Nutrition & Immune Function

In Sigma Statementsby Danny LennonLeave a Comment

Estimated Reading Time = ~ 30 minutes

Important: This article makes no claims about eating to prevent COVID-19 or to improve resistance to SARS-CoV-2. This article is for educational purposes to clarify the relationship between nutrition and immune function, so that the reader can more easily identify pseudoscientific claims that are circulating on this topic

What is Immunity & Immune Function?

Across the general population it is acknowledged that one’s immune system is important in order to keep us healthy, primarily by preventing or limiting infection. However, what is meant by immune function, and especially how that relates to diet and lifestyle behaviours, is perhaps not well understood by many.

The immune system can distinguish between normal, healthy cells and unhealthy cells. The immune system (itself a complex network of cells) is sensitive to certain cues that allow it to distinguish which cells are normal/healthy and which are abnormal/unhealthy. Such cues are known as danger-associated molecular patterns (DAMPs). The immune system can also identify infectious microbes (e.g. viruses and bacteria) via recognizing pathogen-associated molecular patterns (PAMPs), that are released from such microbes. 

Once the immune system recognizes these patterns, it can mount a response to deal with the problem. If an adequate immune response is unable to be activated when it is required, then this can lead to infection or other problems. Hence why people with compromised immune systems are susceptible to a range of pathogens that typically are not problematic to individuals with a healthily functioning immune system. Also, as we are seeing with the current COVID-19 pandemic, if a novel pathogen is present and therefore we don’t have existing antibodies to it, then we are unable to mount that immune response and therefore experience infection and symptoms. Conversely, if an immune response is activated without a real threat or remains chronically (over)activated, this can play a role in driving autoimmune disease or allergy.

As mentioned above, the immune system is a complex network of cells. There are numerous different types of cells that are either located in particular tissues or in circulation. As you may expect, the different cell types have different roles, and a robust immune system relies on communication between cells to mount an appropriate response. Immune cells are derived from stem cells, which differentiate into lymphoid and myeloid progenitors. These further branch out to the more specific cell types associated with both adaptive and innate immunity (see image below). 

Innate Immune Response: Immediately (or within the first few hours of an antigen showing up in the body) a set of non-specific defense mechanisms are initiated in response to chemical properties of the antigen. These defences include the skin (acting as a physical barrier) and certain immune system cells that attack what are perceived as “invading” cells. Cells of the innate immune response include phagocytes (e.g., macrophages and monocytes), neutrophils, dendritic cells, mast cells, eosinophils, and others.

Adaptive Immune Response: The second line of defence is the adaptive immune response. This response is antigen-specific; meaning that once an antigen has been recognized, immune cells designed to attack that specific antigen are created. Therefore, once these antigen-specific immune cells have been created, they can be now used in future responses to that specific antigen, and thus mitigating/preventing the infection or degree of illness that could be caused by a previously unrecognized antigen.

Whilst the innate immune response has the advantage of speed, it is non-specific. Whereas the adaptive immune response, whilst slower, is specialized and thus more effective. By way of crude and simplistic analogy, think of it like the current strategies being used to suppress the spread of the SARS-CoV2 virus: First, as an immediate response we may decide to enforce a national lockdown. This has the advantage of speed and being able to rapidly and dramatically reduce community transmission of the virus. However, it is non-specific; people who do not have the virus, and thus cannot transmit it to others, are targeted in the same way as those who may have the virus. So the heavy lockdown restrictions are like that first-line of defence that is the innate immune system. In contrast, the longer-term response that takes longer to kick in and is generally slower, would be a strategy of aggressive testing and contact tracing on a population level, whilst society is open. In this response, although there is a lag-time before this response can kick in, it has the advantage of being highly specific; it targets those with the virus (and those in close contact) and removes them from the community until recovered, thus it doesn’t mount the same response to all people. This parallels with the adaptive immune response, which also takes longer to kick in but only targets the pathogens, in a specific manner, minimizing impact on cells that are not problematic.

As seen in figure 1, the adaptive immune system’s central players are the lymphocytes; T cells and B cells. B cells are responsible for immunoglobulin (Ig), or antibody, production. Igs are pathogen-specific molecules, which help the immune system to recognise and destroy pathogens. The B cells can differentiate into plasma cells, which produce one of five classes of Ig (IgM, IgD, IgG, IgA, and IgE). 

T cells are present in a large number of various subtypes that coordinate different types of immune responses, but that can be generally thought of as either:

  1. Cytotoxic T cells: involved in direct killing of infected damaged cells
  2. T-helper (Th) cells: involved in coordinating the responses of other immune cells

It is beyond the scope of this statement to delve into the various subtypes and specific roles of B cells, antibodies, T cells and Th cells, so for the curious reader it is suggested to read this review by Hoffman et al. for more on B cells and antibodies, or this overview by Pennock et al. for more on T and Th cells.

