Frontiers in Immune Function and Nutraceutical Innovation

Advances in immunology are redefining nutraceuticals for immune health, moving the focus beyond cold and flu season toward continuous, year-round support for long-term wellness.

There’s also more attention paid to how external factors like stress, diet, the aging process, and overall lifestyle impact immune function, noted Emilie Puppinck, senior product manager of biotics at Gnosis by Lesaffre.

“Consumers do not consider immunity just a response to common colds, but a way to improve their long-term health and longevity,” she said.

Fortune Business Insights valued the global immune supplements market at $24.38 billion in 2023, and projected it will grow to $44.04 billion by 2032 at a compound annual growth rate (CAGR) of 6.9%

“We’ve seen a noticeable jump in the number of consumers who say that they are concerned about immune health,” said Brie Zemien, marketing specialist at Cargill. “Half of all U.S. consumers are extremely or very concerned about their immune system, up 10 percentage points in the last two years. Among households with children, the number’s even higher; 63% worry about immune health,” she said, citing HealthFocus International.

“According to our 2024 consumer survey, 37% of immune health consumers reported considering their immune health every day, and another 39% at least weekly,” said Maria Stanieich, senior marketing manager at Kyowa Hakko USA. Additionally, “68% said immune health is more important to them, and 43% reported having spent more to maintain it … What stood out in our survey is that 84% of respondents said they would consider purchasing immune health supplements, and 64% strongly agreed they were likely to buy them within the next three months.”

A recent consumer survey from Kerry found that 77% of consumers recognize the link between immune health and overall health, shifting the needle from cold and flu season to more holistic approaches, noted Mollie Mulligan, global marketing manager, Kerry. One in two consumers takes an immune supplement daily, and “the importance of clinically-supported ingredients is greater than ever, with ‘clinically proven’ the number one claim consumers want to see on supplement products targeting immune health.”

Immunity is complex, and shoppers feel like they’re in the dark, said Leslie Gallo, president of Artemis International. “The proliferation of products, with limited regulation or enforcement around extract types, standardization ratios, equivalencies, or clinically validated dosages, has made it difficult for consumers to make informed choices. Many still rely on the quantity of an ingredient listed on the label, without fully understanding its quality, efficacy, or whether it aligns with clinical research.”

Steve Fink, vice president of marketing at PLT Health Solutions, noted that validated ingredients stand out from conventional commodity options. He pointed to PLT’s Promunel propolis as an example. The raw material propolis is sourced from three geographical regions close to the 45th geographic parallel, ensuring supply stability and consistency as a result of seasonal similarities before the ingredient is standardized to six marker polyphenols.

Year-Round Support: From ‘Boosting’ to ‘Balancing’ Immunity

According to Stanieich, “year-round support presents a bigger opportunity for innovation and consumer loyalty.” With these products, meant to be taken daily for the long run, enjoyable delivery formats are paramount, as “pill fatigue is real, and people are expecting more sophisticated formulations and formats.”

Beyond popular supplement formats, “what’s really driving innovation right now is the integration of immune support ingredients into everyday items like coffee, hydration beverages, and various snacks,” she noted.

“Brands are launching more multifunctional, broad-spectrum formulations that offer added value,” said Gallo. “These ‘immune-plus’ products often pair well-known immune ingredients like elderberry with complementary components such as probiotics, adaptogens, nootropics, and essential vitamins and minerals,” for product concepts such as immune and stress, immune and energy, or immune and sleep to encourage year-round use.

“The conversation around immune support is shifting toward overall wellness and resilience, helping people bounce back faster, manage stress better, and maintain well-being in the face of modern lifestyle pressures,” said Melanie Bush, vice president of science and research at Artemis. “For forward-thinking brands, this offers a chance to lead research in a more holistic direction of what immune health really means.”

Researchers in immunology are focusing on how immune factors promote a “regeneration and rejuvenation of cells, organs, and tissues,” and implications for longevity, according to Jeffrey Bland, PhD, functional medicine researcher, and founder of the Institute of Functional Medicine and Big Bold Health.

To put it simply, the immune system does much more than what we notice when we catch a cold. “The immune system is working 24/7, 365 to surveil the outside world and tell the body how to work, and it’s present in every organ in our body,” Bland said. Together with other bodily systems, from what we ingest and breathe to stress, chemical exposure, sunburn, and more, “it is so quick to respond to new information … We produce about a million new immune cells every second.”

Much has been learned from studies on SARS-CoV-2 about how the innate immune system can be “trained” just like the adaptive system, Bland said. “The reason that we in America did, as a country, more poorly [by death rate] than any developed nation in the world is in part because our innate immune systems were not up to snuff, which put all the weight on the second level of defense.”

