RHR: The Gut-Immune Axis

In this episode, we discuss:

• What is the “gut–immune axis”?
• The five pillars for supporting the gut–immune axis
• Why you should care about the gut–immune axis
• Dietary strategies for supporting the gut–immune axis
• Key nutrients and superfoods for the gut–immune axis, including probiotics, prebiotics, colostrum, lactoferrin, and beta-glucans
• The role each of these plays in supporting the gut–immune axis
• Dietary sources of colostrum, lactoferrin, and beta-glucans and considerations for supplementation

Show notes:

• “Oral Supplementation with Bovine Colostrum Decreases Intestinal Permeability and Stool Concentrations of Zonulin in Athletes” by Hałasa et al
• “Potential use of Colostrum Bovinum supplementation in athletes – A review” by N. Główka and M. Woźniewicz
• “Effects of Bovine Immunoglobulins on Immune Function, Allergy, and Infection” by Ulfman et al
• “Flood Control: How Milk-Derived Extracellular Vesicles Can Help to Improve the Intestinal Barrier Function and Break the Gut-Joint Axis in Rheumatoid Arthritis” by Aarts et al
• “Lactoferrin reduces the risk of respiratory tract infections: A meta-analysis of randomized controlled trials” by Ali et al
• “Can Lactoferrin, a Natural Mammalian Milk Protein, Assist in the Battle against COVID-19?” by Einerhand et al
• “Lactoferrin as Antiviral Treatment in COVID-19 Management: Preliminary Evidence” by Campione et al
• “Bovine Lactoferrin Induces Cell Death in Human Prostate Cancer Cells” by Rocha et al
• “Lactoferrin Alleviates Inflammation and Regulates Gut Microbiota Composition in H5N1-Infected Mice” by Huang et al
• “The Effect of Nutritional Intervention with Lactoferrin, Galactooligosacharides and Vitamin D on the Gut Microbiota Composition of Healthy Elderly Women” by Konstanti et al
• “The Functional Role of Lactoferrin in Intestine Mucosal Immune System and Inflammatory Bowel Disease” by Liu et al
• “Training innate immunity: the changing concept of immunological memory in innate host defence” by M.G. Netea
• “β-glucans: a potential source for maintaining gut microbiota and the immune system” by R.P. Singh and A. Bhardwaj
• “Efficacy of orally administered superfine dispersed lentinan (beta-1,3-glucan) for the treatment of advanced colorectal cancer” by Hazama et al
• “β-Glucan produced by Lentinus edodes suppresses breast cancer progression via the inhibition of macrophage M2 polarization by integrating autophagy and inflammatory signals” by Zhu et al
• “Variants of beta-glucan polysaccharides downregulate autoimmune inflammation” by Fahlquist-Hagert et al
• “Can a β-glucan-containing orthomolecular agent (Saccharomyces sp.) containing metabolic cofactors attenuate cytokine activation and alleviate hypoxia in COVID-19 patients?” by Saganelidze et al
• “β-1,3/1,6-Glucans and Immunity: State of the Art and Future Directions” by E. De Marco Castro, P.C. Calder, and H.M. Roche
• “Yeast-Derived Beta 1,3/1,6 Glucan, Upper Respiratory Tract Infection and Innate Immunity in Older Adults” by Fuller et al
• “Effects of an Immunomodulating Supplement on Upper Respiratory Tract Infection Symptoms in Wildland Firefighters” by S.G. Harger-Domitrovich, J.W. Domitrovich, and B.C. Ruby
• Edible mushrooms: an ancient remedy rediscovered by modern science blog post by Chris Kresser
• “RHR: The Nutritional and Therapeutic Health Benefits of Mushrooms, with Jeff Chilton” podcast episode
• Learn more about the Adapt Naturals Core Plus bundle or take our quiz to see which individual 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 Twitter, Instagram, or Facebook
• Get your free LMNT Recharge Sample Pack when you purchase any LMNT product at Kresser.co/lmnt
• Get 15% off your order at Paleovalley.com/Chris with the code KRESSER15

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Hey, everyone, Chris Kresser here. Welcome to another episode of Revolution Health Radio. If you’ve been following my work for any length of time, you know that what happens in our gut has a profound impact on virtually every system of the body. We’ve talked about the gut–brain axis, gut–skin axis, gut–heart axis, gut–bone axis, and gut–lung axis. There’s even a gut–eye axis, which describes the interplay of the gut and ocular health.

In this episode, we’re going to discuss the gut–immune axis. I’ve come to believe that this is one of the most important places to focus our attention if we want to improve our health and extend our life span. Gut health is foundational to overall well-being because the gut plays a central role in nutrient digestion, absorption, and waste elimination, ensuring our body receives everything it needs for daily functioning while keeping out toxins, pathogens, and other antigens that may cause harm. The gut is also home to trillions of microorganisms known as the gut microbiota, which perform essential metabolic tasks, assist in the breakdown of complex foods, and produce critical vitamins. A balanced gut microbiota protects against pathogens and supports immune regulation, whereas an unhealthy or imbalanced gut can lead to a wide range of problems from malabsorption and inflammation to increased susceptibility to infections, and even chronic diseases like obesity, type 2 diabetes, and autoimmune conditions.