The majority of immune cells within the human body are found in the gut (specifically within the gut-associated lymphoid tissue). The mucosal surface is thin and acts as a permeable barrier to the interior of the body, which is obviously vital to the absorption of nutrients. However, due to this permeability most pathogens invade the human body via this route. And therefore it creates vulnerability to infection. So our immune system must be able to provide effective protection against invading pathogens, whilst simultaneously allowing movement of food proteins and commensal bacteria. Given the high concentration of immune cells within the gut, gut health has become a focus in some discussions around immune function; including discussions about how diet can influence the microbiome, the role of plant-based diets and specific nutrients (e.g. vitamin D) playing a role in gut permeability. These will be discussed later in this statement.

The activation of an immune response results in an expected inflammatory response. This acute inflammation that occurs (presenting as redness, swelling, pain, etc.), is a normal part of an effective immune response. However, when inflammation is present chronically (as in common in states of metabolic dysfunction) this can potentially lead to negative health outcomes. There is a potential for diet (both composition and total energy) to play a role here.

The “Immune Boosting” Fallacy

With an understanding of what the immune system is and what is meant by immune function, a common yet erroneous question one could ask is “how do I boost my immune system?” And it's understandable why such questions are commonplace; we’ve long been bombarded with messages of “boosted immunity” or “immune system boosting” protocols. A quick Google search for “immune boosting foods” throws up endless articles suggesting superfoods, tonics and juices to boost your immune system (with even generally reputable sources misusing terminology):

But not only is it not accurate to say eating watermelon, drinking tea or supplementing with vitamin C will “boost” your immune system, one wouldn’t want to be able to “boost” their immune system so easily. True boosting of the immune system, or in other words hyperactivity of the immune response, is what sets the stage for allergy development. For example, many people suffer from allergic rhinitis, where they will experience symptoms like sneezing, a runny nose, and swelling of the nasal passages due to having an overactive immune response to substances (in this case allergens) that should be harmless, such as dust or pollen. So having an allergic reaction is a case of the immune system being activated beyond normal. Overactive immune response is also implicated in autoimmune disorders. Therefore, it’s clear that it would be problematic if we were capable of “boosting” our immune system everytime we ate a fruit, vegetable or whatever special concoction is touted as an immune booster.

Whilst in many cases the phrase “immune boosting” is used as a marketing buzzword to push nonsense, there’s also likely plenty of cases where the messaging was made with good intent, but the phrasing used is just unfortunately inaccurate. And perhaps some would say it’s pedantic to get hung up on such a point, but it’s important to be precise in our language. Being precise in our language is what allows for consistent messaging as well as being able to hold people accountable for giving erroneous information. 

Also, it’s important to point out that while we can’t eat to “boost” our immune system, there certainly is a role of diet and specific nutrients for maintaining/supporting normal immune function and reducing susceptibility to illness. So with that, let’s explore what this role of diet is, and what aspects can support or hinder immune function.

Immune Function: Role of Diet

First, let’s be explicitly clear: When talking about immune function or the immune system, we are dealing with a multifaceted physiological system that is so incredibly complex that it’s absurd to think it’s possible to give simple recommendations of diet or supplement strategies that can easily influence immunity in a nice clean-cut way, if at all. And there is not one marker that can currently be used to predict the effect of a dietary intervention on immune function. So if you see anyone trying to portray the immune system as something simple that can be easily targeted with nutrients or supplements, be very, very skeptical.

The complexity of nutritional immunology is especially apparent when attempting to examine the role of chronic inflammation in disease development. For example, it has been proposed that inflammatory diet patterns contribute to specific cancers due to the influence of inflammation on the anti-tumor, adaptive immune response. And while there will be some need to mention systemic inflammation and its role in chronic disease here, that isn’t the primary focus of this statement. Rather the focus of this statement is more biased towards risk of acute infection and diets role in prevention of, or recovery from, such an infection. For a discussion on the inflammation-chronic disease relationship, the reader is referred to this previous podcast episode.

With all that said, there is a role for diet in maintaining “good” immune function, as well as dietary patterns and behaviours that could compromise immunity. In order to evaluate the diet-immunity relationship, it’s important to understand that assessing immune function in diet trials isn’t simple or consistent. Some trials will measure one, or a combination, of various immune/inflammatory biomarkers, for example cytokines (e.g. TNF-α, IL-6), C-reactive protein, and immunoglobulins (e.g. IgA). One can also look at the incidence of end outcomes such as frequency of infection, time to recover from an infection, etc.

With that in mind, let’s explore how nutrition can maintain good immune function (or negatively impact it) by examining some sub-elements of diet, namely; energy balance, macronutrients, micronutrients, specific compounds/supplements, and overall diet patterns.

