What are the innate and adaptive immune systems, and how can supplements support them?

  Our immune systems are like our mothers: We never fully appreciate what they do for us until we need them. And with the 2014–2015 flu season turning out to be deadlier than usual, per the  Centers for Disease Control and Prevention (CDC), and with the accompanying vaccine apparently inadequate at fighting it, we need our immune systems fully primed now more than ever.

In fact, human immunity has been much in the spotlight of late, as residual fears over the Ebola virus continue their hum. Moreover, as healthcare cost containment merges with society’s shifting preference for prevention over treatment, defending the body’s built-in defenses is beginning to look downright trendy.

This is one trend the supplement industry is poised to address. Products ranging from single vitamins to antioxidant blends have long helped support the immune system, as the structure-function claim has it. But the more we learn about immunity, the more complex and exquisitely specific this architecture of cells, proteins, and defensive barriers proves to be. Which raises the questions: In an era of emerging immune challenges, what roles can supplements play? And how can we tailor our products to enhance both innate and adaptive immunity-the two interlocked “arms” of the immune response-without sending either into overdrive?

Getting a handle on supplements’ role in immunity requires getting a handle on immunity itself, and that’s no easy task. As Don Cox, PhD, senior vice president, healthcare research and development, Biothera (Eagan, MN), notes, “The human immune system is one of the most complex systems of the human body.”

With foot soldiers as varied as circulating proteins and the lining of the gut, the immune system exists to protect the body from foreign microbes and environmental toxins that would otherwise harm it. To do so, it mobilizes two branches of a joint force: innate and adaptive immunity. We can best describe these two branches as “separate but equal” in their contributions to the immune response. But while they’re equally important to mounting the body’s defenses, they differ in the rapidity, length, and specificity of their responses, as well as in the molecules, cells, and tissues involved.

Consider the innate immune system the vanguard force of cells and proteins always on alert and ready to shoot first and ask questions later. Its troops comprise physical barriers like skin and the epithelia of the respiratory and gastrointestinal tracts; phagocytic leukocytes, including neutrophils and macrophages (white blood cells that phagocytose, or “eat,” harmful microorganisms); dendritic cells that not only phagocytose invading microbes but generate signaling chemicals called cytokines, express microbial receptors, and link innate and adaptive immunity; natural killer (NK) cells that attack general classes of bacteria and viruses and eliminate weakened or infected cells; and circulating plasma proteins, including those of the complement system, that bind invaders, promote phagocytosis, and participate in adaptive immunity.

Phew! That’s a lot of work! And the fact that some soldiers of the innate response also participate in adaptive immune functions illustrates the blurry boundary separating the two systems. But generally speaking, while innate immunity acts as the body’s frontline infantry, the adaptive system is more like its special forces, trained not only to catch threats that escaped innate assault, but to target specific invaders and continue targeting them in subsequent attacks.

And that difference really is a matter of “training.” While innate immunity “has a number of set strategies for recognizing and destroying infections quickly without needing to be trained to identify them,” Cox says, the adaptive response “isn’t able to respond instantly to infections, as it needs time to adapt-or learn-to recognize them. Once it’s learned, however, it’s extremely effective and able to remember particular pathogens that have previously infected the body so that when they try to infect again, the next response is rapid, accurate, and effective.”

The trick lies in the activation and proliferation of specialized white blood cells called B and T lymphocytes.

B lymphocytes, so named because they come from bone marrow, produce antibodies that project from their membranes and “recognize” antigens-proteins, fats, sugars, other molecules-that are signs of microbial invasion. Once B cell antibodies “notice” these antigens, they differentiate into plasma cells that pump out yet more antibodies that bind the antigens, neutralize their microbial presenters, and mark them for phagocytosis. Part of what makes this response uniquely adaptive is that once it’s activated, “memory” B cells continue circulating, ready to respond quickly and forcefully if the antigen they “remember” invades again.

T lymphocytes, by contrast, recognize antigens not by way of antibodies, but by picking up on protein fragments bound to the surfaces of antigen-presenting cells. Thus stimulated, T cells of two different types get to work. Helper T cells secrete substances that goad B cells into producing antibodies and phagocytes into eliminating microbes. Cytotoxic T cells, meanwhile, secrete their own set of soluble molecules that directly participate in the killing of infected or ailing cells. As with B lymphocytes, “memory” T cells also persist after an infection, on alert should their targets strike again.