The immune system is the body’s primary defense mechanism against foreign invaders like pathogens, environmental toxins, and antigens. It also protects against potentially harmful changes in our cells like cancer and against hyperactive responses to our own tissues as in autoimmunity. It can be broadly categorized into two arms: innate immunity, which provides immediate but general protection through barriers like the skin and white blood cells like macrophages; and adaptive immunity, which involves specific responses tailored to particular pathogens remembered from previous encounters, mainly orchestrated by T cells and B cells. The immune system is also involved in wound healing and inflammation, and as you probably know, chronic inflammation is at the root of virtually all modern disease. Prioritizing the health of the immune system is paramount not only to prevent infections, but also to maintain overall vitality. A robust immune response means quicker recovery from illness, reduced risk of chronic disease, and optimal function of nearly every system in our body. The profound interconnection between the gut and the immune system, aka the gut–immune axis, highlights that maintaining a balanced gut microbiota and a robust immune response is not merely about avoiding gastrointestinal issues; it’s central to warding off a spectrum of modern diseases, many rooted in chronic inflammation.

As our understanding deepens about these intertwined systems, it becomes increasingly evident that by nurturing our gut, we are in essence fortifying our body’s defenses, optimizing our health, and paving the way for a longer, more vibrant life. It’s no exaggeration to suggest that nourishing and supporting our gut–immune axis is one of the most important things we can do to improve our health and extend our longevity.

In this episode, I’m going to describe the gut–immune axis in more detail, make dietary recommendations for supporting it, and then share the key nutrients and superfoods that can heal and fortify this critical system. Ready? Let’s dive in.

The dynamic relationship between the gut and immune system is crucial for maintaining overall well-being. The gut is more than just a food processing machine. It’s a complex ecosystem teeming with trillions of microorganisms collectively known as the gut microbiota. These microscopic residents include bacteria, viruses, fungi, and more, and they play a pivotal role in maintaining gut health. On the other side of the equation, we have the immune system—our body’s shield against invaders like bacteria, viruses, and pathogens. It’s the immune system’s job to distinguish between friend and foe and mount an appropriate response to protect us from harm. The gut and the immune system communicate constantly [through] the gut–immune axis. This dynamic interplay involves intricate molecular signaling, cellular interactions, and immune responses. It’s like a hidden network connecting our digestive tract to our immune defenses. The gut microbiota play a crucial role in the gut–immune axis. The microbes in the gut are essential for maintaining a balanced immune system for two primary reasons. Number one, they help educate the immune system. Early exposure to microbes in the gut trains the immune system to distinguish between harmless substances and potential threats. This education is crucial for preventing inappropriate immune responses like allergies. Number two, they contribute to immune regulation. They produce molecules that can help control inflammation, keeping it in check. This regulation is critical for preventing chronic inflammatory diseases.

The gut barrier is also crucial for immune health. It’s like a protective shield that separates the gut’s contents from the rest of the body. It consists of a single layer of cells held together by tight junctions. A healthy gut barrier is essential for preventing harmful substances like toxins and pathogens from entering the bloodstream. When the gut barrier is compromised, which we call intestinal permeability or leaky gut, it can lead to chronic inflammation and immune dysfunction. The gut barrier also helps maintain the delicate balance of the gut microbiota. When the barrier is intact, it controls the movement of microbes and their byproducts, preventing harmful bacteria from proliferating and causing infections. Research has linked disruptions in the gut–immune axis to various health conditions. Dysbiosis, an imbalance in the gut microbiota, can trigger immune system dysfunction and contribute to the development of autoimmune diseases, allergies, and even mood disorders like depression. Conversely, a healthy gut can bolster immune resilience and reduce the risk of infections and a wide range of chronic modern diseases. Maintaining a harmonious gut–immune axis is essential for overall health and optimal immune function. There are five pillars for doing this.

The first is diet. Specifically, I’m talking about consuming foods that nourish the gut and support immunity. The second is supplements—taking specific gut-immune nutrients and superfoods like probiotics, prebiotics, colostrum, lactoferrin, beta-glucan, zinc, vitamin D, etc. The third is sleep. Prioritizing quality sleep is critical because it supports both the gut and immune system. Sleep is also when the body conducts crucial maintenance and repair work. Number four is stress management. Chronic stress can disrupt the gut–immune axis. Implementing stress management techniques like meditation, deep breathing exercises, or yoga can help promote a healthier balance. Fifth is physical activity. We know that exercise stimulates immune function and promotes gut health in several ways and is one of the most important things we can do to support the gut–immune axis.

I’ve written and spoken about sleep, stress management, and physical activity at length over the past 15 years. You can refer to my website, ChrisKresser.com, for lots of free resources on these topics. In this show, I’m going to focus on the first two pillars, diet and supplementation, for gut–immune axis support. Specifically, I’m going to focus on three lesser-known but highly effective nutrients and superfoods: colostrum, lactoferrin, and beta-glucan. But before we dive in [to those], let’s first talk about why you should care about the gut–immune axis in a little bit more detail.

