The content of this post is excerpted from the Standard Monograph, Foundational Principles and Nutrient Strategies for Building Immune Resilience.


When confronted with the need to build immune system strength, we instinctively gravitate toward pills, injections and powders. For functional medicine clinicians, this pharmaceutical imprinting is very often translated into non-pharmacological immunomodulating agents (e.g., herbs, mushrooms, etc.). But this approach is still often reactionary and overlooks the fundamental physiological relationship between the immune system and the biological functions with which it interfaces.


10 Fundamental Principles for Building Immune Strength

If the COVID-19 pandemic has taught us anything, it is that the immune system is not an isolated network of cells; it influences (and is influenced by) nearly every physiological system in the body. COVID-19 “co-morbidities” and “risk factors” could simply be the losses of physiological resilience and metabolic reserves. I am still profoundly convinced that these agents have great limitations in subjects who haven’t engaged the foundational principles for building their immune health.


1. Maintaining and Protecting Barrier Functions

Even though immune system function is often measured by immune cell numbers or cytokine concentrations in the peripheral blood, most of the activity of the immune system occurs within the various tissues and specialized organs/glands that control the interface between our bodies and the outside world. In fact, most immune system cells are found within specialized mucosal membranes that make up the gastrointestinal tract (GALT), where it is said greater than 75% of all mature immune cells reside and function.

Breaches in the barrier function of the gut (sometimes called leaky gut syndrome) are one of the most potent immune challenges a person can face (including many autoimmune and autoinflammatory challenges).1,2 This is why protecting barrier function, especially the integrity of the barrier within the intestinal mucosa, is vital for basic immune function and appropriate immune responses.


2. Maintaining/Restoring Commensal-Friendly Microenvironments

This support mechanism is closely related to the gut barrier function mentioned above since commensal organisms reside almost exclusively in the skin or mucosal membranes (mouth, GI, vagina, etc.), where the immune system is concentrated. An environment that is conducive to the proper number, type, and diversity of commensal organisms, and is unfriendly to most harmful organisms, is important for overall health and vital for proper immune function.3 Because so much of the immune system resides in the GI tract, the “training” and maturation of immune system cells are dependent on the interaction with commensal organisms within the gut microflora. Gut dysbiosis, or an imbalance in the gut microbiota, has been linked with numerous immune challenges, including COVID-19.4


3. Practicing Appropriate Hygiene Practices

In the historic battle between human health and infectious diseases stands the appropriate role of personal and community hygiene practices. Implementation of personal hygiene practices, access to clean water, properly designed sewage facilities, quarantine of infectious individuals and similar practices have saved countless lives. Where these practices are less common or where certain infrastructure is limited, infectious diseases are still common and devastating.


4. Building Micronutrient and Antioxidant Reserves

One of the hallmarks of modern nutrition is the connection between specific nutrient deficiencies and disease susceptibility, but understanding how nutrient insufficiencies can also create immune vulnerabilities or how supplementing until a person reaches optimal nutrient status is not always well appreciated. In other words, many individuals with immune challenges or illnesses may benefit from consuming well above the USRDA levels of particular vitamins or minerals, intake which is designed to build reserve capacity rather than merely to prevent a nutrient deficiency.

Additionally, active immune systems produce a wide range of oxygen radicals as a natural consequence of mounting a strong defense. It is critical these oxygen radicals are swiftly neutralized by a strong network of antioxidants. While many micronutrients are vital to the antioxidant reserve (e.g., vitamin C, vitamin E, selenium, etc.), building antioxidant reserve requires manufacturing adequate glutathione levels as well as triggering appropriate upregulation of antioxidant enzymes.


5. Maintaining/Building Cellular (Mitochondrial) Energy Reserves

Mitochondria and the energy they produce within immune cells are vital for controlling innate and adaptive immune cell responses.5 When the immune system is actively fighting an infection, those energy reserves can be quickly depleted, leaving the patient exhausted and even lethargic, which is part of the classic illness syndrome. When cellular energy reserves are already depleted due to poor diet, stress, strenuous exercise, short sleep duration, or to perform other critical metabolic functions, such as detoxification, our immune system can be easily overwhelmed. Therefore, a comprehensive immune-building strategy should always consider the role of cellular energy and mitochondrial function.