Innate immune functions reside primarily where we are exposed to the outside world: the intestinal tract, the lungs, and nasal passages, and “between 40% and 70% of our innate immune system is trained by the foods and nutrients we eat,” Bland said.

While randomized, placebo-controlled clinical studies provide the best evidence to support an individual dietary supplement for immune support purposes, these studies “are relatively short-term, focusing on immediate outcomes,” noted Puppinck. “There is a gap in research examining these supplements’ long-term effects on overall immunity and health.”

While studies overall are becoming more sophisticated, evaluating cytokine activity, NK cell function, mucosal immunity, and gene expression, “many studies still suffer from small sample sizes, short durations, and inconsistent endpoints, which limits generalizability and comparison,” said Bush.

While there’s no consensus on a single validated endpoint to determine optimal immune function, measures of recovery, inflammation, and stress resilience continue growing in importance. Therefore, studies on year-round support take a more foundational approach, with maintenance doses, and a greater emphasis on underlying mechanisms of inflammation, stress, and gut-immune signaling; high-polyphenol berries, adaptogens, beta-glucans, probiotics, and prebiotics shine here with their long-term safety profiles.

Consumers are also moving past simplistic views of their immunity, noted Alphons Philips, PhD, director of scientific affairs at Sabinsa. “Now, people understand that immune function is impacted by things like stress, a poor microbiome condition, or poor-quality sleep. They also understand that rather than ‘boosting’ the immune system, it needs to be balanced, hence the growth in demand for adaptogens like ashwagandha.”

Adaptogens, characterized by their ability to mitigate stress-related imbalances, are emerging as a potential strategy to address the feedback loop between stress and immune imbalance. “Phytonutrients which can support a healthy immune system include curcumin, ginger, black cumin seed, and ashwagandha, among others,” said Philips. “Overall, ashwagandha is known to help the body restore balance and resilience, which is especially important in combating the impact of stress on immune function.”

Seasonal Challenges

Immune supplement sales trends are still very seasonal, Mulligan noted. For instance, SPINS data from 2023 revealed that immune support sales from July to September were only half of those from October to December. With many consumers only thinking to use immune supplements in times of need, fast-acting products are still in demand.

Validating a nutraceutical for its role in reducing infections or their severity during cold and flu season remains a cornerstone. These kinds of studies can offer important mechanistic insights and demonstrate real-world outcomes.

Fink noted that cold and flu season studies are intuitive and easy for consumers to understand in relation to their own experience. “In many ways, the experience of a product has become just as important as the science behind it.”

Clinical study windows should align with allergy or cold and flu seasons, according to Justin Green, PhD, scientific affairs lead for EpiCor at Cargill. Having consistent dosage across all research is a major benefit to formulators in this space. While immune markers like natural killer cell and T-cell activity, or the production of cytokines or immunoglobulin, are important to look for in early stages, clinical endpoints related to symptoms are easier for consumers to understand; they also align more closely with FDA expectations, Green said. 

Similarly, PLT Health Solutions has focused on real-world clinical outcomes for Spectramune, its complex of ashwagandha and haritaki. Evidence has shown it can promote a range of innate and adaptive (cell-mediated and humoral) immune activities, Fink said. Three clinical studies support claims such as “23% fewer sick days,” “30% less severe symptoms,” “23% better quality of life scores,” and other claims related to subjective measures of immunity and increased white blood cell count.

In a 12-week human clinical study, daily treatment with 500 mg of Spectramune was associated with significant improvements in respiratory illness incidents, symptom and quality of life scores during illness, improved psychological general well-being, and enhanced markers of adaptive immunity, Fink said.

Studies typically evaluate higher doses of fast-acting or symptom-targeting ingredients like zinc, vitamin C, elderberry, or echinacea during cold and flu season, travel, or high-exposure environments, Bush said.

“Interestingly, formulators are recognizing that the line between acute and daily support doesn’t need to be so rigid,” she said. Hybrid formulas that offer base-layer support paired with optional acute dosing structures open the door to flexible delivery systems and multifunctional products.

Randomized, placebo-controlled trials are “focused on different and validated tests to analyze numerous endpoints related to immune response, including the inflammatory markers,” noted Enrica Vella, scientific communication specialist at Indena SpA. “Tools like metabolics and microbiome sequencing help us to better understand how a supplement might influence immune pathways at the molecular level.”