While adaptive immunity is critical, Cox makes an important point. “Researchers often focus on adaptive or acquired immunity because it has specific memory of immune challenges. But the innate immune system contains the largest population of immune cells in the body. In fact, neutrophils, macrophages, and monocytes account for approximately 65% of the body’s entire immune cell population.” And though innate and adaptive immunity are intertwined, he says, innate immunity has historically attracted most of industry’s attention. “We’re interested in understanding how supplementation can help the innate system fully function,” he says, “so that it’s ready when it’s most needed.”

One way to do this involves supporting the gastrointestinal tract. After all, says David Keller, vice president, scientific operations, Ganeden Biotech (Mayfield Heights, OH), “The gut is the first line of defense of the innate immune system.”

Of all the supplements known to promote GI health, perhaps none holds as much promise as probiotic bacteria. From a digestive standpoint, Keller notes, research shows that those who consume probiotics end up with a healthier digestive tract. A variety of mechanisms explain why, he adds, “whether through helping you make better use of the nutrients you eat, or reducing pathogens by adjusting the pH of the gut.”

 notes that probiotics may reinforce the barrier function of the gut mucosa, perhaps via their influence on cell adhesion or cell-to-cell signaling. Through their action on GI receptors, probiotics appear essential not only to our innate defenses but to triggering the adaptive immune response, as well. 

models even show that some probiotic strains promote a type of helper T cell known as Th1 while down-regulating pro-inflammatory cytokines and allergic responses associated with helper cells of the Th2 type. Regardless of what’s going on, Keller says, “Overall, the gut itself is healthier.” And so is the immune system.

All of which is why people should be thinking about the role probiotics can play in immune modulation, he continues. “Parents, kids, anyone who deals with lots of people on a regular basis should be taking a probiotic every day, and one that has data supporting how it affects the immune system.”

He points to studies showing that his company’s patented probiotic GanedenBC30 (

 GBI-30, 6086) modulates a number of blood markers, including some of the positive cytokines and anti-inflammatory cytokines that participate in the immune response. Results of a randomized, double-blind, placebo-controlled crossover study of healthy seniors conducted at the University of Reading, England-full results of which await publication-demonstrated both digestive and immune benefits associated with the ingredient as measured in increases in healthy gut bacteria and levels of protective cytokines.

“We’ve also recently published a study on HIV-positive patients where we showed increases in beneficial blood markers even within that immunocompromised population, without having any negative side effects,” he continues. The randomized, double-blind, placebo-controlled study

, found that 90 days of supplementation with two billion CFU of the probiotic ingredient correlated with increased blood percentages of “helper” T cells compared to the placebo, while also proving safe, well-tolerated, and effective at ameliorating chronic gastrointestinal symptoms in the subjects.

That adds another brick to the growing wall of evidence supporting probiotics’ immune benefits. But good gut bugs need support themselves, and they get it from prebiotic fiber, which not only feeds them but benefits our own immune systems, as well.

Bryan Rodriguez, global product manager, Lonza Inc. (Allendale, NJ), points out that prebiotics possess “noted immune-modulating activity, in part by increasing lactic acid bacteria and the production of short-chain fatty acids in the GI tract.” Among the prebiotic fibers designed to do this is Lonza’s ResistAid, a proprietary larch arabinogalactan (LAG) that Rodriguez says “helps aid the digestive tract, where 70% of the immune system is located.”

Because of the fiber’s unique structure-it’s a soluble polysaccharide comprising arabinose and galactose monomers-it escapes hydrolysis by stomach acid and absorption through the small-intestinal walls, letting it reach the large intestine intact, where it “has the ability to optimize the immune system by utilizing direct and indirect modes of action,” Rodriguez explains.

As a prebiotic, the ingredient’s contribution to innate immunity is straightforward: it serves as a fermentable substrate for beneficial colonic microflora that then proliferate and “produce substances that provide localized protection against pathogenic bacteria, while also influencing other parameters of the immune system,” Rodriguez says.

But the LAG also helps modulate the adaptive immune response. Because galactose and arabinose are common structural components of microbial cell walls, including those of pathogenic bacteria, “Immune cells directly recognize these components and bind” the ingredient, Rodriguez says. The upshot: the LAG acts as a “biological response modifier via receptor sites on immune cells.”

