Americans are quite a well-stressed lot. From international security threats to a full day of meetings and toting the kids around, stress is a constant companion.

John Quilter, business development director, Wellmune/Kerry Functional Ingredients & Actives, Eagan, MN, cited a study from Carnegie Mellon University reporting that stress levels have increased 18% for women and 25% for men over the past 25 years. “With stress being a major factor for many adults, it is crucial for people to support the immune system to better manage the everyday stress that can compromise an otherwise healthy body,” he opined.

Through it all, when people feel “ok,” they take their immune systems for granted, barely giving it a thought—until symptoms start to appear. Formulating and marketing an immune system supplement that addresses healthy stress management, therefore, may help millions of Americans to better weather stress storms.

Nena Dockery, technical services manager, Stratum Nutrition, Springfield, MO, observed, “In general, stress isn’t considered when creating immune support formulas, even though it is definitely a critical factor in immune system functioning and can impact optimal effectiveness of immune support formulations.”

She added that it is challenging to convey to consumers accurately how a particular type of stress affects the immune system; most immune support formulations are designed to address a specific aspect of immune function through targeting a bodily system or health concern (such as seasonal vulnerability). “However,” Ms. Dockery said, “creating immune support formulations that focus on stress as a contributing factor in immune system depletion could fit into a unique niche in the marketplace. With appropriate research support, formulations that provide immune system support for stress-induced depletions in immune functioning could be created to target acute stress as a contributing factor.”

Acute and chronic stress may need varied approaches in certain cases. According to Tim Hammond, vice president of sales and marketing, Bergstrom Nutrition, Vancouver, WA, since acute stress episodes may become a chronic, long-term concern, both should be considered during formulating—although each may require different approaches. “Acute bouts of stress are often healthy and necessary for maintaining health, requiring formulations that focus on preparing and bolstering the body to react quickly before subsequent damage is done,” he explained. “Chronic stress, however, is usually innately harmful. When addressing chronic stress, it is important to focus not only on bolstering the body but also on reducing stress.”

The idea of targeting healthy stress reduction with immune support is one that Paul Dijkstra, CEO, InterHealth Nutraceuticals, Benicia, CA, said is relevant and intriguing. “Emerging evidence is tracing the pathways of the mind-body interaction,” he reported. “Research has shown that stress of any significant duration—from a few days to a few months or years negatively affects all aspects of immunity. Thus, long-term or chronic stress, through too much wear and tear, takes a toll on the immune system.”

Bérengère Feuz, marketing group manager, Lallemand Health Solutions, Montreal, Canada, asserted that high chronic stress and immune function are definitively linked. “Chronic stress, or for example high intensity exercise (a source of stress for the organism) increases the risk of common infections due to an immunosuppressive effect,” she explained. Therefore, populations exposed to a high degrees of physical and environmental stress, such as athletes and those in high-stress situations, like first responders, may suffer from an increased incidence of infections, such as upper respiratory tract illness. “So, by managing stress, immunity can be indirectly improved,” she added.

Hilde Raa, science manager, NutraQ, Oslo, Norway, noted that research has shown chronic stress can exert a negative impact on the immune system through suppressing protective immune responses, lowering defensive ability against invading microorganisms and thus increasing vulnerability to infections. She explained, “While acute stress actually seems to enhance immune functions temporarily, the opposite happens when stress persists over longer periods of time. Chronic stress suppresses and dysregulates the immune system, rendering it less fit to fight infections and stop inflammation, and it can even induce pathological immune responses.”

A large majority of immune support supplements are aimed at seasonal distresses (notably the rash of colds and flu that occur prominently during winter), but opportunities abound when considering how stress affects immunity.

Ms. Dockery explained that the link between high stress and immune function is complex and involves pituitary and hypothalamic hormones along with immune system cells, predominantly white blood cells (leukocytes). Under any given circumstance, stress can be either beneficial or harmful to immune system functioning. 

“In times of acute stress, most cell-mediated immune system processes are temporarily depressed, increasing susceptibility to infection and disease,” she elaborated. “However, certain immune responses are actually enhanced. For example, published research has shown that acute stress occurring immediately after skin exposure to an antigen may increase mobilization of leukocytes from the blood to the skin as a result of signals sent from the brain to the immune system. The response may be similar to the fight-or-flight system that occurs through the action of stress hormones that ‘inform’ the immune system about impending challenges, such as wounding or infection, caused by a stressor. Studies such as this led to the proposal that acute fight-or-flight stressors may cause redistribution of immune cells into the compartments in which they can act most quickly and efficiently against invaders.”

Shaheen Majeed, marketing director, Sabinsa Corporation, East Windsor, NJ, said that though stress of all sorts is a daily occurrence and people correlate stress to a negative aspect of the modern lifestyle, individual responses to a particular stressor are varied. “However, in general, stress has a bidirectional effect on the immune system,” he noted.