Given the crucial role that both the gut and immune system play in our overall health, it shouldn’t be a surprise that the gut–immune axis is a major player in several chronic health conditions. For example, food and environmental allergies, asthma, and skin conditions are often characterized by intestinal permeability, a disrupted gut microbiome, and immune dysregulation. These disruptions in the gut–immune axis cause the telltale signs and symptoms of these conditions, such as hypersensitivity to normal food or environmental antigens, bronchial inflammation and hyperresponsiveness, and a disrupted skin barrier, which leads to rashes and other skin issues. Autoimmunity and low immune function are other obvious examples. In both cases, the gut–immune axis is dysfunctional, but the manifestation is different. With autoimmunity, the immune system has become hyperactive and is attacking self tissue. With low immune function, the immune system cannot mount an effective response against viruses, bacteria, or other pathogens. So whether you have an autoimmune disease or you get frequent or severe colds, flus, or COVID-19, you almost certainly have a gut–immune axis issue. But there are other examples of gut–immune axis dysfunction that may not be as obvious.

One is cognitive and mood disorders. These include brain fog, poor memory, and conditions like dementia and Alzheimer’s [disease], as well as depression and anxiety. If you’ve followed my work for any length of time, you’ve probably heard me talk about the gut–brain axis. This describes the bidirectional connection between the gut and the brain and the complex interactions between these two organ systems. Research over the past two decades has shown that a compromised gut barrier and disrupted microbiome, and the inflammation that results, are primary drivers of mood and cognitive dysfunction. Another, less obvious example is the relationship between the gut–immune axis and bone health. Studies have shown that the gut microbiota and its associated metabolites like short-chain fatty acids modulate bone metabolism and several metabolic bone diseases, such as osteoporosis, osteoarthritis, and rheumatoid arthritis. And we know that inflammation, the immune part of the gut–immune axis, negatively impacts bone health in several ways and is one of the primary drivers of bone loss. So while the gut–immune axis can sound like an esoteric concept, you can see that it’s central to our health and longevity and is a major factor in most chronic inflammatory conditions.

Let’s dive into dietary strategies for supporting the gut–immune axis. Bone broth is a rich source of nutrients that can benefit both the gut and the immune system. It contains collagen and amino acids like glycine and proline, which support the integrity of the gut lining, and it contains minerals like zinc and magnesium, which are essential for immune function. Fermented foods like yogurt, kefir, kimchi, sauerkraut, and kombucha are loaded with beneficial probiotic bacteria. Probiotics assist training the immune system, ensuring it responds appropriately to threats while avoiding overreactions like allergies and autoimmune conditions. So including a variety of fermented foods in your diet can contribute to a healthy gut–immune axis. Fiber-rich foods like fruits, vegetables, starchy tubers, and legumes, if tolerated, are essential for a thriving gut microbiota. Fiber serves as a prebiotic, meaning it provides nourishment for beneficial gut bacteria. When these microbes digest fiber, they produce short-chain fatty acids like butyrate, which promote gut health and regulate the immune system. Not all fiber is created equal, though, when it comes to the ability to feed gut bacteria. Fermentable fibers include soluble fiber, resistant starch, and inulin, whereas insoluble fiber plays more of a mechanical role in supporting peristalsis and motility but is not as fermentable by our gut bacteria. Organ meats, which are often overlooked in modern diets, are nutritional powerhouses that offer a wide array of vitamins and minerals. Liver, for instance, is a rich source of vitamin A, vitamin D, and various B vitamins, which play crucial roles in immune function and can bolster the gut–immune axis.

Mushrooms like shiitake, reishi, and maitake contain bioactive compounds that can enhance immune function. Beta-glucans, which are polysaccharides (or long sugar molecules) found in mushrooms, have been shown to stimulate immune cells and modulate the immune response. We’ll be talking a lot more about beta-glucan shortly. Fatty fish like salmon, mackerel, and sardines are high in omega-3 fats, which have anti-inflammatory properties, and those healthy fats can help modulate the immune system and reduce the risk of chronic inflammatory diseases. Garlic and onions are rich in sulfur compounds that have antimicrobial properties and can help promote a healthy gut microbiota, and they also contain prebiotic fibers that feed beneficial gut bacteria. Berries like blueberries, strawberries, and raspberries are packed with antioxidants and fiber, and these antioxidants can help to reduce inflammation while the fiber, as we just discussed, supports a diverse gut microbiota. Turmeric contains curcumin, which has potent anti-inflammatory and antioxidant properties. However, the bioavailability of curcumin in turmeric is pretty low. So while you will get some benefit from eating it, and it’s definitely a healthy spice to include in your diet, you’ll need to supplement with curcumin to get the best results. Green tea contains catechins, which are antioxidants that have been shown to boost the activity of immune cells, and it can also have a positive impact on the gut microbiota. And then last but not least, herbs and spices like oregano, thyme, ginger, and cinnamon have antimicrobial and anti-inflammatory properties. It’s a little known fact that herbs and spices are among the most nutrient-dense foods we can eat, ounce for ounce. So I always recommend including them in your cooking if you tolerate them because they can have several immune-boosting benefits.

