The Gut-Immune Connection: The Role of the Gut Microbiome in Your Immunity

The gut is home to trillions of microbes that collectively comprise your gut microbiome. As the largest and most diverse microbiome of the body, the gut microbiome is most often associated with digestion and gastrointestinal health, though its role extends far beyond these functions. 

One of the most critical areas of impact is the immune system. The gut is centrally located and serves as a communication switchboard, connecting to the immune system through various pathways known as the gut-immune axis, or gut-immune system. Your resident gut microbes are a key component of this connection as they can directly impact the function of the immune system. To better understand this relationship, it’s important to first understand the foundational basics of this system and how it works.

The immune system is a vast network of cells, proteins, and organs that fight harmful substances which come into contact with the body (i.e., pathogenic bacteria) or disease-causing changes that occur within the body (i.e., damaged cells). It’s activated by substances the body doesn’t recognize as its own, called antigens. When the immune system is functioning properly, it recognizes, identifies, and neutralizes antigens, so they go unnoticed by you. But if it becomes weak or unable to fend off certain threats, you can get sick. 

When an antigen attacks the body, two separate, yet interrelated, branches of the immune system are activated: the innate immune system and the adaptive immune system. While each system has its own distinct mechanisms, they both work together to recognize foreign materials and neutralize, eliminate, or metabolize them to protect the body from illness. 

The innate immune system defends against non-specific pathogens that enter the body and is the first response to foreign substances. This system is responsible for generalized immune responses like inflammation and fevers, and defense mechanisms like saliva and tears. It also includes physical barriers like the skin and gastrointestinal tract. 

Like the skin, the gastrointestinal tract provides a protective barrier between the bloodstream and external inputs (food, liquids, air), regulating what can pass through the gut wall. 

The adaptive immune system, or acquired immunity, targets specific pathogens that your body has already encountered, mounting a more specialized attack. Because the adaptive immune system can learn and remember specific antigens it’s been exposed to in the past, it provides long-lasting immunity against recurrent infections. 

So, how does the immune system learn to perform these critical functions? 

Microbes are foundational in the development and training of the immune system. This relationship begins before birth. In utero, metabolites produced by maternal microbes, maternal immune cells, and antibodies help prepare the prenatal immune system, ensuring a newborn is able to mount an immune response directly after birth.¹ Though the presence of a prenatal microbiome is still debated, some preliminary evidence in animal models suggests select microbes may actually seed and colonize the fetus before birth, contributing to immune and microbiome development.  

After birth, the immune system continues to develop in coordination with the newborn microbiome. This early colonization plays an important role as resident microbes help train the immune system to distinguish between benign substances (i.e., the body’s own cells, outdoor particles like pollen, commensal microbes) and pathogenic antigens (i.e., infectious microbes). This is also when the immune system learns how to “immunoregulate”—how to appropriately coordinate the inflammatory response to stressors and infections. 

Factors like diet, antibiotic use, and environmental exposure all shape a newborn’s microbiome and affect the development of the immune system during this time. Disruptions to these early microbial interactions can have long-term effects on the immune system’s immunoregulatory capability. For example, if the immune system has trouble determining what is self versus non-self, it may attack the body’s own cells (known as autoimmunity) or over-respond to harmless antigens causing food or pollen allergies. 

The relationship between microbes and the immune system continues to evolve after these first few years of life through extensive cross-communication between intestinal microbiota and immune receptors and cells. For example, gut microbes break down proteins and carbohydrates within the body, synthesize vitamins, and produce a range of other metabolic products known as metabolites that can facilitate communication between gut cells and immune cells.² 

The gut microbiome also regulates and fine-tunes the immune system, inducing protective reactions to pathogens and maintaining proper immune responses within the body. Gut microbes protect you from external factors through various tactics.³ They: 

• Help control inflammation and mediate the inflammatory immune response. This helps your immune system respond to inputs appropriately, initiating a response when stimulated by a foreign antigen, while remaining passive to inputs that don’t pose a threat, like food or pollen.
• Strengthen gut barrier integrity. Gut microbes support the presence of tight junctions, intercellular connectors that form the main scaffolding of the gut barrier. Tight junctions are important to reinforce the integrity of the gut wall and prevent foreign materials and contaminants from crossing. Disruptions in the intestinal barrier structure can result in flaring of local immune reactions and allow for growth of unwanted microbes.⁴
• Compete with potential pathogens for resources. ​​If your gut microbiota utilize all of the available resources, such as space and nutrients, pathogens can’t survive.
• Produce antimicrobial substances. For example, certain bacteria⁵ in the gut produce bacteriocins, proteins that inhibit or kill pathogenic bacteria such as Listeria, Clostridium, and Salmonella through targeted cell death.  