Acute stress can actually incur a temporary immune-enhancing effect, while chronic stress has been shown to be detrimental to overall health through exerting an immune suppressive effect. The body reacts to a stressor by releasing hormones such as cortisol, whose key function is to restore homeostasis; however, the continued presence of cortisol can negatively affect the immune response, which can lead to vulnerability against diseases and infections. “Therefore,” Mr. Majeed concluded, “the immune system needs to be supported to overcome the effects of stress. This is a function carried out by adaptogens, which increase the resistance of the body against the stressors (elements causing the stress), therefore, increasing the threshold against stress converting into a chronic condition and effecting the immune system.”

Formula Considerations
Many compelling ingredients demonstrate attractive viability for immune and stress support.

Sabinsa’s Curcumin C3 Complex, Mr. Majeed explained, is a standardized extract from turmeric root (Curcuma longa) with a unique composition of curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin). Curcumin C3 Complex has been scientifically proven to be a potent antioxidant preventing formation of free radicals and neutralizing already-formed free radicals.

Further, curcumin has been found to be a very potent immunomodulator and can modulate the activity of T cells, which are responsible for cell-mediated immunity. In fact, the broad immunomodulatory activity of curcumin can affect B cells, macrophages, neutrophils, natural killer cells and dendritic cells. Apart from these activities, curcumin’s anti-inflammatory activity can also affect and down-regulate several pro-inflammatory molecules, such as NFkB, TNF, interleukins and other chemokines.

Wellmune is a 100% natural food, beverage and supplement ingredient clinically proven to help strengthen the immune system. Numerous published, peer-reviewed clinical studies showed positive results among a broad range of stressed consumers, according to the company’s Mr. Quilter.

One double-blind, placebo-controlled clinical study published in Nutrition examined the effects of Wellmune on 100 fourth-year medical students. Participants taking 250 mg of Wellmune for 90 days experienced a 22% reduction in days with upper respiratory tract infection (URTI) symptoms.

Further, said Mr. Quilter, Wellmune can help aid in overall mood states, which can suffer from physical and lifestyle stress. A double-blinded, placebo-controlled study published in the Journal of Sports Science and Medicine included 75 marathon runners, ages 18-53, and measured psychological states using a Profile of Mood States (POMS) questionnaire. Subjects who consumed 250 mg of Wellmune daily saw a significant increase in vigor as well as a significant reduction of fatigue, confusion and tension when compared to those receiving the placebo.

Another ingredient, OptiMSM from Bergstrom Nutrition, is also viable to address immune support through modulating stress induced from heavy exercise and athletic activities.

Rod Benjamin, director of R&D and technical service at Bergstrom, said a study suggested that 3 grams per day of OptiMSM may boost the immune system following exhaustive exercise. This small pilot study published in the Journal of the International Society of Sports Nutrition (JISSN) evaluated blood collected from subjects involved in a double-blind, placebo controlled exercise study. The blood serum was subjected to lipopolysaccharide (LPS) to stimulate an immune response by inducing the generation of inflammatory cytokines. A dramatic increase in inflammatory cytokines was observed only in the samples from the subjects taking MSM. The placebo group showed no increase in the inflammatory cytokines from LPS stimulation.

Research has also shown that 250 mg of Interhealth’s Relora, a patented blend of Magnolia officinalis and Phellodendron amurense extracts, taken two to three times per day is safe and effective in supporting healthy mood, according to Mr. Dijkstra. Two key studies, published in JISSN and Nutrition Journal, have shown that Relora reduces stress and short-term anxiety, positively affects mood state scores—such as depression, tension and anger—maintains weight in stress eaters and reduces cortisol levels.

According to Lallemand’s Ms. Feuz, the company recently conducted a clinical trial in stressed subjects. The aim of the study was to evaluate the effects of three individual probiotic strains on the percentage of healthy days in academically stressed students (around and during final exams). This is a known model of acute psychological stress that is associated with increased incidence of cold/flu. The study showed that the higher the level of stress, the more sensitive students were to developing cold/flu symptoms. Further, the probiotic strain Bifidobacterium bifidum R0071, which was beneficial in reducing cold and flu days, had an even more important beneficial effect on the population of students with high stress levels. Researched was published in the British Journal of Nutrition in 2015.

“Concerning stress management for better immune status, I would add another angle,” Ms. Feuz added. “More and more data are now available on the brain-gut axis and the involvement of the digestive microflora. We have also shown that a specific probiotic formula, through its beneficial action on the gut microflora, represents a valuable solution of stress management. This formula has shown in clinical trials the ability to alleviate both psychological and physiological symptoms of stress, which enhances immune function.” (Diop et all 2008; Messaoudi et al., 2010).