Energy Balance & Immunity: Hypocaloric & Hypercaloric Diets

It is well established that there is an interaction between energy balance and immune function. We could consider the caloric requirements of someone currently fighting an infection. In clinical settings, patients fighting an infection in the intensive care unit (ICU) are at an increased risk for malnutrition, which creates a vicious cycle that in turn can worsen the ability to effectively fight the infection, something which has been discussed in dietetics in relation to managing patients with a SARS-CoV-2 infection. To make matters worse, commonly there is an increased energy cost to fighting an infection. For example, there is an increase in energy expenditure in cases where the immune response includes presentation of a fever. 

However, it is presumed that most readers of this statement will be concerned with a different context of the energy balance-immunity relationship, and likely related to one of these contexts:

  1. Influence of acute under-/overfeeding on immune function.
  2. Influence of chronic under-/overfeeding on immune function.
  3. Influence of body composition on immune function.

Considering the impact of acute and chronic energy balance is important, especially as the impact of any chronic-term positive/negative energy balance will alter body composition, which itself may play a role in immune function. To address these issues, it may be useful to do so through attempting to answer three common questions (and particularly common since the SARS-CoV-2 outbreak):

  1. How does body composition impact immune function?
  2. Will being in a calorie deficit negatively impact my immune system?
  3. Will fasting negatively impact my immune system?
1 - How does body composition impact immune function?

In relation to body composition, infection risk seems to follow a U-shaped curve, with “normal weight” being associated with lowest risk, whilst both obesity and underweight seem to increase infection risk in adults. However, there are some exceptions and nuances that highlight the complexity of this issue. In a review by Dobner and Kaser, they found two outcomes that run contrary to the general trend of increased risk at the extremes:

  1. Anorexia nervosa was not associated with increased viral infection risk in most studies.
  2. Often obesity seemed to impart a protective effect to critically ill patients, with respect to mortality.

Associations have been reported between obesity and diminished function of natural killer cells, dendritic cells and macrophages. Disruption of lymphoid tissue integrity by fat accumulation has been suggested to explain immune dysfunction in those with obesity, although much of the data is based on rodent models. Both animal and human studies are suggestive of an association between obesity and susceptibility to infection. However, one should consider whether this increased infection risk is due to the increased adiposity per se, or the factors commonly associated with it (e.g. poorer nutrition, lower physical activity, presence of comorbidities, etc.). Regardless of risk at an individual level, on average a higher degree of adiposity will increase risk of infection or complications arising after infection, as seen with data relating to various viral infections.

For example, the Centers for Disease Control and Prevention state that individuals with a BMI of more than 40 kg/m2 are at higher risk for flu complications. In a Canadian study, it has been demonstrated that people with obesity are at increased risk for respiratory hospitalizations during seasonal influenza periods, and for those with a BMI ≥ 35 the association remains whether the individual has a diagnosed chronic medical condition or not. Emerging data suggests the severity of COVID-19 increases with BMI; in a French retrospective cohort study, the proportion of patients in ICU requiring ventilation was greatest in patients with BMI >35 kg/m2. Although more data on this specific disease is required. There is also evidence of obesity being associated with skin infections and post-operative infection.

When looking at the effect of body weight change on risk, it’s found that significant weight can increase risk of pneumonia acquisition. In participants of the Health Professionals Follow-up Study and the Nurses' Health Study II, those who gained >18 kg (as opposed to weight maintenance) had a two-fold increase in risk of community-acquired pneumonia.

Therefore, when it comes to energy balance and immune function, overconsumption of calories (chronic positive energy balance) may be problematic due to its role in driving fat accumulation and in turn obesity, type 2 diabetes and other metabolic issues, each of which could translate to increased infection susceptibility or poor immune response to infection. There is much nuance to the discussion around the relationship between BMI and immune function, or adiposity and immune function, and deeper discussions elsewhere can provide more context.

2- Will being in a calorie deficit negatively impact my immune system?

In most people, running a slight calorie deficit is unlikely to be problematic. A two-year trial of 218 healthy adults without obesity, had the intervention group on a 25% calorie restriction (CR) diet. Over the course of the study, the CR group experienced an average  weight loss of 10.4%, hence leading to a reduction in several markers of inflammation. Importantly, the CR condition did not lead to any more clinically significant infections than the control group. Nor were there any negative impacts on in vivo cell-mediated immunity (as assessed by delayed type hypersensitivity skin response (DTH) and antibody response to 3 vaccines). There was however a decrease in white blood cell and lymphocyte count in the CR group.

It’s possible that with extended diets or aggressive deficits, problems may arise, especially in already lean individuals. However, the data isn’t clear cut on this. The importance of an adequate calorie intake to meet demands of training for athletes in order to support immune function has long been recommended in sports nutrition. And recent work examining Olympic athletes demonstrated an association between chronic low energy availability and illness. It may be contraindicated for athletes to diet aggressively or for an extended period, although evidence is difficult to point to in order to evaluate what the threshold may be. For those who acquire an infection, it is advisable to avoid a hypocaloric diet in order to ensure there are bodily resources to fight the infection. 