To adequately carry out these protective functions, the composition of your gut microbiome needs to maintain a stable profile, populated primarily by beneficial microbes, with a low presence of microbial species typically characterized as “harmful”. However, when the balance is disrupted, which can arise from infection, inflammation, immune deficiency, sleep pattern, changes in diet, or exposure to antibiotics or toxins, the gut microbiome can shift in composition, causing uncontrolled or heightened immune responses. 

An imbalance in microbial composition is known as dysbiosis.⁶ Dysbiosis of the gut microbiome triggers pro-inflammatory effects in the body, and has been linked⁷ to immune dysregulation (a breakdown in the control of immune system processes). Dysbiosis has also been implicated in a myriad of conditions and disorders, including a wide array of autoimmune conditions, Inflammatory Bowel Disease (IBD), Type 1 Diabetes, food allergies,⁸ asthma, neurodegenerative disorders,⁹ and even obesity.¹⁰

This is why nurturing your gut microbiome is important to support a resilient immune system.

While certain factors like age and genetics are fixed, diet, exercise, sleep quality, stress, and environmental exposures can all shape the structure and function of the microbiome throughout life. 

Here are four science-derived strategies to foster a healthy gut-immune connection: 

• Increase your daily fiber intake. In the digestive tract, certain fibers are fermented by gut microbes and biotransformed into short-chain fatty acids (SCFAs), which have a range of benefits in the body, including the maintenance of immune health.¹¹ SCFAs interact with immune cells and regulate anti-inflammatory and antioxidant responses to assist in defense against pathogens and certain autoimmune conditions.^12,13
• Prioritize sleep. Your body operates on a 24-hour cycle, known as your circadian rhythm, which plays a key role in maintaining homeostasis of the microbiome. Emerging data¹⁴ also show that the gut microbiome has its own circadian clock, exhibiting daily shifts in its composition. Changes to your normal “rhythms” induce what is known as “circadian misalignment”, which may disrupt your microbes and therefore, the important functions they perform.
• Manage stress. The inflammation that often accompanies high levels of stress triggers blooms of pathogenic microbes that promote dysbiosis and increased intestinal permeability (aka leaky gut). 
• Take a probiotic. Specific strains of probiotics have been studied to support a range of benefits within the gastrointestinal system, including the reinforcement of gut-barrier function and the support of cross-talk between gut and immune cells. 

The immune system co-evolved with microorganisms, learning to tolerate and even collaborate with the microbes living in and around us. As you now know, this intrinsic connection between the gut and the immune system contributes to immune homeostasis, immune responses, and protection against pathogen colonization.¹⁵ However, modern living (antibiotics, Westernized diets, environmental toxins, lack of exposure to nature) has disrupted our relationship with microbes, giving rise to myriad immune diseases and disorders that are linked to the health of our microbiome. As we search for ways to prevent, remediate, and even eradicate these issues, the microbiome holds vast potential to validate new solutions and revolutionize how we think about our health. 