Lastly, antioxidant activity courtesy of polyphenolic flavonoids represents what Rodriguez calls “the third pathway” of the product’s “triple-action immune support benefits.”

Clinical substantiation for those benefits appears in a randomized, double-blind, placebo-controlled study published in October 2013 in 

The Journal of the American College of Nutrition

, 75 healthy adults received 1.5 g/day or 4.5 g/day of the ingredient or a placebo for 60 days. At 30 days, they underwent both tetanus and influenza vaccinations-a research model “widely used to evaluate the impact a nutrient has on normal immune function and provide high-quality information on its protective 

effect on immune responsiveness,” Rodriguez explains. At 15 and 30 days following vaccination, subjects underwent measurements of IgG antibodies for tetanus and IgG and IgM antibodies for influenza A and B. The researchers found that while all three groups’ IgG levels for tetanus had increased by days 45 and 60, subjects receiving 1.5 g/day of the LAG saw a significant (p = 0.008) rise in tetanus IgG levels compared to the placebo, validating, Rodriguez says, the ingredient’s “capability to influence an expected and beneficial serum antigenic response from the immune system while simultaneously confirming its ability to do so at a low dosage.”

While prebiotic fibers help support immunity, in part, by helping support beneficial microbial growth, one form of beta-glucan boosts immune function using a very different mechanism.

The product, Biothera’s Wellmune, is a natural beta 1,3/1,6 glucan derived from the cell walls of a proprietary strain of 

or baker’s yeast. According to the company’s website, immune cells in the GI tract take up the beta-glucan and transport it to immune organs where macrophages break it down into fragments released gradually over the course of days. These fragments then bind complement receptor 3 (CR3) sites on neutrophils, priming and strengthening the cells to circulate more rapidly throughout the body.

Biothera’s Cox notes that “one of our goals is to identify biomarkers for measuring the significant health benefits observed in clinical studies with our immune-health ingredient. We evaluate outside research that can help us develop reference values better to define at a cellular level how it benefits the immune system.”

based on the results of two clinical studies conducted by Brian McFarlin, PhD, FACSM, assistant professor, department of kinesiology, health promotion and recreation, University of North Texas, as providing evidence. As Cox puts it, “Dr. McFarlin sought to answer one question: Does supplementation with Wellmune improve mucosal immunity-the first line of defense against bacteria and viruses-in athletes?” In one study of marathoners, he found that unlike the placebo group, those taking the ingredient had a 37% reduction in the number of cold/flu symptom days reported for 28 days following their marathons, indicating a higher degree of immune support against upper respiratory tract infections both before and after exercise.

The other study measured changes in mucosal immunity among stationary cyclists exercising in a heat-stress lab. Those who supplemented for 10 days with the beta-glucan saw a 32% increase in salivary immunoglobulin-“considered the gold-standard measure for mucosal immunity,” Cox says-at two hours following exercise. “Overall,” he concludes, “these published studies demonstrate that not only can Wellmune cause a statistical reduction in the number of symptomatic days, but it can also clinically reduce symptoms so that athletes can recover quickly and get back to training.”

Cox is quick to note that the ingredient improves the immune system’s defenses without sending them into overdrive. There are, on the other hand, immune-health ingredients out there “that stress the immune system in ways that may be harmful over time,” he says. “Overstimulation may cause immune-health issues such as inflammation, causing suppression of normal immune functions.”

Increasingly, immune-supplement formulators are designing products specifically to avoid such overstimulation, taking a path of modulation instead. The difference, Rodriguez says, is that immune-

supplements “enhance the appropriate response to an antigen, as opposed to indiscriminately up-regulating other arms of the immune system that wouldn’t be expected to respond.”

Keller agrees, noting that simply “ramping up” the immune system is not what you want to do. An effective supplement helps the immune system in a manner proportional to the challenge. “Sometimes,” he says, “that means you want to up-regulate it, and sometimes you want to down-regulate it.” Either way, “there are a lot of good ingredients out there that we can take preventatively to help the body be prepared when it’s challenged to react more appropriately.” And we can all feel better about that.

