affect record numbers. The recognition is growing that chronic illness is, at its root, almost always an immune problem. Yet for all the attention immunity gets, the most important piece of the puzzle is almost never discussed, either in mainstream medicine or in the broader wellness conversation. That piece is the gut.

Over my 15 years in clinical practice as a functional medicine clinician, the gut-immune axis, the dynamic bidirectional relationship between the gut and the immune system, was central to virtually everything I saw. Autoimmune disease, chronic skin conditions, recurring infections, respiratory problems, mood disorders. Underneath conditions that looked different on the surface, there was often the same underlying disruption: a gut that had been compromised by modern life, and an immune system paying the price.

The research has caught up with what functional medicine clinicians have been observing for decades. A 2023 review in the journalInternal and Emergency Medicine examined the relationship between gut microbiome disruption, intestinal permeability, and systemic disease, and found that a compromised gut barrier is connected to conditions spanning almost every organ system: obesity, fatty liver disease, neurodegeneration, cardiovascular disease, and more. This matters because mainstream medicine overwhelmingly treats these conditions as separate problems requiring separate solutions. Dermatologists treat the skin. Pulmonologists treat the lungs. Rheumatologists treat autoimmune disease. What is missed is the common thread running beneath all of them: a gut that isn’t functioning as it should, feeding a chronic immune response that drives disease across organ systems. By the end of this episode, you’ll understand what the gut-immune axis is and why it matters, what modern life is specifically doing to undermine it, which common conditions it’s driving that most people would never connect to their gut, and what the evidence says about supporting it. Let’s dive in.

What is the Gut-Immune Axis?

The gut is the largest immune organ in the human body. That surprises most people. We tend to think of immunity as something that lives in the bloodstream or maybe the lymph nodes, but roughly 70 to 80 percent of the body’s immune tissue is located in and around the gut wall. It’s called gut-associated lymphoid tissue, and its placement there isn’t accidental. The gut is where the outside world meets the inside of your body, every single day, through everything you eat, drink, and breathe. Living inside that gut is the microbiome, a vast community of trillions of microorganisms, primarily bacteria, but also viruses, fungi, and other microbes. They are not passive residents. They are active co-regulators of immune function. From the earliest days of life, gut bacteria help train the immune system to distinguish between harmless substances and genuine threats, to mount proportionate responses, and to tolerate the body’s own tissues. They produce metabolites, particularly short-chain fatty acids like butyrate, that regulate immune activity, maintain the integrity of the gut lining, and influence the immune behavior in tissues far from the gut itself. The immune system has two arms and the gut shapes both of them. The innate immune system provides rapid, non-specific responses, your first line of defense. The adaptive immune system is slower but highly specific, producing targeted responses to particular pathogens and building immunological memory. A well-functioning gut microbiome helps calibrate both arms, keeping them balanced, responsive, and proportionate. Dysbiosis, [which is] disruption of the microbial community, throws both off.

Then there’s the gut barrier itself, a single layer of epithelial cells running the full length of the digestive tract held together by proteins called tight junctions. That barrier has two jobs that have to remain in constant tension. It has to be permeable enough to absorb the nutrients your body needs and impermeable enough to keep pathogens, toxins, and bacterial byproducts out of the bloodstream. When that balance holds, everything downstream of it works. When it breaks down, a state researchers call intestinal permeability, or more commonly, leaky gut, the consequences extend far beyond the digestive tract.

This is the gut-immune axis, the continuous, bidirectional communication between the microbiome, the gut barrier, and the immune system, mediated by an elaborate network of signals, metabolites, immune cells, and molecular messengers. When the axis is functioning well, the immune system is educated, calibrated, and balanced. When it’s disrupted, you get an immune system that’s either underperforming, overreacting, or doing both simultaneously in different tissues.

The LPS Mechanism: How a Leaky Gut Drives Systemic Disease

One of the most important mechanisms through which a compromised gut damages the immune system involves a class of molecules called lipopolysaccharides, or LPS. LPS are proteins found in the outer membrane of certain bacteria that normally live in the gut. Under healthy conditions they stay there, contained within the digestive tract, never reaching the systemic circulation. But when the gut barrier becomes permeable, LPS can cross through the lining and enter the bloodstream. You can think of the gut lining as a fine mesh screen with a carefully calibrated pore size. Its job is to allow the right things through, like nutrients, water, certain small molecules, while keeping out everything that doesn’t belong in systemic circulation. Bacteria and their structural proteins are supposed to stay on the other side of that screen. When the mesh tears, bacterial proteins like LPS start crossing over. Once in the bloodstream, they trigger the immune system as if the body is under sustained attack, because in a real sense, it is. The problem isn’t a single immune response, it’s the persistence of it. If the gut barrier remains permeable, LPS keeps leaking through and the immune system keeps being triggered. That chronic low grade alarm state is what the researchers increasingly identify as a primary driver of modern inflammatory disease.