Let’s talk a little bit about supplements for the gut–immune axis. Probiotics play a critical role in supporting both the gut and the immune system, and there are three primary mechanisms for this. One is maintaining microbial harmony. Probiotics can increase the richness and diversity of our microbial community, which helps to crowd out harmful bacteria and maintain balance within the gut. Probiotics also educate the immune system. They train it and ensure that it functions optimally. Friendly bacteria release bioactive compounds that modulate our immune responses, essentially teaching our body to differentiate between harmless substances and potential threats. This education helps to prevent the overreactions like allergies and autoimmune disease that can be seen in an imbalanced immune system. And third, probiotics help to regulate inflammation. Inflammation is a double-edged sword. It’s, of course, necessary for fighting infections and helping to heal wounds. But when it becomes chronic, it can lead to a variety of health issues. Probiotics act as conductors that help regulate the immune system’s inflammatory response, ensuring that it’s appropriate and not excessive.

Prebiotics, on the other hand, are non-digestible fibers found in certain foods that serve as fuel for beneficial gut bacteria. They support the gut–immune axis via four primary mechanisms. One is, again, by enhancing microbial diversity, similar to probiotics. But in this case, prebiotics are the fuel for the beneficial bacteria that are already living in our gut, or perhaps for supplements that we might take. And when we take prebiotics, those beneficial bacteria multiply and outcompete harmful bacteria in our gut, which leads to more bacterial diversity and more balanced gut microbiota. The second is by producing short-chain fatty acids. Prebiotics are primarily fermented in the colon by beneficial bacteria, and during that fermentation process, they produce essential metabolites called short-chain fatty acids like butyrate, acetate, and propionate. And those short-chain fatty acids are known to play a crucial role in maintaining gut health and regulating immune responses. Third, prebiotics strengthen the gut barrier. They promote the integrity of the tight junctions and ensure that the gut barrier remains intact and keeps harmful substances inside of the gut and out of our systemic circulation. And fourth, prebiotics can help modulate the immune response. Short-chain fatty acids that are produced during prebiotic fermentation have immunomodulatory effects. They can influence the function of immune cells, including regulatory T cells, which help maintain immune tolerance and prevent excessive immune responses like allergies and autoimmune diseases.

Colostrum is the nutrient-rich fluid female mammals produce in the first few days after giving birth. It serves as the first source of nourishment for newborns and is packed with essential nutrients, antibodies, growth factors, and other bioactive compounds. Mammals have been around for about 200 million years, and colostrum is still, after all that time and evolutionary pressure, the first food that every mammal on the planet gets after birth. That should tell us something about its nutritional value and health benefits. Colostrum is renowned for its potent immune-boosting properties, making it an exciting subject of research in the context of the gut–immune axis. It supports this axis in at least seven distinct ways. The first is by producing immunoglobulins, or antibodies. Colostrum is rich in various classes of antibodies, particularly [immunoglobulin A] (IgA) and [immunoglobulin G] (IgG). These antibodies are essential components of the immune system. IgA is found in mucosal tissues, including the gut, respiratory tract, and lining of the [gastrointestinal] (GI) and urinary tracts. It acts as a first line of defense against pathogens by neutralizing them and preventing their attachment to mucosal surfaces. IgG circulates throughout the bloodstream and provides systemic immunity. Number two, colostrum contains numerous immune factors like lactoferrin, lysozyme, and cytokines. These factors have antimicrobial properties and contribute to the body’s defense against infections. Lysozyme has antibacterial properties and helps break down the cell walls of certain bacteria. We’ll talk a lot more about lactoferrin in the next section because it’s such a significant player. Number three, colostrum supports the intestinal barrier. It contains growth factors and other bioactive molecules that promote the growth and repair of the gut lining. Number four, colostrum is involved in the modulation of the immune response, helping the immune system to avoid overreaction to harmless substances and reducing the risk of allergies and autoimmune disorders. Number five, colostrum is antiviral. Some components in colostrum, like interferons, have direct antiviral properties. Interferons are signaling proteins that play a crucial role in the body’s antiviral defense system, and colostrum-derived interferons can help inhibit viral replication and protect against viral infections. Number six, colostrum stimulates immune cells. Colostrum contains factors that can stimulate the activity of immune cells, including macrophages and lymphocytes. These cells are responsible for identifying and destroying pathogens, infected cells, and abnormal cells in the body. And by enhancing the activity of these immune cells, colostrum contributes to a more robust and balanced immune response. And number seven, colostrum has prebiotic properties. It contains oligosaccharides and other compounds that serve as prebiotics, and by promoting the growth of beneficial microbes, colostrum indirectly supports immune function.