6. Maintaining a Circadian Lifestyle

The immune system, like many other important metabolic systems, is highly coordinated by circadian signals. Disruptions to these signals can reduce immune system function and increase the risk for (and exacerbation of) autoimmune disorders.6 Entrainment by the light/dark cycle (some of which is signaled through circadian cortisol production) is critical for immune cell function, including some of the communication between certain immune cells and microbes within the gut.7,8

Maintaining a consistent and adequate sleep/wake cycle that is closely synchronized with the dark/light cycle has been shown to improve resilience against many acute and chronic diseases.9,10 Likewise, properly managing (or avoiding) frequent circadian disruptors, such as shift work, sleep deprivation, jet lag, and sleep disruption, can radically improve a person’s immune and chronic disease resilience. It is also important to mention that meal timing is also an important circadian cue, where consumption of food during normal daylight (and activity) hours reinforces a strong circadian signal.11,12


7. Limiting Stress and Other Signals That Diminish Immune Integrity

While this principle covers a range of signals, it is a critical step in assessing someone’s immune system vulnerabilities and is often critical in a successful therapeutic plan to build immune strength. Some of the most obvious are unmanaged or chronic stress (cortisol is a potent immune-suppressing hormone),13,14 environmental toxins,15 destructive lifestyle behaviors, EMFs,16 and many psychosocial and community factors. While the solutions to diminishing the effects of some of these factors are complex and multifactorial, addressing these factors can have some of the most profound effects on a person’s health and wellbeing.


8. Reducing Chronic Inflammatory Triggers and Mediators

Inflammation is one of the core functions of the innate immune system and is vital to a healthy immune response. However, inappropriate or chronic inflammatory signaling is a hallmark of almost every chronic disease, and the appropriate modulation of inflammation is critical for a healthy immune system. Clinicians should always assess and treat a patient for chronic inflammatory triggers and mediators, especially those coming from the diet.


9. Avoiding Antigens and Allergens in Adulthood

This advice appears to be basic, but it is fundamentally associated with the phenomenon of immune system aging known as immunosenescence. As we age, our immune system is less able to adapt new strategies when encountering new antigens, and it appears to be more vulnerable to immune-related disorders. Elderly subjects seem to be especially vulnerable to seasonal infectious agents, chronic inflammatory diseases and, of course, malignantly transformed cells not removed by the immune system before multiplying. During the COVID-19 pandemic, age was the single most predictive risk factor for mortality amongst those infected.17

While it is clear that there are many ways to build a stronger immune response and increase the metabolic reserve the immune system relies upon at any age, it is also clear that avoiding unnecessary exposure to novel antigens and allergens may be a prudent way to stay healthy and avoid episodes of critical illness in older subjects. While the hygiene hypothesis may explain the need for appropriate antigen/allergen exposure in children, this is not a strategy for improving immune health in the elderly.


10. Using Immune-Modulating Agents to Strengthen Immune Function

While the foundation of immune support is in building metabolic reserves, there are a number of ways to specifically enhance immune function using agents generally referred to as immune modulators. These agents vary in their mechanisms but are mostly derived from plants, fungi and other microbes. Some of these agents are antimicrobial, antiviral, antifungal or antiparasitic, while other agents act in ways to directly stimulate or modulate immune cell function. However, the benefits of some of these agents are tremendously weakened when the fundamental principles above have been neglected, and their ineffective use will often frustrate both patient and clinician.