The 2023 Internal and Emergency Medicine review I mentioned in the intro mapped this process in detail, documenting how LPS translocation and sustained gut barrier disruption are connected to obesity, non-alcoholic fatty liver disease, neurodegeneration, cardiovascular disease, Type I diabetes, and inflammatory bowel disease, to name a few. On the surface, those conditions don’t look related, but they share this underlying mechanism, a gut barrier that’s letting through what it shouldn’t, and an immune system chronically mobilized in response.

A 2024 review published in Cold Spring Harbor Perspectives in Medicine expanded this picture further, examining the role of gut dysbiosis in aging itself. What researchers are now calling ‘inflammaging,’ the persistent low-grade activation of the immune system that drives age related disease and accelerates biological aging has a significant gut microbiome component. As the microbiome becomes less diverse and the gut barrier becomes more permeable over the course of a lifetime, systemic immune activation increases. The gut isn’t just relevant to digestive health, as you can see, it’s central to how quickly and how well we age.

In this episode, we break down how gut health shapes immunity, inflammation, and chronic disease—and what you can do to fix it. From microbiome science to powerful compounds like colostrum and beta glucan, this is a root-cause roadmap to better health. #ChrisKresser #immunity

Modern Life as an Assault on the Gut-Immune Axis

Modern life is, unfortunately, a near continuous assault on the gut-immune axis. Diet is the primary driver, and processed food is the main culprit. Ultra-processed foods now account for the majority of calories consumed in Western countries, and they’re, in multiple ways, destructive to the gut microbiome and the gut barrier. They’re stripped of fermentable fiber, which is the primary fuel source for beneficial gut bacteria. Without that fuel, microbial diversity declines, beneficial species lose their competitive advantage and short-chain fatty acid production, including butyrate, which maintains the gut lining, drops. Ultra-processed foods also contain emulsifiers, artificial sweeteners, and other additives that have been shown in research to degrade tight junction integrity and reduce microbial diversity independently of their effects on fiber content. High refined sugar content feeds pathogenic and inflammatory bacteria. Industrial seed oils skew the fatty acid composition of gut cell membranes in ways that affect their function. The gut microbiome evolved over hundreds of thousands of years eating whole, unprocessed food. This shift to a diet dominated by processed food happened in a few decades, not remotely enough time for any meaningful adaptation, even if such adaptation could occur to these types of foods.

Environmental toxins are a significant second factor. Pesticides, herbicides, heavy metals, and microplastics are pervasive in modern environments, and many have documented negative effects on gut microbial composition and barrier function. Glyphosate, the most widely used herbicide in the world, has been shown in research to disrupt the balance between beneficial and pathogenic gut bacteria. Heavy metals damage the epithelial lining directly. Microplastics, which I discussed in great detail on a previous episode, have now been detected in human gut tissue, blood, and even breast milk, and they’re only beginning to be studied in the context of the microbiome. But the early signs are concerning. These aren’t exposures people choose. They’re the background conditions of modern life. Antibiotic use is another major factor. Antibiotics are essential medicines, and there are situations where their use is genuinely necessary and even life saving. But decades of overuse in both human medicine and in the animals we eat have taken a measurable toll on the diversity and resilience of the human gut microbiome. A single course of broad-spectrum antibiotics can disrupt microbial diversity for months, and in [the] case of some studies, perhaps permanently. Multiple courses over a lifetime can cause disruptions that are difficult or impossible to fully reverse. This is not an argument against antibiotic use when it’s needed. It’s an argument for understanding the cost and taking active steps to support microbiome recovery afterward.

Chronic stress is another factor. The gut and the brain are in continuous communication through the enteric nervous system, the vagus nerve, and the hypothalamic-pituitary-adrenal axis, or HPA axis. Chronic psychological stress activates this system in ways that directly increase gut permeability, shift microbial composition toward dysbiosis, and impair immune regulation. In acute situations, the stress response serves a purpose. Chronically activated, it degrades the gut-immune axis from the inside. What makes this particularly difficult is that these factors compound each other. Processed food, environmental toxins, antibiotics, and chronic stress aren’t four separate problems. They’re a mutually reinforcing assault on the same underlying system. And for most people in the modern world, some combination of them is simply the baseline.