Conversely, it may be possible for individuals with a very high degree of adiposity, to be able to improve immune function through reductions in fat mass (via a caloric deficit), due to the associations between high BMI/obesity and infection susceptibility and/or immune response. The loss of fat mass may also improve overall health, thus theoretically decreasing risk of comorbidities. 

3 - Will fasting decrease immunity?

It’s difficult to give concrete answers here, again owing to the complexity of the immune system and the lack of studies that directly mimic the conditions that most people are asking about. However, if we consider the physiology that arises in the fasted state, we can make some broad assumptions that may nod us towards the right direction. First, there is little evidence to suspect that short-term fasting (≤ 24 hours) or time-restricted feeding protocols will cause any problems. Indeed, if such eating strategies allow an individual to control caloric intake and body composition effectively, they would have positive benefits for immune function. 

However, the question mark is over longer-term fasts, i.e. those of multiple days in duration. With long-term fasting the normal physiological response, across all animals and humans alike, includes a depression of hormones that support immune function. It is also known that extended fasts lead to decreases in immune cells, however they are restored upon refeeding (see image below). Similarly, we see rises in cortisol with prolonged fasts, which theoretically at least, could have negative implications for immune function. There is likely an evolutionary biological underpinning to this, with it being prudent for the body during an extended fast (~ > 3 days) to preserve its resources for immediate processes required for survival, by diverting them away from other resource consuming systems, including the immune system. However, it should be made clear that this relationship is by no means certain (at least to this author) and remains mechanistically plausible, rather than established with clear evidence. For this reason, it is suggested that it be something factored into the overall risk equation during any individual’s decision-making process. Such a process also takes into account many other factors relevant to that individual.  In cases in which it is better to err on the side of caution or to aim to avoid any reductions in immune function (say, in the middle of a novel virus pandemic), it may be prudent to avoid extended fasts, even without clear evidence of harm.

Macronutrients & Immunity

Carbohydrates

There isn’t strong evidence to suggest that a specific carbohydrate content of the diet is “better” for immune function. It is likely that an individual can have good immune function on a wide range of carbohydrate intakes, from very-low to very-high, once other dietary factors are met (food sources, micronutrients, energy).

Carbohydrates are proposed to have a role for athletes, with some claims that intense bouts of exercise can have an immunosuppressive effect (more on this in a later section). So the mechanistic argument is that provision of carbohydrates during/after exercise can offset the immunosuppression. However, in addition to the claim around post-exercise immunosuppression being strongly contested, there isn’t reliable and consistent data showing carbohydrates meaningfully affect outcomes, for example a reduction in the incidence of upper respiratory tract illness after intensive exercise.

Protein

Protein-energy malnutrition can increase susceptibility to infection by negatively affecting both innate and adaptive immune system responses. This type of malnutrition is most commonly seen in children and older adults in developing countries. However, individuals that are hospitalized with some infections may be at risk of protein-energy malnutrition, which increases risk of complications and comorbidities.

For healthy individuals in the general population, there are plenty of reasons why a low protein intake may be negative, although there isn’t much evidence to suggest it would directly affect immune function in a negative manner. But given there is no reason to conclude a high-protein diet would be negative, it is recommended to continue to avoid a low protein intake.

There are some suggestions specific amino acids can be prioritized with the goal of improving immune function, with glutamine being one of the most commonly suggested. But despite mechanistic rationale, human studies have produced inconsistent results in terms of glutamine supplementation providing any direct benefit to immune function, with the exception of specific clinical cases (i.e. in response to acute injury/infection).

Dietary Fat

Saturated Fatty Acids

There is evidence from in vitro, animal and epidemiological studies that saturated fatty acids promote inflammatory processes. In line with general healthy eating guidelines, keeping saturated fat intake to less than 10% of calories is recommended.

Omega-6 Fatty Acids

Claims are often made about omega-6 polyunsaturated fatty acids (PUFA) having an inflammatory effect. This likely stems from the fact that arachidonic acid is pro-inflammatory and omega-6 PUFA are the precursor to arachidonic acid. However, (as discussed in this podcast episode) there's no evidence that increasing omega-6 PUFA intake changes circulating levels of arachidonic acid. Similarly, human trials do not show omega-6 PUFA to cause chronic inflammation or inflammation-driven disease.

Omega-3 Fatty Acids

Omega-3 fatty acids have effects on the function of many types of immune cells. Omega-3 fatty acids can inhibit production of inflammatory mediators (e.g eicosanoids, NF-α, IL-6). Increasing the amount of omega-3 (DHA + EPA) in the diet leads to a dose-dependent increase in EPA and DHA in neutrophils, and as they replace arachidonic acid, it thus leads to a dose-dependent decrease in AA. This suggests a decrease in inflammation is plausible via this mechanism. Lipid mediator Protectins (lipid mediator derivatives of the parent omega-3 fatty acid DHA) have been suggested to have anti-viral properties and therefore mechanistic research has suggested a role in treating influenza, via suppression of influenza virus replication.