Children’s immune systems are frequently under duress from physiological and environmental stressors that cause them to be more susceptible to bouts of ear infections and strep throat. Stratum Nutrition offers an oral-cavity probiotic, BLIS K12, designed to support immune health in the upper respiratory tract for children and adults. This probiotic ingredient has been shown in several clinical trials to reduce incidence of throat and ear infections in both children and adults, and in those bouts from both viral and bacterial etiologies.

“Because of the importance of a healthy oral cavity microbiome, BLIS K12 is an ideal supplement to take during times of increased stress or exposure when susceptibility to irritants and pathogens is higher, such as during the winter months or when traveling via mass transit,” Stratum’s Ms. Dockery suggested.

NutraQ markets Nutramunity Beta-Glucan (NBG) beta-1,3/1,6-glucan, a natural component of the inner cell wall of baker’s yeast (Saccharomyces cerevisiae). According to the company’s Ms. Raa, studies with physically and psychologically stressed subjects have shown that yeast beta-glucan can decrease susceptibility to upper respiratory symptoms, counteracting the negative effects of these types of stress on the immune system (Journal of Sports Science and Medicine, 2009; Journal of the American College of Nutrition, 2012).

This suggests that even though yeast beta-glucan does not have a psychoactive effect, the improvement in physical well-being has a positive impact on mood. Yeast beta-glucan also increases the levels of Immunoglobulin A (IgA), an antibody that plays a critical role in infection defense in mucosal surfaces of the body, the main entry route for pathogens (Clinical & Experimental Immunology, 2006; Journal of Dietary Supplements, 2013).

The immune health benefits promoted by yeast beta-1,3/1,6-glucan seem to result from its initial interaction with intestinal immune cells. When ingested, Nutramunity encounters immune cells in the gastrointestinal tract such as macrophages and dendritic cells. Evolution has equipped these cells with specialized receptors on their outer surface to recognize and bind to molecular patterns typically found in harmful microorganisms. Although harmless, the yeast beta-glucan molecule is recognized by these receptors. Nutramunity binds to Complement receptors (CR3), Toll-like receptors (TLRs) and Dectin-1 receptors found on various immune cells such as monocytes, macrophages, dendritic cells, neutrophils and natural killer cells.

The binding is highly specific, like a key-in-lock interaction, which explains why beta-glucans from other sources have no or lesser effects on the immune system. When immune cells activated by Nutramunity encounter a harmful microorganism, they are more effective at 1) “killing” the pathogen; 2) recruiting other immune cells to the battlefield; and 3) enlisting the help of the adaptive immune system, increasing immunity against this pathogen in the future. Ultimately, this renders the immune system more potent, supporting overall health and well-being.

Burnout is a condition caused by high chronic stress, which negatively impacts normal healthy immunity. Lactium, from Pharmachem Laboratories Inc., Kearny, NJ, positively impacts concentration, focus and cognitive function indirectly via lessening effects of stress and promoting more restful sleep, which is necessary in increasing healthy immunity. Lactium is a patented hydrolysate of milk proteins that contain a bioactive peptide with relaxing properties that regulate stress. 

In a 2015 study published in the Journal of International Medical Research, a consumer product called Target 1 (featuring Lactium) helped significantly decrease symptoms of burnout. The double-blind, randomized, placebo-controlled clinical trial looked at the effects of the formula on participants with burnout syndrome, and followed study subjects’ symptoms of burnout using different evaluation instruments for the 12-week study period.

Market Conclusions
“As most have seen, the market for immune health products has exploded the past decade—both across multiple immune health market segments (sports nutrition, healthy aging and moms and children) and from a reactive and proactive healthcare approach,” reported Mr. Quilter of Kerry/Wellmune. “For example, immune/digestive health products are a large and growing business across the globe. In the U.S. alone, the estimated market value in 2015 is $14.9 billion (+7% three-year CAGR).”

He opined that the growth of functional foods, beverages and supplements for immune support may still be in its early stages. “Consumers’ embrace of products created to provide specific health benefits is a recent phenomenon. Twenty years ago consumers were focused on the absence of nutritional negatives (e.g., sodium, refined sugar, artificial sweeteners). They’ve since come to accept the presence of nutritional positives (e.g., calcium, fiber) but now are seeking targeted functional benefits (e.g., immune and stress support, heart health, energy, digestion).”

Interhealth’s Mr. Dijkstra emphasized that in today’s world, more than ever, “state of mind affects one’s state of health. From depression to stress, it all takes a toll on the immune system year round. Stress and anxiety are rampant with Americans feeling more stressed than they did five years ago. You can bet that is affecting their immune systems. Stress signals can suppress immune cell function or decrease the production of immune cells.“

NutraQ’s Ms. Raa agreed, noting that modern life is often characterized by three Ds: disappointments, deadlines and demands. Stress has become a way of life. “This makes immune-health formulas relevant all year round as a beneficial input to the immune system of people subject to stress.”