The Conditions Hiding Gut-Immune Axis Problems

Over my years in clinical practice, one of the patterns I noticed most consistently was how many conditions patients have been told were unrelated to their gut, but were, in my assessment, fundamentally gut-immune axis problems. Autoimmune disease is the most important category. The rates of autoimmune disease have been climbing steadily for decades across virtually every condition in the category. No single factor fully explains the trend, but the disruption of the gut-immune axis is central to it. The mechanism goes back to immune education. A healthy, diverse gut microbiome teaches the immune system to tolerate harmless antigens, including the body’s own tissues. When the microbiome is disrupted and the gut barrier becomes permeable, that calibration breaks down. The immune system becomes poorly regulated, and in some people, it begins mounting responses against the body’s own cells. Rheumatoid arthritis, Hashimoto’s, thyroiditis, multiple sclerosis, lupus, inflammatory bowel disease – the research linking these conditions to gut dysbiosis and intestinal permeability has grown substantially.

A 2022 review in Frontiers in Immunology specifically examined how shifts in gut microbiome composition, particularly lots of the beneficial mucosal bacteria like Akkermansia muciniphila, are associated with the development and progression of IBD, obesity, and Type II diabetes. Skin conditions follow the same logic. Acne, eczema, and psoriasis are consistently treated in mainstream medicine as localized skin problems managed with topical treatments, antibiotics, or immune-suppressing medications that address the surface manifestation without touching the underlying driver. The gut-skin axis, the bidirectional relationship between intestinal health and skin health, is well-established in the research literature. Dysbiosis, intestinal permeability, and the LPS-driven immune activation we discussed earlier all show up at elevated rates in people with chronic skin conditions. In my clinical experience, addressing the gut often produced improvements in skin health that years of topical treatment had not achieved.

The gut-lung axis deserves more attention than it typically gets. The gut-immune axis shapes respiratory immune function in ways that are only beginning to be widely appreciated. Asthma, chronic rhinitis, and vulnerability to respiratory infections have all been linked to gut dysbiosis in the research. A 2023 review in The American Journal of Respiratory and Critical Care documented the bidirectional gut-lung relationship in chronic obstructive pulmonary disease, finding that gut microbial disruption and the systemic immune activation that it produces contribute meaningfully to respiratory outcomes. The lungs in the gut are not isolated organ systems. They share an immune regulatory network, and dysfunction in one affects the other. COVID-19 brought this into unusually clear focus. SARS-CoV-2 disrupts the gut microbiome significantly, and the research suggests that disruption contributed to many of the downstream effects of the disease, including some of the persistent symptoms associated with long COVID. People with healthier, more diverse gut microbiomes tended to have better outcomes from acute infection. Those with pre-existing gut dysbiosis were more vulnerable to severe disease and slower recovery. This is not a fringe hypothesis. It’s supported by multiple lines of evidence, and illustrates precisely why the gut-immune axis matters in the real world. Your gut health isn’t just relevant to your digestion, it shapes your immune response to every pathogen you encounter.

What Mainstream Medicine Misses

The science on the gut-immune axis isn’t new, and it isn’t obscure. Researchers have been documenting the relationship between gut microbiome disruption, intestinal permeability, and systemic disease for decades. The evidence base is now substantial, spanning immunology, gastroneurology, neuroscience, cardiology, and dermatology, yet the gut-immune axis is almost never discussed in standard clinical practice. The structural reason is that mainstream medicine is organized around organ systems and specialties. That structure makes it highly effective at treating individual conditions in isolation, but poorly suited to identifying the root causes that span multiple organ systems. The gut-immune connection that links autoimmune disease, skin conditions, respiratory problems, and metabolic disease doesn’t fit neatly into any single specialty, so it tends to fall through the cracks of the system. There’s also the nature of the problem itself. The LPS-driven immune activation that drives chronic disease doesn’t announce itself with dramatic, acute symptoms. It produces a slow, diffused degradation of immune regulation that becomes visible only years or decades later when it manifests as a diagnosable condition. By the time a patient receives an autoimmune diagnosis or develops a chronic skin condition that dermatologists can no longer manage with topical treatment, the underlying gut dysfunction driving it may have been present for a very long time. Conventional medicine is built to respond at the point of diagnosis. Functional medicine starts further upstream, at the point of origin, and that’s where the gut-immune axis lives.

Supporting the Gut-Immune Axis

The same research that documents how the gut-immune axis breaks down also points clearly toward what supports it. Diet is, not surprisingly, the foundation. No supplement strategy compensates for a diet that chronically disrupts the gut microbiome, and the most impactful thing most people can do for their gut-immune axis is change what they eat. Whole, unprocessed, nutrient-dense foods are the baseline. Diversity matters. A wide variety of plant foods supports microbial diversity, which is one of the most reliable markers of gut-immune health. Fermented foods like yogurt, kefir, kimchi, sauerkraut, and kombucha provide beneficial probiotic bacteria, and have been shown in research to directly increase microbial diversity. Bone broth provides collagen and amino acids like glycine and proline that support the integrity of the gut lining. Fiber-rich foods like vegetables, fruits, legumes, and tubers provide the fermentable fuel that beneficial gut bacteria need to thrive and produce the short-chain fatty acids that regulate immune function. Eliminating ultra-processed food is, in my view, the highest leverage dietary change most people can make for their gut health. It’s not the easiest change, but the evidence for it is overwhelming.