Thomas G. Guilliams, PhD (Tom) earned his doctorate in molecular immunology from the Medical College of Wisconsin in Milwaukee. For the past two decades, he has spent his time investigating the mechanisms and actions of lifestyle and nutrient-based therapies, and is an expert in the therapeutic uses of dietary supplements. Tom serves as an adjunct assistant professor at the University of Wisconsin School of Pharmacy and was the VP of Science for Ortho Molecular Products for 24 years (he now serves them as a consultant). Since 2014 he has been writing a series of teaching manuals (Road Maps) that outline and evaluate the evidence for the principles and protocols that are fundamental to the functional and integrative medical community.  He is the founder and director of the Point Institute, an independent research and publishing organization that facilitates the distribution of his many publications. A frequent guest-speaker, Dr. Guilliams provides training to a variety of health care disciplines in the use of lifestyle and natural medicines. He lives in the woods outside of Stevens Point, Wisconsin with his wife and children.




  1. Kinashi Y, Hase K. Partners in Leaky Gut Syndrome: Intestinal Dysbiosis and Autoimmunity. Front Immunol. 2021 Apr 22;12:673708.
  2. Fasano A. All disease begins in the (leaky) gut: role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases. F1000Res. 2020 Jan 31;9:F1000 Faculty Rev-69.
  3. Wiertsema SP, van Bergenhenegouwen J, Garssen J, Knippels LMJ. The Interplay between the Gut Microbiome and the Immune System in the Context of Infectious Diseases throughout Life and the Role of Nutrition in Optimizing Treatment Strategies. Nutrients. 2021 Mar 9;13(3):886.
  4. Hussain I, Cher GLY, Abid MA, Abid MB. Role of Gut Microbiome in COVID-19: An Insight Into Pathogenesis and Therapeutic Potential. Front Immunol. 2021 Oct 14;12:765965.
  5. Steinert EM, Vasan K, Chandel NS. Mitochondrial Metabolism Regulation of T Cell-Mediated Immunity. Annu Rev Immunol. 2021;39:395-416.
  6. Xiang K, Xu Z, Hu YQ, et al. Circadian clock genes as promising therapeutic targets for autoimmune diseases. Autoimmun Rev. 2021;20(8):102866.
  7. Shimba A, Ejima A, Ikuta K. Pleiotropic Effects of Glucocorticoids on the Immune System in Circadian Rhythm and Stress. Front Immunol. 2021 Oct 8;12:706951..
  8. Brooks JF 2nd, Hooper LV. Interactions among microbes, the immune system, and the circadian clock. Semin Immunopathol. 2020 Dec;42(6):697-708.
  9. Ibarra-Coronado EG, Pantaleón-Martínez AM, Velazquéz-Moctezuma J, et al. The Bidirectional Relationship between Sleep and Immunity against Infections. J Immunol Res. 2015;2015:678164.
  10. Besedovsky L, Lange T, Haack M. The Sleep-Immune Crosstalk in Health and Disease. Physiol Rev. 2019;99(3):1325-1380.
  11. Pickel L, Sung HK. Feeding Rhythms and the Circadian Regulation of Metabolism. Front Nutr. 2020;7:39.
  12. Lewis P, Oster H, Korf HW, Foster RG, Erren TC. Food as a circadian time cue - evidence from human studies. Nat Rev Endocrinol. 2020;16(4):213-223.
  13. Fali T, Vallet H, Sauce D. Impact of stress on aged immune system compartments: Overview from fundamental to clinical data. Exp Gerontol. 2018;105:19-26.
  14. Cain DW, Cidlowski JA. Immune regulation by glucocorticoids. Nat Rev Immunol. 2017;17(4):233-247.
  15. Lawrence BP. Environmental toxins as modulators of antiviral immune responses. Viral Immunol. 2007;20(2):231-242.
  16. Piszczek P, Wójcik-Piotrowicz K, Gil K, Kaszuba-Zwoińska J. Immunity and electromagnetic fields. Environ Res. 2021;200:111505.
  17. Alexander HD. Triple Jeopardy in Ageing: COVID-19, Co-morbidities and Inflamm-ageing. Ageing Res Rev. 2021;101494.