1. Kalbermatter, C., Fernandez Trigo, N., Christensen, S., & Ganal-Vonarburg, S. C. (2021). Maternal Microbiota, Early Life Colonization and Breast Milk Drive Immune Development in the Newborn. Frontiers in immunology, 12, 683022. https://doi.org/10.3389/fimmu.2021.683022
2. Yoo, J., Groer, M., Dutra, S., Sarkar, A., & McSkimming, D. (2020, October 15). Gut Microbiota and Immune System Interactions. Microorganisms, 8(10), 1587. https://doi.org/10.3390/microorganisms8101587
3. O’Hara, A. M., & Shanahan, F. (2007, March). Gut Microbiota: Mining for Therapeutic Potential. Clinical Gastroenterology and Hepatology, 5(3), 274–284. https://doi.org/10.1016/j.cgh.2006.12.009
4. Pickard, J. M., Zeng, M. Y., Caruso, R., & Núñez, G. (2017). Gut microbiota: Role in pathogen colonization, immune responses, and inflammatory disease. Immunological reviews, 279(1), 70–89. https://doi.org/10.1111/imr.12567
5. Anjana, & Tiwari, S. K. (2022). Bacteriocin-Producing Probiotic Lactic Acid Bacteria in Controlling Dysbiosis of the Gut Microbiota. Frontiers in cellular and infection microbiology, 12, 851140. https://doi.org/10.3389/fcimb.2022.851140
6. Martinez, J. E., Kahana, D. D., Ghuman, S., Wilson, H. P., Wilson, J., Kim, S. C. J., Lagishetty, V., Jacobs, J. P., Sinha-Hikim, A. P., & Friedman, T. C. (2021, June 8). Unhealthy Lifestyle and Gut Dysbiosis: A Better Understanding of the Effects of Poor Diet and Nicotine on the Intestinal Microbiome. Frontiers in Endocrinology, 12. https://doi.org/10.3389/fendo.2021.667066
7. Wu, H. J., & Wu, E. (2012). The role of gut microbiota in immune homeostasis and autoimmunity. Gut microbes, 3(1), 4–14. https://doi.org/10.4161/gmic.19320
8. Peroni, D. G., Nuzzi, G., Trambusti, I., Di Cicco, M. E., & Comberiati, P. (2020, April 23). Microbiome Composition and Its Impact on the Development of Allergic Diseases. Frontiers in Immunology, 11. https://doi.org/10.3389/fimmu.2020.00700
9. Padhi, P., Worth, C., Zenitsky, G., Jin, H., Sambamurti, K., Anantharam, V., Kanthasamy, A., & Kanthasamy, A. G. (2022). Mechanistic Insights Into Gut Microbiome Dysbiosis-Mediated Neuroimmune Dysregulation and Protein Misfolding and Clearance in the Pathogenesis of Chronic Neurodegenerative Disorders. Frontiers in neuroscience, 16, 836605. https://doi.org/10.3389/fnins.2022.836605
10. Vamanu, E., & Rai, S. N. (2021). The Link between Obesity, Microbiota Dysbiosis, and Neurodegenerative Pathogenesis. Diseases (Basel, Switzerland), 9(3), 45. https://doi.org/10.3390/diseases9030045
11. Kim, C. H. (2021, April 13). Control of lymphocyte functions by gut microbiota-derived short-chain fatty acids. Cellular &Amp; Molecular Immunology, 18(5), 1161–1171. https://doi.org/10.1038/s41423-020-00625-0
12. Mariño, E., Richards, J., McLeod, K. et al. Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes. Nat Immunol 18, 552–562 (2017). https://doi.org/10.1038/ni.3713
13. Park J, Wang Q, Wu Q, Mao-Draayer Y, Kim CH. Bidirectional regulatory potentials of short-chain fatty acids and their G-protein-coupled receptors in autoimmune neuroinflammation. Sci Rep. 2019 Jun 20;9(1):8837. doi: 10.1038/s41598-019-45311-y. Erratum in: Sci Rep. 2019 Nov 20;9(1):17511. PMID: 31222050; PMCID: PMC6586800.
14. Zarrinpar, A., Chaix, A., Yooseph, S., & Panda, S. (2014, December). Diet and Feeding Pattern Affect the Diurnal Dynamics of the Gut Microbiome. Cell Metabolism, 20(6), 1006–1017. https://doi.org/10.1016/j.cmet.2014.11.008
15. Pickard, J. M., Zeng, M. Y., Caruso, R., & Núñez, G. (2017). Gut microbiota: Role in pathogen colonization, immune responses, and inflammatory disease. Immunological reviews, 279(1), 70–89. https://doi.org/10.1111/imr.12567