Beyond diet, several specific nutrients and functional food compounds address the gut-immune axis in ways that are well supported by the research. Probiotics and prebiotics are foundational. Probiotic bacteria from fermented foods or quality supplements help maintain microbial diversity, train the immune system, and regulate the inflammatory response. Prebiotics are the fermentable fibers that feed those bacteria, or more recently, bacteriophages that crowd out harmful bacteria and allow beneficial bacteria to proliferate. Without adequate prebiotic support, probiotics can’t do much because the bacteria have nothing to sustain them or protect them. Postbiotics, particularly butyrate and its precursors, are a category that deserves more attention than it typically gets. Butyrate is the short-chain fatty acid produced when gut bacteria ferment fiber, and it’s the primary energy source for the cells that line the gut wall. It plays a direct role in maintaining tight junction integrity and regulating immune function at the gut barrier. When diet alone is insufficient to produce adequate butyrate levels, tributyrin, a stable, highly bioavailable form of butyrate, is the most direct way to support gut barrier function. Polyphenols, found in foods like berries, pomegranate, grape seeds, and dark chocolate, act as selective prebiotics, feeding beneficial gut bacteria while also providing direct antioxidant support to the gut lining. They’re also underappreciated as a gut health intervention, partly because their mechanism isn’t as intuitive as probiotics, but the evidence for their effects on microbial composition is already solid and growing every day.

Colostrum is one of the most well-studied tools available for supporting gut barrier integrity specifically. It’s the nutrient-rich fluid that female mammals produce in the first days after birth, and it’s the first food every mammal on the planet has received for over 200 million years of mammalian evolution. Its primary effect on the gut is structural. It seals the gut barrier. It contains immunoglobulins, growth factors, lactoferrin, and other bioactive compounds that repair and reinforce the gut lining, support tight junction integrity and promote a balanced immune response. A 2017 randomized controlled trial found that colostrum supplementation measurably decreases intestinal permeability and improves zonulin levels, a validated marker of gut barrier function. The research supporting these effects used at least two grams per day, and many products on the market contain significantly less than that. Lactoferrin, a glycoprotein found in colostrum and other mammalian secretions, has several relevant mechanisms. It sequesters iron in the gut, depriving pathogenic bacteria of a key nutrient they need to proliferate, it has direct antimicrobial properties against a wide range of bacteria, viruses, and fungi, and it supports the gut’s immune regulation, helping the immune system mount calibrated rather than excessive responses to potential threats. A meta-analysis of randomized controlled trials found that lactoferrin supplementation significantly reduced the risk of developing respiratory tract infections, a reminder that gut-targeted interventions have systemic immune effects.

Beta-glucan, particularly the high-branching forms derived from yeast, has a property that distinguishes it from almost every other immune supporting compound. It trains the innate immune system. Not suppresses it, not globally stimulates it. Trains it. Beta-glucan binds to receptors on innate immune cells and primes them to respond more quickly and efficiently when they encounter an actual pathogen. Researchers describe this as ‘trained immunity,’ and it’s a mechanism with very few parallels in the natural world. It’s one of the reasons I’ve become increasingly enthusiastic about beta-glucan over the past several years, both personally and as a clinical tool. These ingredients address the gut-immune axis at multiple levels: the microbiome, the gut barrier, and the immune response itself. The right combination for any individual depends on their specific situation, and working with a practitioner who understands this territory is worthwhile if you’re dealing with significant immune or gut health challenges.

What I keep coming back to, looking at the research and reflecting on my years in practice, is that the gut-immune axis isn’t a niche concept. It’s a description of how the body fundamentally works. The immune system can’t function well if the gut isn’t functioning well. That relationship is as basic as any in human physiology, and understanding it gives you a different kind of leverage over your health. Not a new supplement to chase, necessarily, but a root cause framework that makes sense of conditions that otherwise seem disconnected and unmanageable. The evidence is there. It’s substantial and growing. What’s needed now is for it to reach the people who need it, the patient sitting in doctors’ offices being prescribed their fourth course of antibiotics or their third autoimmune medication who’ve never once had a conversation about their gut. That’s what I’m hoping this episode contributes to, even in a small way.

Thanks for listening. You can find show notes and links to all of the studies I mentioned at ChrisKresser.com. You can find my line of clinical grade evidence-based supplements at AdaptNaturals.com. If you have questions about this episode or suggestions for future topics, head over to ChrisKresser.com/podcastquestion and leave me a message. I read all of them, and your questions help shape the content I create. Until next time, be well.