Whilst lots of work done in rodents shows effectiveness against pathogenic microbes, the impact of dietary supplementation of omega-3 fatty acids in human trials varies across studies, mith most positive results seen in diseased populations. And when it comes to evidence in healthy humans, there is no strong evidence that omega-3 supplementation will be effective for either “general immune health” purposes or for altering viral immunity. So in what will be a recurring theme, aiming for a dietary intake to avoid deficiency should be the advice to most individuals. An intake of 250mg of EPA + DHA per day will achieve this in adults, with the best sources being fish (such as mackerel, salmon, sardines). Vegetarians and vegans will rely on sources of ALA such as flax ,hemp or chia seeds and walnuts.

Micronutrients & Immunity

There are many micronutrients that are involved with the normal immune function, including selenium, zinc and vitamins A, C, D and the B-vitamins. However, one needs to discern the difference between a vitamin deficiency compromising immune function and if supplementing or eating high amounts of foods rich in that nutrient have an immune “enhancing” effect. Indeed, for most people in the developed world, eating a variety of foods as part of a healthy diet pattern (addressed later) will be sufficient to avoid nutrient deficiencies and in most cases negate any benefit of additional supplementation.

Speaking more broadly, there are two ways in which to view the impact of micronutrients on health outcomes: one is reductionist, whilst one is more global and useful. In the case of nutrition and immunity, one could focus on supporting specific actions of immune cells and then seeing what nutrients play a role in such a process. For example, it could be noted that arginine (an amino acid) plays an important role in the generation of nitric oxide by macrophages. And whilst such knowledge is important for the academic knowledge base, it’s too reductionist to be of real value for practitioners wishing to communicate how one can eat to support immune function. So it may be more useful to stick to looking at evidence that has clear demonstration of the effect of a nutrient (or ideally food/diet) on an actual clinical outcome.

For the purposes of this statement, the details of specific roles of many micronutrients will be either simplified, summarised or omitted, and instead the focus will be on a non-exhaustive list of some of the nutrients commonly discussed in relation to immunity. Later sections will discuss what dietary patterns would allow for ample amounts of those of relevance. So with that in mind, remember that even if there is no direct evidence of benefit to isolated supplementation of a nutrient, it doesn’t necessarily mean that the nutrient plays no role in immune function per se. However, it is likely more important to consider it in the context of an overall diet.

Vitamin A

Vitamin A deficiency (even subclinical deficiency) has been reported to have a detrimental impact on immune function. This may be due in part to vitamin A’s role in maintaining the integrity of mucosal cells in first-line defences of the immune system like the skin and respiratory tract. The only benefit to vitamin A supplementation is likely in populations with clear vitamin A deficiency, usually where malnutrition is present. But even then, supplementation results are condition-specific (for example, it may have no effect on pneumonia, or even be counter-productive).

Vitamin C

As vitamin C deficiency can impair immune function and lead to increased risk of infections (hence why pneumonia is a common complication of scurvy), maintaining an intake sufficient to avoid deficiency is obviously recommended. Thankfully, the amount of vitamin C necessary to do so is very easy to do via a healthy diet pattern that contains a variety of plants. In those with low intakes, supplementation may help prevent and treat respiratory infections. There is some data on established infections showing that supplemental vitamin C could have a beneficial impact, although this seems to be in cases where individuals’ vitamin C levels are low. Similarly, some studies suggest high-dose vitamin C can reduce duration of the common cold, there is disagreement among studies, leaving an overall inconclusive picture.

Vitamin D

There is an increasing number of studies investigating the immunomodulating effects of vitamin D, especially now that it is known that many of the immune cells contain the vitamin D receptor (VDR). Also, immune cells are a site of vitamin D metabolism, with 25(OH)D being converted into the active form of vitamin D; 1,25(OH)2D. As vitamin D is implicated in preventing intestinal permeability, mechanistically there is further rationale as to how it can maintain immune function. It has also been shown that 1,25(OH)2D has a key mediating role in innate immune responses (e.g. via induction of antimicrobial proteins). And whilst a large amount of data is now available, a lot of the data comes from in vitro studies in which vitamin D is used at levels above the normal physiological range. In looking at human trials, one can consider the role of vitamin D status on immune function, as well as the impact of vitamin D supplementation (or dietary intake).

One of the issues with determining a target vitamin D status to support immune function is that there is no consensus on this matter across research groups and organizations. In fact, even on the topic of vitamin D and bone health, where historically most of the research focus has been, there is still a lack of consensus on what constitutes an optimal vitamin D status. The Institute of Medicine sets a figure of 50nmol/L for good bone health, and the Endocrine Society states that vitamin D sufficiency is above 75nmol/L. When it comes to immune function specifically, there is even less data and therefore a lack of an established vitamin D status that likely maximally supports immunity. With that said, some evidence does show a clear relationship and suggests thresholds at which benefits are observed.