Gut health is foundational to overall well-being. Tune into this episode of Revolution Health Radio to learn why this is one of the most important places to focus our attention if we want to improve our health and extend our life span. #chriskresser #colostrum #lactoferrin #betaglucans

Let’s look at a few selected studies to get a better idea of how colostrum supports the gut–immune axis and its related conditions. A little-known fact is that intense physical training can increase the risk of intestinal permeability. Colostrum has been studied as a potential therapeutic agent to reduce gut permeability in athletes and improve their performance and recovery. A 2017 randomized controlled trial found that colostrum supplementation decreased intestinal permeability as measured by the lactulose/mannitol test, and also improved levels of zonulin, another marker of permeability, in the stool. Other studies have found similar results. A 2019 review states that, “The presence of growth factors, immunoglobulins, cytokines, lactoferrin, and hormones suggest that colostrum may improve the functioning of the digestive, immune, and neuroendocrine systems and exercise performance.” The administering of colostrum seems to be most effective during periods of high-intensity training, probably due to its high concentration of [insulin-like growth factor-1] (IGF-1), the ability to increase muscle buffering capacity, or its high secretory IgA concentration. Studies in infants and adults have shown that bovine colostrum can prevent [GI] tract infections, upper respiratory tract infections, and LPS, or lipopolysaccharide-induced inflammation. LPS are large molecules found in the outer membrane of gram-negative bacteria. When the gut becomes permeable, LPS escape and enter the bloodstream, where they can elicit a strong immune response. This immune response can cause food and environmental allergies, asthma, skin conditions like eczema and psoriasis, and other atopic and inflammatory diseases. It also weakens our defense against pathogens of all kinds. Studies have shown that bovine colostrum supplementation can strengthen gut barrier integrity and reduce LPS-induced inflammation, which in turn prevents, or even reverses, allergies and atopic disease and strengthens immune defenses.

A 2021 paper reviewed the effects of bovine colostrum supplementation on the gut–immune–joint axis, which is the connection between the gut, immune system, and our joints. The researchers noted that leaky gut dysbiosis and gut inflammation are associated with the pathogenesis of many inflammatory and autoimmune diseases, including rheumatoid arthritis and lupus. They note that bovine colostrum has been shown to reduce arthritis in animal models. This involved a reduction of inflammatory markers and an improvement in bone remodeling and other markers of bone health. The immunoglobulins and other compounds in colostrum modulate T-cell function, especially TH17 and T regulatory cells, which play a crucial role in rheumatoid arthritis and other autoimmune conditions.

Now let’s talk about how to get the benefits of colostrum. Colostrum is present in the milk of mammals, but only for a few days after [they’ve given birth]. It’s not part of the regular dairy production process, so you won’t find it in milk, cheese, or other dairy products that you buy in a store. You’ll need to supplement it. It’s important to choose colostrum from pasture-raised, grass-fed cows, as it will contain higher levels of immunoglobulins and other immune factors, and is free of hormones, antibiotics, and [genetically modified organisms] (GMOs). Also note that most studies documenting the benefits of colostrum for the gut–immune axis used a dose of at least 2 grams per day. Many colostrum supplements on the market contain only 500 milligrams to 1 gram per serving. Colostrum should preferably be taken with 6 to 8 ounces of water on an empty stomach, 30 to 45 minutes before or two hours after a meal. That’s not a hard and fast rule. If you miss the chance to take it on an empty stomach one day, you’d still benefit from taking it with a meal. But it’s generally best to aim for taking it on an empty stomach. It’s important to note that colostrum does contain lactose. The estimates vary, [but] the range is usually 1 to 3 percent lactose by volume. In my clinical practice, I’ve seen that many patients who are lactose intolerant are not only able to tolerate colostrum, they actually thrive with it. That’s not true in 100 percent of cases. I certainly have had patients who are severely lactose intolerant who are not able to tolerate colostrum. But I would say more often than not, people who have lactose intolerance do pretty well with colostrum. So if you are in that group, I would suggest proceeding with caution, maybe just trying a very small amount initially and seeing how you react, and then building up very slowly to determine whether you’re able to tolerate it and get the benefits of it. I get that question a lot, so I just wanted to address it here because it’s not necessarily true and even not commonly true that if you are lactose intolerant, you can’t benefit from colostrum.

Let’s move on to lactoferrin. It’s often referred to as the iron-binding protein. We’ll get into why that is a little bit later. And it’s naturally present in mammalian milk, tears, saliva, and other bodily secretions. It plays a vital role in defending against microbial invaders, promoting gut health, and enhancing the immune system’s effectiveness. Lactoferrin supports the gut–immune axis in five key ways. Number one is by sequestering iron. And this is, as I just mentioned, lactoferrin’s most renowned role—its ability to bind iron with high affinity. Iron is an essential nutrient for many microorganisms, including pathogenic bacteria. By sequestering iron in the gut, lactoferrin restricts the growth and proliferation of harmful bacteria, effectively acting as a natural antibiotic. Number two, lactoferrin possesses direct antimicrobial properties and is capable of destroying various pathogens, including bacteria, viruses, and fungi. It does this by disrupting the integrity of microbial cell membranes, preventing their entry and colonization in the gut. Number three, lactoferrin is anti-inflammatory. It’s been shown to inhibit the production of proinflammatory cytokines and promote the production of anti-inflammatory molecules. Number four, lactoferrin helps to modulate the immune system by interacting with immune cells, including macrophages and lymphocytes. It helps regulate immune responses, ensuring that the immune system distinguishes between harmful pathogens and beneficial microbes or harmless substances. And number five, lactoferrin promotes the health and integrity of the gut barrier. It repairs damaged epithelial cells, tightens junctions between those cells, and reinforces the mucosal lining.