“The ability to measure specific immune biomarkers, such as cytokines or the activation of T-cells, has advanced significantly,” said Puppinck, providing deeper understanding of mechanisms of action. For example, the latest clinical evidence on LifeinU BSCU1 aimed to provide insight into the most likely mechanism of action through which [it] could modulate the immune system and support protection against infections.”

Sabinsa is now integrating “advanced biomarker panels and machine learning algorithms that assess comprehensive immune profiles beyond basic antibody measurements to identify subtle immune response patterns” into its protocols, said Philips. This work is informing AI-driven predictive modeling to help researchers better understand how psychological stress, diet, and microbial composition can co-regulate immunity, he noted. 

Also emerging in next-generation trials are novel precision medicine approaches based on immune profiling. However, there are still challenges with recruiting healthy participants with optimal immune function, and setting standards for measuring longer-term outcomes, said Philips. 

Gut-Immune Connections

Around 60% of the immune system is located in the gut, Bland noted, and systemic immune processes react strongly to what happens there. 

The gut-immune connection has significantly influenced the immune health segment, and is a primary reason why consumers expect immune support products to have wider-ranging benefits than just cold and flu claims, noted Gallo.

Dysbiosis has been linked to challenges like worsened autoimmune disease outcomes, allergies, and systemic inflammation. “Another key insight is that gut permeability, measured via markers like zonulin, can trigger systemic inflammation and immune over-activation,” Philips said.

The gut-immune space isn’t limited to biotic formulations, experts noted.

Probiotic-botanical combinations can achieve an even greater degree of balance both inside and outside the gut, noted Philips. “Our probiotic LactoSpore and adaptogen Shagandha ashwagandha are being explored for their role in modulating immune, cognitive, and stress responses via the microbiome-neuroendocrine interface … Our focus formulations are multi-targeted immune support solutions aligned with today’s evolving health paradigms. As microbiome research integrates with immunology and gut-brain axis signaling, it’s being revealed that microbiome strains can influence not only immune resilience, but also neuroimmune communication, highlighting the microbiome as a central hub in systemic health.”

Gallo noted that mushrooms rich in beta-glucans have gained traction for their immune-modulating bioactives in recent years. “Adaptogens like ashwagandha are also on the rise, with ashwagandha standing out for its ability to support both stress and immune health.” Artemis has responded to these product trends with ElderCraft High Fiber, a version of its leading elderberry ingredient with additional prebiotic benefits.

Researchers are also investigating mushrooms’ “synergistic effects with probiotics, prebiotics, and other microbiome-derived compounds for their role in gut-immune signaling,” Bush said. 

Additionally, ElderCraft was evidenced in a recent human clinical study to promote alpha and beta microbial diversity, with lasting increases in beneficial bacterial strains, specifically Akkermansia muciniphila, which exhibits immune-modulating effects by improving the gut barrier, noted Bush. This dysregulation, known as “leaky gut,” is thought to be a risk factor for a wide range of immune challenges, like autoimmunity, digestive conditions, allergies, and even issues like neuroinflammation or skin conditions.

“Another interesting finding in this area is that vaccine efficacy is also linked to the gut,” Bush noted, with studies linking certain microbiome compositions to improved immunization outcomes.

“New botanicals and their innovative formulations are now investigated as immune enhancers or modulators, acting through the rebalance of the intestinal microbiome,” said Vella. “In this sense, innovative formulations such as the combination of botanicals with Indena Phytosome technology may improve dispersion of natural compounds in the gastrointestinal environment, improving interaction with microbiota and consequently benefiting immunity.”

For those who prioritize delivery formats like beverages, gummies, chewable tablets, or effervescent products, for instance, only spore-forming strains can survive harsh manufacturing conditions, with few exceptions.

Gnosis by Lesaffre’s spore-forming LifeinU BSCU1, a patented strain of Bacillus subtilis, has a high resistance level to survive in industrial processes, noted Puppinck. “It is one of the most stable probiotics on the market, making it suitable for several matrices, including dietary supplements and functional foods.” The spore form “remains stable even in hot environments or at high humidity levels.”

Postbiotics are gaining traction for their formulation flexibility, Zemien noted. These inanimate components of microbes are stable during processing, don’t require refrigeration, and are suitable for a wide range of formats.

From cell wall fragments to metabolites, postbiotics are also “generally regarded as safer for sensitive groups, like kids or those with weakened immune systems,” said Bush.

Due to these factors, their impact on immune function is more targeted, consistent, and therefore predictable than conventional approaches with live bacteria, addressing challenges especially in areas with stricter regulatory controls on live microbes, Philips said.