With regard to vitamin D status (determined by measured 25(OH)D in circulation) and infection incidence, in the UK a study on over 6,000 adults found that of the participants with a circulating 25(OH)D of less than 25nmol/L, 12% had a respiratory tract infection in the month prior to testing, whereas only 6% of those with 25(OH)D above 100 nmol/L had experienced an infection in the same period. And the association remained even after accounting for lifestyle and socio-economic factors. The findings demonstrated a linear relationship, with each 10 nmol/L increase in circulating 25(OH)D reducing risk of acute respiratory infection by 7%. In a cohort study of ~200 healthy adults, maintaining a vitamin D status (circulating 25(OH)D) of more than 95 nmol/L during 114 days of autumn and winter in a temperate zone was associated with a two-fold reduction in the risk of acute viral respiratory tract infection (confirmed by swabs).

In a RCT of vitamin D supplementation, an intervention group was given 5,000 IU/day of vitamin D3 for 14 weeks. Compared to the placebo group, the supplementation group experienced increases in salivary secretion rates of both IgA and antimicrobial peptides, thus potentially imparting an immune function benefit. However, the evidence as of yet isn’t as strong or consistent enough to conclude that vitamin D supplementation will reduce actual infection incidence and/or duration. Studies show mixed results, while many use self-reported measures of infection, which likely leads to inaccurate quantifying of true infection rate. The mixed results in this area may also reflect that there are distinct differences in supplementing to reverse a deficiency versus supplementing in individuals with a sufficient baseline status.

Pragmatically, maintaining sufficient vitamin D status (perhaps > 50/75 nmol/L) is likely beneficial for immune function and resistance to infections. Therefore a recommendation for regular exposure to sufficient sunlight is prudent. In situations where this isn’t possible (due to geographical region, limited outdoor access, season or ethnicity), the use of a vitamin D3 supplement at a dose of ~ 2000 IU/d has been recommended.

Vitamin E

Vitamin E is the collective term for tocopherols and tocotrienols found in food (with each group having four sub-types: α, β, γ, and δ). However, only α-tocopherol meets the human vitamin E requirement. Clear mechanisms have been confirmed that demonstrate the important role vitamin E plays in the function of many immune cells, and deficiency impairs cell-mediated immune function. Although evidence in human research is mixed, some trials suggest that supplementation with vitamin E (as α-tocopherol) can improve resistance to upper respiratory tract infections. Similarly, in older adults it has been shown that vitamin E supplementation can improve function of various immune cells; namely T-cells, neutrophils and Natural Killer cells. Effective dosages seem to be in the range of 200-800 IU/day.

Zinc

It’s well accepted that zinc plays a role in both innate and adaptive immunity, and a mild zinc deficiency is associated with detrimental impacts on the immune response, thus increasing susceptibility to infection. There is also evidence that acute zinc supplementation can reduce the duration and severity of illness, particularly the common cold. There is a time-sensitive nature to this as the benefits are observed when zinc is supplemented within 24 hours of the onset of symptoms. Zinc acetate lozenges specifically reduce the time to recovery in cases of the common cold. 

However, in a similar narrative to that of vitamin D, whilst a clear association exists between zinc deficiency and impaired immune function, human trials examining zinc supplementation are not as consistent as one would wish. There seems to be a wide variation in response to zinc supplementation and there is also the potential for negative impacts on immune function from zinc overload. So zinc supplementation may be useful for those with a deficiency (children and older adults are most at risk), but broad supplementation is not supported. Targeted, specific use of zinc lozenges with the onset of a cold has enough evidence to warrant consideration. Recommended intake of zinc (from the diet) for the purposes of preventing a deficiency is 8-10mg/day, whilst a supplemental dose of 75mg/d is suggested for reducing the duration and severity of a cold.

Polyphenols

There are known to be about 8,000 polyphenols found in plants, divided into four main classes: flavonoids (~50% of all polyphenols), phenolic acids, lignans, and stilbenes. A 2016 systematic review and meta-analysis showed that flavonoid supplementation (ranging from 0.2 to 1.2 g/day) was associated with a 33% decrease in upper respiratory tract infection, compared with control. However, when looking at markers of inflammation and immune function, differences between groups were negligible.

Anthocyanins are a flavonoid subclass and are found in red, purple and blue plant foods, including most types of berries, red apples, grapes, red cabbage and black beans. An evaluation of inflammation markers in the Framingham Heart Study Offspring cohort suggests that high anthocyanin intake imparts an anti-inflammatory impact. The study used a collection of 12 inflammatory markers to designate an Inflammation Score (IS), and looked at the intakes of the flavonoid subclasses across the cohort. Comparing the highest quintile (median intake = 32mg/d) to the lowest quintile of anthocyanin intake shows a 73% lower overall IS for higher intakes. The higher anthocyanin intake was also inversely associated with all twelve subgroups, including: acute inflammation score (100% decrease), cytokine score (75% decrease) and oxidative stress score (52% decrease). Even when total fruit and vegetable intake was accounted for in the model, the inverse association still remained.