I mentioned that lactoferrin is most commonly known as an iron-binding protein. It is worth noting that it’s been shown in clinical research to be a more bioavailable source of iron than typical sources. It has a greater ability to bind iron than other transferrins and is the only one capable of binding iron over a wide pH range. Lactoferrin binds the iron already present in the body, helping us to utilize and absorb it more efficiently. One study showed that lactoferrin increased iron levels by nearly six-fold compared to other iron sources. What’s more, it does this without causing the GI side effects like abdominal pain, bloating, constipation, etc., that most iron supplements are associated with. Lactoferrin can be very useful if you’re iron deficient, and I’ve used it in my practice for many years with great success. Another cool thing about lactoferrin is that it doesn’t tend to increase iron levels if your iron levels are normal or high. It has more of a regulatory effect than taking iron supplements. Having said that, if you do have high iron levels, I would definitely speak with your healthcare provider before starting lactoferrin. But as far as I’ve seen in the research, and also with my clinical experience, it generally has a negligible effect on iron levels for people who have normal iron levels or even high iron levels.

Let’s look at some selected research to get a better idea of lactoferrin’s gut–immune potential. A recent meta-analysis of lactoferrin intervention studies in infants and adults reported a significant risk reduction of developing respiratory tract infections. It’s also effective for gastrointestinal viruses like the ones that cause stomach flu. An interesting study published in December 2022 summarized the ways in which lactoferrin could offer support at different phases of [severe acute respiratory syndrome] coronavirus 2 [(SARS-CoV-2)] infection. Lactoferrin prevents binding of SARS-CoV-2 to cells and has been shown to inhibit the replication of several SARS variants. And a study out of Italy in 2021 found that COVID-19 patients treated with lactoferrin recovered faster and had lower levels of inflammatory markers like interleukin 6, ferritin, and D-dimer than controls. Given lactoferrin’s many roles in immune function, it’s not surprising that it has an effect on cancer. It has antioxidant activity, meaning it can help neutralize harmful free radicals in the body. Free radicals can damage DNA and other cellular components, potentially leading to mutations and cancer development. By reducing oxidative stress, lactoferrin may contribute to cancer prevention. It’s been shown to inhibit angiogenesis, the process by which tumors develop new blood vessels to support their growth. And by preventing the formation of these blood vessels, lactoferrin may slow down tumor growth and progression. It may also help protect DNA from damage caused by carcinogens or radiation, and by preserving the integrity of DNA, lactoferrin can reduce the likelihood of genetic mutations that lead to cancer.

So with this in mind, researchers are studying lactoferrin as a therapeutic agent for cancer. For example, a 2022 study found that bovine lactoferrin induced cell death in human prostate cancer cells. We definitely need more research here, but the research that we do have so far is promising. Lactoferrin has been shown in both animal and human studies to reduce inflammation in the gut and regulate the microbiome. In a study of mice infected with the H5N1 virus, the highly pathogenic avian influenza, lactoferrin not only reduced lung and intestinal injury, but also alleviated inflammation and reversed the changes in intestinal microflora composition, while increasing the abundance of beneficial bacteria. That’s a really important effect to be aware of. As you may know, there’s a lot of research suggesting that COVID-19 and other viral infections can have a pretty significant negative impact on the gut flora, and that effect can persist over a long period of time and may even be a primary driver of long COVID for the patients who experience that. So the fact that [lactoferrin] has been shown to reverse the viral-induced changes in intestinal microflora is really exciting and promising, and it’s definitely one of the things that we explored using in the clinic with patients who had been affected by COVID-19.

A 2022 study of healthy, elderly women found that lactoferrin supplementation increased levels of beneficial bacteria relative to controls. And other studies have shown that lactoferrin may be an effective treatment for inflammatory bowel diseases like Crohn’s [disease] and ulcerative colitis. So, where do we find lactoferrin? Well, it is present in small amounts in dairy products like cheese and yogurt, and to an even lesser degree in beef and other meats. And again, as with colostrum, dairy and meat from pasture-raised, grass-fed cows will be a better choice because it will have higher levels of lactoferrin. Having said that, if you want to get meaningful doses of lactoferrin, you’ll need to supplement unless you’re consuming huge amounts of pasture-raised dairy products. There are a lot of forms of lactoferrin on the market. My favorite is probably Bioferrin. This is not a supplement, but an ingredient that is used in some supplements. It’s a milk-derived lactoferrin compound partially saturated with iron, which gives it the capacity to bind with free iron in the intestine, transporting it so it can be absorbed. This eliminates the free iron in the gut that can feed harmful bacteria and disrupt the gut microbiome, while simultaneously increasing systemic iron absorption. So you get a two-pronged beneficial effect there. Some studies suggest, as I mentioned earlier, that Bioferrin lactoferrin is more effective at increasing iron levels with fewer side effects than traditional iron supplements. But of course, it also has all of the other immunomodulating properties that we’ve talked about throughout the podcast.