“Research suggests that in some cases, a postbiotic outperforms the equivalent probiotic in terms of efficacy,” said Green. “While that’s not the case with every postbiotic, these bioactive compounds can deliver significant benefits, from how products are formulated to how they support immune health.”

Some prebiotic fibers offer precise effects, and help specific beneficial bacteria flourish. One standout fiber not often found in the diet is D-Chiro-Inositol, which promotes the growth of Akkermansia muciniphila, Bland said. This mucus-forming species creates a protective lining, preventing absorption of toxins that lead to immune over-activation.

For certain consumers with digestive sensitivities, yeast-based pre- and postbiotics are the answer.

Prebiotic fibers “are known to be effective with several daily grams, which can cause bloating and flatulence,” said Puppinck. “Gnosis by Lesaffre launched Lynside Prebiotic Yeast as the first patented yeast-based prebiotic … Combined with a very low daily dosage requirement, this scenario promotes a continuing prebiotic response with low gas production.”

Emerging research suggests this prebiotic yeast may be helpful in supporting broader, systemic immune function, “showcasing a unique interaction between the gut and the immune system. It strengthens the intestinal barrier by promoting tight junction protein production, which prevents toxins and pathogens from entering the bloodstream,” she said. “By balancing the gut microbiota, it supports the production of beneficial metabolites that help regulate immune responses.”

Additionally, S. boulardii yeast stimulates anti-inflammatory cytokines like IL-10 while reducing pro-inflammatory signals, while aiding in the production of the toxin-neutralizing immunoglobulin-A, to support an overall balanced immune response.

Kerry’s yeast beta-glucan postbiotic, Wellmune, has been validated to support measures of innate immunity during cold and flu season and measures of respiratory function amid seasonal allergies, making it a go-to for year-round formulations, Mulligan noted.

Many postbiotics have only been on the market for a few years, and are relatively under-studied, noted Kate Pawlik, product manager of postbiotics at Kerry. Wellmune, by contrast, is “shown to train the innate immune system to respond more effectively to unpredictable health challenges, with over 12 clinical studies showing efficacy in children, adults, and seniors … It is vital that the postbiotic selected is clinically supported to meet the consumer demand for clinically-backed solutions.”

Immunity and Aging

There’s a complex relationship between the chronic, day-to-day status of immune function and biological markers of age. “Where ‘healthy aging’ was the buzz phrase in years gone by, ‘longevity’ and ‘health span’ are now at the forefront of consumers’ minds,” said Mulligan.

“Consumers are more interested in long-term benefits, like a health-span companion,” said Puppinck, which implies “enjoying more active, productive years and delaying the onset of age-related health problems. A well-functioning immune system is essential for maintaining a longer health span and supports overall well-being throughout life.”

Bland added: “Our immune system, like our nervous system, is fast-reacting to change, and remodels our cells, our tissues, and our organs, and has strong ties to longevity. In fact, there is research that shows that if you wanted to predict how many years you’re going to live and what your life expectancy might be, the best single thing you could measure would probably be the age of your immune system.”

In “Blue Zones,” where life expectancies are greater, researchers noticed consistencies in the epigenetic expressions of their immune cells, Bland said. Many of these expressions correlate with a high and diverse intake of polyphenols and flavonoids. But some mechanisms behind how these compounds impacted immune aging were just discovered recently.

In a pilot study published in November 2024, Bland and co-authors found that Tartary buckwheat, an ancient grain with 126 polyphenols, reduced the rate of immunological aging by 47% after 90 days of supplementation. This was measured by alterations in several epigenetic age clocks, immune markers, and changes to gene ontology pathways.

“We were able to demonstrate the effect of these nutrients on training the immune cells by epigenetically programming how they express their function,” he said, “imprinting them with the signals that lead to a better outcome associated with longer life and slower aging.”

These changes weren’t impacted by factors like overall diet, lifestyle, or sleep issues. “That’s why we use the term ‘immune rejuvenation,’ rather than ‘immune boosting.’ It was able to cut through those factors by improving the resilience of the immune system to accommodate those known stresses and changes,” said Bland.

And while Tartary buckwheat is a standout ingredient, there are thousands of dietary polyphenols to explore, Bland noted.

As a concept, immune resilience relates to striking a balance between effective anti-microbial defenses (immunocompetence) and controlling inflammation and minimizing tissue damage from an immune response (immunoregulation), said Sonja Nodland, PhD, director of immune health at Kerry.