Other Compounds & Supplements

Probiotics

It is common to see probiotics touted as a supplement that can enhance immune function, perhaps due to the connection between the gut microbiome and the immune system. However, rather than asking do probiotics as a general class have a global result of “supporting the immune system”, one must instead evaluate the role of a specific probiotic strain for a specific clinical outcome. As discussed in a previous Sigma Statement on Probiotics, some specific strains of probiotics have some evidence of efficacy in treatment of certain food allergies (which are Ig-E mediated immune reactions). Also, probiotics have been used in treatment of irritable bowel syndrome (IBS), in which there is altered mucosal immune function, but results in this area have been mixed.

A 2011 Cochrane Systematic Review hinted at a potential benefit for probiotics in reducing frequency of URTI compared to placebo. However, these results are of limited value given the disagreement between studies included, the fact that different strains were used in studies, and for some outcomes there were only a small number of studies that contributed to that result in the review. For example, the review results didn’t show any benefit in terms of duration of URTI episodes, but only two of the included trials reported this outcome. Given the degree of heterogeneity among studies and results, it is difficult to draw sound conclusions from such an analysis.

So outside of some very specific clinical cases, based on current evidence, there is little reason to suggest people should take probiotic supplements with the aim of supporting their immune system.

Green Tea/ECGC

Green tea contains catechins including EGCG, which is believed to be responsible for much of green tea's reported health benefits. Green tea and EGCG have been suggested to be effective in influencing several aspects of the innate and adaptive immune system in mechanistic and animal studies, although the evidence in humans is essentially non-existent.

Other Natural Compounds

Other “immune-supporting” supplements you’ll likely stumble across on walking into any health food store include products that include ingredients such as echinacea, ginkgo or elderberry. At this current time the data on these ingredients is unconvincing or interpretation of that data is being stretched beyond what an accurate appraisal of the research would suggest. Others such as American Ginseng, have been suggested to have microbial activity, and a limited amount of data suggesting they may reduce incidence of common cold and influenza episodes). However, at this time it is difficult to conclude whether consuming any of these natural compounds will impart a clinically meaningful effect.

Diet Patterns

While most of the nutrition-immunity research has focused on individual nutrients, as discussed in the previous sections, very few studies have examined overall diet patterns and impact on immune function in healthy populations. And there is very little in the way of evidence to demonstrate an impact of nutrition on disease risk due to mediating immune function, as there are very few high-quality RCTs assessing clinical endpoints, such as a reduction in clinical events. To date, the European Food Safety Authority have not authorised any claim for a food or food component to be labelled as protecting against infection. But as with many nutrition-related topics, a hyperfocus on individual nutrients ignores the context in which humans actually consume those nutrients; within foods as part of a food matrix and within an overall dietary pattern. 

Lower diet quality (as determined by the Diet Quality Index and the Healthy Eating Index) is associated with increased C-reactive protein (CRP) and serum amyloid A (SAA) concentrations. The typical Western diet (characterised by a diet high in sugar, trans and saturated fats, but low in complex carbohydrates, fibre, micronutrients, and other bioactive molecules such as polyphenols and omega 3 polyunsaturated fatty acids) is a risk factor for both obesity and chronic inflammation, both of which have previously been discussed as factors potentially altering immune function. 

Dietary patterns rich in vegetables, fruit, nuts, legumes, fish, and unsaturated fat sources (especially omega-3), such as the Mediterranean Diet or DASH Diet, tend to be associated with lower levels of inflammatory markers. Plant-based diets are likely beneficial for overall “gut health” owing to their high-fibre content (both soluble and insoluble), provision of micronutrients and polyphenols, and ability for nutrients to reach the large intestine before digestion (e.g. resistant starch reaches the large intestine where bacteria can “feed” on it, leading to production of butyrate, which is beneficial to intestinal cells).

After adjusting for potential confounders, it was found that a 5% increase in the prevalence of low fruit/vegetable consumption was associated with a 12% increase in influenza-related hospitalization rates (95% CI 1.08, 1.17). When obesity, low fruit/veg intake, and low physical activity were all included in a single model, while adjusting for confounders, those rates of increased hospitalizations were 6%, 8%, and 7%, respectively.