The third and final gut–immune axis superfood I want to talk about, or super nutrient in this case, is beta-glucan. Beta-glucan is a naturally occurring polysaccharide (or long sugar) molecule that serves as an energy store and structural component of plant, algae, fungal, and bacterial cell walls. They’re found in various foods and substances in the diet like oats, mushrooms, and yeast. But the specific structure of beta-glucans differs from food to food, and not all beta-glucans have the same health benefits. [All] beta-glucans share a similar molecular backbone, but the full molecular structure depends on the source. This leads to a wide range of molecular structures within the beta-glucan family, and because of this, a wide range of health impacts. For example, while oat-derived beta-glucans have been shown to act as dietary fibers that improve metabolic health, they don’t have the immunomodulatory effects of yeast- and mushroom-derived beta-glucans. Only beta-glucans with a high degree of branching, like those from fungi and yeast, act as biological response modifiers and have a strong effect on the immune system. And I’ll say more about what that means in a second. In fact, the connection between beta-glucans and immunity was first discovered by two scientists, Pillemer and Ecker, working with Saccharomyces cerevisiae yeast back in the 1940s, almost 100 years ago. The immune system consists of two primary components. Innate immunity involves rapid, nonspecific responses to a pathogen or threat, and inflammation is a part of that response. That’s followed by a slower but more specific and targeted response, known as adaptive or acquired immunity. Beta-glucans help to prime innate immune cells. They trigger a cascade of responses that make the immune system function more efficiently. They stimulate the activity of macrophages—cells that destroy invading pathogens and trigger other immune cells to go on the attack. Macrophages also release cytokines that enable cells to communicate with one another. Beta-glucans stimulate lymphocytes that bind to tumors or viruses and release chemicals to destroy them, and as I just mentioned, they’re known as biological response modifiers, which are a class of compounds that regulate immune function.

Many compounds and medications that affect immune function either suppress it or boost it. For example, steroids are used to globally suppress a hyperactive immune response in people with autoimmune disease. And while suppressing the immune system can relieve the symptoms of these conditions, the obvious downside is that it reduces immune defense against pathogens and cancer. On the other hand, some botanicals like echinacea and astragalus boost the immune response. This can support our defense against infections caused by viruses and other pathogens. But the problem with boosting is when it goes beyond supporting and causes overstimulation. This can manifest as autoimmunity, allergies, asthma, or other immune-related dysfunction. Biological response modifiers, including beta-glucans, are fundamentally different from immune-suppressing or immune-boosting compounds. They support innate immunity by priming and training the body’s innate immune cells to react more quickly when a pathogen is detected. Training the body’s immune system refers to a newly recognized phenomenon that occurs when innate immune cells encounter specific pieces of microbes, either living or nonliving, causing the cells to adopt a more effective response to a future threat. In essence, this means that beta-glucans train the innate immune cells to retain a memory of the experience that allows them to respond more quickly and effectively when they encounter another pathogen. This is an incredible effect that beta-glucans have. There are not many substances that we know of, either pharmaceutical or natural, that have this immune-balancing effect. Like I said, most drugs just globally suppress the immune system, and even some botanicals that boost the immune system tend to be much stronger in boosting than they are in regulating. Beta-glucans have this unique ability to balance and modulate and regulate the immune system so that it can function more efficiently. And it’s one of the few substances that we know of that actually trains the innate immune system to become faster and more efficient at recognizing threats. This is obviously very important in the world that we’re living in today, with the recent COVID-19 pandemic and, almost certainly, pandemics that we’ll be facing in the future. So this is one of the reasons I’m so excited about beta-glucans. And this ability of beta-glucans to train the immune system is obviously essential for immune defense in the modern era because it provides protection from pathogens we’ve never encountered before.