These measures can then be placed against sets of “omics” data from large patient cohorts. “Some well-known examples of these types of metrics in the field are iAge, PhenoAge, and DNAm IC. These ‘clocks,’ which measure biological age in various ways, give researchers information about how healthy a study population is, and may also be able to serve as readouts in clinical studies investigating the salutogenic benefits of bioactive compounds.”

For example, Nodland noted a recent analysis of over 17,000 individuals, which unveiled specific gene activity that may be usable as an indicator of immune resilience published in Aging Cell in July.

“Resilience is not just about fighting off infections, but also about the ability of the immune system to recover from challenges and maintain overall balance,” noted Vella. Researchers are identifying classes of compounds called senolytics, which eliminate senescent cells, through preclinical research on models like the nematode C. elegans, which can provide emerging insights thanks to their simplicity, ease of cultivation, and lifespan.

Inflammaging, or chronic, low-grade inflammation brought on by age-related decline, is influenced by the body’s immune cells, said Puppinck. “Changes in the inflammatory cytokine network control the direction of inflammation’s development. Sporulated bacteria such as LifeinU BSCU1, offer a viable way to regain control of the inflammatory response. The latest clinical study showed that LifeinU BSCU1 intake reduced low-grade inflammation in the elderly by significantly reducing circulating levels of several pro-inflammatory cytokines (MIP-1α, IL-8, TNF-α).”

Advances in Personalization

Bland noted once-rarified technologies that can provide insights into one’s epigenetic immune expression, relevant to immune function, biological age, and more, are at the cusp of becoming widely accessible. He compared the situation to the early days of gene sequencing, which once cost tens of thousands of dollars. “But now, you can get a full genome sequencing done for between $100 and $200.” 

Another accessible tool is the Systemic Immune-Inflammation Index (SII), which may already be covered by most health insurance plans, Bland noted. Essentially, this index takes data on various immune cells already provided by Complete Blood Counts, usually featured in a standard blood panel, but runs the data through a different algorithm that “assesses the overall balance and resilience of your immune system … We’re just starting to teach doctors about this,” he said. “We’re just finishing up a small observational clinical pilot trial with a group of physicians and their patients looking at SII as a marker of immune system function, and so far, the data looks very interesting.”

Apart from evidence in existing literature, companies should consider separate research among sensitive populations. For example, children aren’t just small adults, noted Green, and that was “a big reason why we fielded a clinical trial to evaluate the efficacy of EpiCor in younger populations.”

While EpiCor was supported by 15 clinical studies in adults, a recent study in Pediatric Research found that children who supplemented with the postbiotic during cold and flu season experienced significant improvement in symptom severity, symptom-related complaints, or medication usage.

“It’s one of the first peer-reviewed studies to evaluate postbiotics in a pediatric population, and it used the kid-preferred gummy format … While the term postbiotics is still relatively new, a growing body of research suggests these beneficial compounds have a lot to offer.”

Additional Breakthroughs

The immune system plays a vital role in the ability of muscles to self-repair and maintain mass, which is critical for aging. 

Specialized pro-resolving mediators (SPMs, or PRMs), metabolites of EPA and DHA, occur naturally in fish oil, especially when less refined. The bulk of the research on SPMs is centered around their ability to bind to certain inflammatory receptors to resolve inflammation, in a more targeted way than NSAIDs. This mechanism also goes beyond pain relief to prime a more balanced innate immune response, Bland said. Myokines, the messenger molecules muscles make after damage, are immune-active substances, produced to trigger the healing process. “But you don’t want that healing process to be indefinite. You don’t want inflammation to be around forever … It’s another example of how the immune system is everywhere.”

Resolvins, protectins, and maresins, the families of SPMs that occur in fish oil, were just recently discovered, and are just now “getting a tremendous amount of attention,” he said. “These minimally processed omega-3 oils are much richer in these additional valued fatty acids.”

The immune-muscle axis “presents a strategic opportunity for Sabinsa’s R&D Innovation Labs, which includes science-researched ingredients such as Curcumin C3 Complex and BioPerine, which have shown measurable benefits in preserving muscle strength and immune function in older adults,” noted Philips.

The immune system is also implicated in challenges related to weight management, obesity-related risk factors, and appetite control, Bland noted.

Intra-endocrine hormones including GLP-1 are produced by the gut mucosa, and how they interact with the immune system impacts how the body responds to them. Further, excessive fat tends to become “angry fat,” Bland said, producing inflammatory adipokines, which are associated with diabetes, arthritis, and dementia, and are likely part of the reason obesity is a risk factor for those diseases.

“When we tune up the immune system, it has collateral benefits across things like weight management, obesity-related risk factors, and appetite control,” he added.