Many of the conclusions for eating “to support the immune system” will be the same as fundamental principles of a healthy diet pattern. Namely:

  1. Energy: Eat at a caloric intake that allows maintenance of a healthy body composition. Prolonged (multiple day) fasts could have acute detrimental impacts on immunity, although data is lacking. 
  2. Food quality: Eat a diet primarily based on vegetables, fruits, legumes, wholegrains, nuts/seeds, fish and dairy. Allows avoidance of micronutrient deficiencies.
  3. Fibre: Consume ≥ 30g/d via a variety of foods. It is beneficial to consume fibre that makes it to the large intestine and therefore can lead to production of short-chain fatty acids by gut bacteria, as the SCFAs contribute to the health of the epithelial cells of the gut. 
  4. Polyphenols: A variety of fruit and vegetables will allow for a polyphenol-rich diet. Anthocyanins seem to have particularly good anti-inflammatory effects and can be obtained via consuming a variety of red, purple and blue fruits and vegetables.
  5. Saturated fat: Limit to < 10% of calories

Other Lifestyle Behaviours to Support Immune Function

  • Sleep: Sleep restriction modulates immune system cells. During infection, the immune response also influences sleep processes, and thus a bi-directional sleep-immunity relationship exists. There are also aspects of immunity influenced by sleep processes, and others by circadian processes. For a full discussion of sleep and immune function, the reader is pointed to this review by Irwin.

  • Exercise/Activity: In close to all cases, exercise is beneficial. It is commonly claimed that very intense exercise will negatively affect immunity, at least acutely. However, this idea has been strongly challenged recently, with the point being made that the increased incidence of illness seen after certain athletic endeavors (e.g. a marathon) not being simply down to the exercise, but rather to the myriad of other stressors (anxiety, travel, time-zone change, loss of sleep, etc.) that come along with athletic pursuits. In cases of the common cold, it’s highly likely that exercising won’t be a problem (just be considerate of others and perhaps exercise alone rather than going to your gym class!). If symptoms are more severe, such as a fever or extreme fatigue, then maybe taking a rest wouldn’t be a bad idea. Of course, always discuss any symptoms with your doctor.

  • Stress: Short-term stress can be beneficial in some cases (e.g. wound healing, vaccination). However, chronic stress (i.e. most of our “life stresses”) can “suppress protective immune responses and/or exacerbate pathological immune responses”. Interestingly, it seems that someone’s psychological stress state before exercise exerts an important moderating effect on the immune response to that exercise.

  • Environmental factors in infancy: The environment during infancy can have long-term implications for immune function, with an effect seen due to: urban vs rural living, exposure to pets, antibiotic use, and breastfeeding.

  • Hygiene: Good hygiene and hand washing are beneficial behaviours for avoiding infections, not due to supporting immune function per se, but rather by simply avoiding exposure to potential pathogens.

Summary of Key Points

  1. The immune system is sensitive to certain cues that allow it to distinguish which cells are normal/healthy and which are abnormal/unhealthy. Immune responses consist of innate immunity (immune response) and adaptive immunity.

  2. We can’t eat to “boost” our immune system. However, there is a role of diet in maintaining/supporting normal immune function and reducing susceptibility to illness.

  3. In relation to body composition, infection risk seems to follow a U-shaped curve, with “normal weight” being associated with lowest risk, whilst both obesity and underweight seem to increase infection risk in adults.

  4. Overconsumption of calories may be problematic due to its role in driving fat accumulation and in turn obesity, type 2 diabetes and other metabolic issues, each of which could translate to increased infection susceptibility or poor immune response to infection.

  5. In most people, running a slight calorie deficit is unlikely to be problematic. Hypocaloric diets (when leading to low energy availability) may be problematic for athletes.

  6. There is little reason to suspect that short-term fasting (≤ 24 hours) or time-restricted feeding protocols will meaningfully compromise immune function. Little data is available on longer, multiple day fasts.

  7. There are many micronutrients that are involved with the normal immune function, including selenium, zinc and vitamins A, C, E and various B-vitamins. Hence diet patterns that allow nutrient deficiencies to be avoided should be promoted.

  8. Data on supplementation of various micronutrients is largely mixed, making it difficult to make clear conclusions, except for some specific scenarios and nutrients.

  9. Maintaining sufficient vitamin D status is likely beneficial for immune function and resistance to infections, so regular sunlight exposure or supplementing with ~ 2000 IU/d vitamin D3 is recommended.

  10. Supplementation with zinc lozenges (~75 mg/d) at the onset of a common cold may reduce time to recovery.

  11. Outside of some very specific clinical cases, based on current evidence, there is little reason to suggest people should take probiotic supplements with the aim of supporting their immune system.

  12. Many of the conclusions for eating “to support the immune system” will be the same as fundamental principles of a healthy diet pattern.

  13. Other lifestyle behaviors will influence immune function, including sleep, stress, physical activity, hygiene and environmental factors in infancy.

Statement Author: Danny Lennon
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Danny is the founder of Sigma Nutrition and head of content creation. Known for hosting the top-ranked podcast Sigma Nutrition Radio, Danny is also a respected educator in the field. Danny has a master’s degree (MSc.) in Nutritional Sciences from University College Cork, during which time Danny took classes in biochemistry, clinical nutrition, micronutrient interactions and physiology. Previous to this Danny also completed a BSc. Degree in Biology and Physics Education and spent a year teaching these subjects.

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