Let’s look at some specific research on beta-glucans and the gut–immune axis. A 2023 study examining the impact of beta-glucans on the gut and immune system found that it increased several species of beneficial bacteria, including Lactobacillus casei, Lactobacillus acidophilus, and Bifidobacterium animalis lactis. They found that beta-glucans activate several different types of immune cells, including dendritic cells, macrophages, neutrophils, monocytes, and natural killer cells. Importantly, stronger immune-modulating and anti-cancer actions were correlated with higher beta-glucan structural complexity. This explains why beta-glucans from yeast and mushrooms have unique immune benefits that beta-glucans from grains like oats and barley don’t. Beta-glucans are being intensively studied for their ability to protect against, and perhaps even treat, cancer. And in fact, this is one of the best researched applications of beta-glucans, particularly out of Japan. One study showed that beta-glucans from mushrooms and yeast protect against colorectal cancer via modulation of the gut microbiota and regulation of immune genes. Beta-glucans also increased the production of short-chain fatty acids like butyrate, which plays a vital role in inhibiting colon cancer because of its capacity to renew the intestinal epithelial cells. Another study found that beta-glucan suppressed breast cancer progression by promoting autophagy, which is a cellular cleanup and repair process, and tumor cell death and blocking inflammatory pathways. Given the immunomodulatory effects of beta-glucan, it’s not surprising to see that it also has a positive impact on autoimmunity. A 2022 study found that beta-glucans downregulate autoimmune inflammation and reduce the symptoms of psoriasis and psoriatic arthritis. Beta-glucan has been shown to protect against several viral infections, including COVID-19. In a 2023 study, researchers argued that beta-glucan could help prime the immune system’s response to [SARS-CoV-2], reduce cytokine activation, and alleviate hypoxia.

So, where do we find beta-glucans? Well, as mentioned, they are found primarily in grains like oats, barley, mushrooms, and yeast. But beta-glucans from grains do not have the same health impacts as those in mushrooms and yeast. Beta-glucans in grains primarily feed the beneficial gut microbiota and increase short-chain fatty acid production, which are great effects. Whereas beta-glucans in mushrooms and yeast have the potent immunomodulatory effects we’ve been talking about in this podcast. From a dietary perspective, consuming a wide variety of mushrooms is the best way for getting immune-supporting beta-glucans. But supplementation is another strategy for increasing your intake of these types of beta-glucans, and maybe a better option, especially if you’re not eating specific types of mushrooms regularly. Unfortunately, some of the mushrooms that are the best source[s] of beta-glucans, like turkey tail and reishi, are not great to eat. They’re tough, bitter, and chewy, and they’re not widely available locally. So when it comes to supplementation, you have two options: mushrooms and yeast-derived beta-glucans. I have discussed the benefits of supplementing with mushrooms on my blog and previous podcasts. You can check out my interview with Jeff Chilton recently about mushrooms, and then I have an article about superfood mushrooms on my website, ChrisKresser.com. We’ll put links to both of these in the show notes.

I’m going to focus in this remaining part of the episode on yeast-derived beta-glucans because I haven’t really talked about these as much. My favorite yeast-derived beta-glucan is Wellmune. Again, like Bioferrin, this is not a supplement. It’s an ingredient that supplement manufacturers use when they’re trying to include the benefits of beta-glucan. Wellmune is a yeast-derived, 1,3/1,6 beta-glucan extracted from the cell wall of a proprietary strain of baker’s yeast. It’s taken up in the body through specialized immune cells in the intestines where those cells engulf it and degrade it into smaller fragments that bind to neutrophils. And then, primed by that beta-glucan, the neutrophils move more quickly to recognize and kill foreign challenges, as we’ve discussed.

Let’s look at a few studies looking specifically at Wellmune’s immune-modulating properties. A study out of China found that Wellmune supplementation kept children healthier during the cold and flu season by significantly decreasing the incidence and duration of the common cold by almost 70 percent compared to placebo, which is a pretty remarkable effect. In a study published in Nutrition, researchers reported that older adults taking Wellmune demonstrated a trend toward reducing the number of upper respiratory tract infections, reducing symptom days of cold, and statistically significant changes in the body’s response to viral encounters and inflammation. In studies on high-stress populations, including firefighters, medical students, and people with chronic stress lifestyles, Wellmune maintained overall physical health and minimized the incidence and duration of upper respiratory tract infections. A study on people with ragweed allergies found that Wellmune led to a significant reduction in total allergy symptoms and symptom severity, [and an improvement in] quality of life, sleep, activity levels, and nasal symptoms, along with improvements in mood.

I have been using and aware of colostrum and lactoferrin for many years in my clinical practice, and I’ve been using mushrooms for many years as a trained herbalist and someone who studied Chinese medicine earlier in my career. Mushrooms have been a big part of Chinese medicine. In fact, lingzhi, which is the Chinese name for reishi mushroom, was one of the first medicinal substances mentioned in the first medical text that we know of in the world, thousands and thousands of years ago. So mushrooms have a long history of use. I’ve more recently become aware of yeast-derived beta-glucans, and I’ve been really impressed with their effects in my work with patients and also in my own personal experience. And they seem to complement the beta-glucans in mushrooms very well. I’m not sure how to explain it from a research-based perspective, but I think it’s a question of different branching profiles and similar but different and distinct effects that you get from yeast-derived versus mushroom-derived beta-glucans. They’re both great. You can get benefits from taking one or the other. But I’m finding increasingly that I use both and that I recommend both for the best results.

Well, we’ve reached the end of our show. Thanks, everybody, for listening. I hope you got a lot out of this. And before we finish up, I just want to let you know that I’ll be making a pretty exciting announcement in the next few days related to what we’ve discussed in the show. So stay tuned for that. Keep sending your questions in to ChrisKresser.com/PodcastQuestion, and I will talk to you next time.

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