Ezendam J et al., “Probiotics: Immunomodulation and evaluation of safety and efficacy,” 

Yang OO et al., “Immunomodulation of antiretroviral drug-suppressed chronic HIV-1 infection in an oral probiotic double-blind placebo-controlled trial,” 

Udani JK, “Immunomodulatory effects of ResistAid: A randomized, double-blind, placebo-controlled multidose study,” 

The Journal of the American College of Nutrition, 

McFarlin BK et al., “Baker’s yeast beta glucan supplementation increases salivary IgA and decreases cold/flu symptomatic days after intense exercise,” 

 vol. 10, no. 3 (September 2013): 171-183

Articles

What are the innate and adaptive immune systems, and how can supplements support both of them?

Immune-Health Supplements: Supporting Innate and Adaptive Immunity

 L.) is known for its flat, weed-like leaves, but the tiny seeds that birth each plant are worth just as much interest. A sizeable market already exists for hemp seeds and, with U.S. regulations starting to relax on hemp, the market can only get bigger-right?

For manufacturers eager to exploit the nutty taste and nutrition of hemp seeds, oil extraction has provided a popular dietary supplement–based route. But for consumers in need of a snack and not a supplement, hulled hemp seeds and toasted hemp seeds are two of the most edible options.

Hulled, or shelled, hemp seeds are suitable for food products in which chewiness is desired over crunchiness. The removal of the seed’s fibrous shell doesn’t just soften the seed’s texture; it makes available the inner meat of the seed, sometimes called the “hemp heart.” This portion of the hemp seed is highest in essential fatty acids, protein, vitamins, and minerals.

Manufacturers can use hulled hemp seeds as garnishes, for mixing in dips and yogurts, and for blending in baked goods and nutrition bars. The ingredient can be sprinkled like parmesan cheese. One restaurant in Winnipeg, Canada, is even rumored to serve a hemp-encrusted walleye fish.

While hulling of hemp seeds unearths their softer and, in some cases, more nutritous insides, the process also does away with the pesky seed shells that would otherwise need to be sterilized before consumption. Since hulled hemp seeds don’t require heat sterilization, they can qualify as a raw food.

With their shells still intact, toasted hemp seeds offer a much different hemp-eating experience than do hulled seeds. Toasted hemp seeds are crunchy by nature, thanks to their shells, and this makes these seeds quite high in dietary fiber.

For food safety concerns, hemp seeds with the shells still on should be sterilized before consumption. While such seeds cannot be considered raw, a toasting treatment can sterilize as well as provide flavor, and, fortunately, at least for some companies, the toasting process doesn’t damage the seed’s integrity.

“When we produce toasted hemp seed, we’re not degrading either the protein or the omega-3 or omega-6 fats,” says Shaun Crew, founder and CEO of hemp seed supplier Hemp Oil Canada (Ste. Agathe, MB, Canada).

Because of their particularly crunchy texture, toasted hemp seeds might have fewer applications than hulled hemp seeds, but inclusions in crunchy products or grinding these seeds in pepper mills can provide some unique food product opportunities.

Human consumers aren’t the only ones who can benefit from a diet rich in hemp seeds. It appears that when hens are fed hemp, the omega-3 contents of their eggs go up.

 in 2011, researchers at the University of Manitoba assigned 49 laying hens to a diet including hemp seed or hemp oil. Without affecting the number of eggs produced, the inclusion of either hemp seed or hemp oil in the diet significantly increased omega-3 fatty acid contents in eggs compared to a standard diet. While hemp is particularly rich in omega-3 alpha-linolenic acid (ALA), measurements of omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also increased in eggs from hemp-fed hens, suggesting that ALA efficiently converted into these other important omega-3 fatty acids.

Whether addressing the needs of humans or animals, hemp provides some worthwhile opportunities.

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Photo © iStockphoto.com/Wolfgang Lienbacher 

Small as they are, hemp seeds are full of opportunity.

The Utility of Hemp Seeds

I have spent the past 20 years researching supplements to discern which ones I can recommend as alternatives or additions to other therapies, including pharmaceutical drugs. I always prefer to use natural products because of their general safety and minimal, if any, side effects. Of course, “doing no harm” or “having no side effects” does not necessarily make a nutraceutical efficacious.

I have dedicated considerable time to finding products proven to work as evidenced by rigorous scientific research. For decades, we have known about the role of vitamin K1 on coagulation. (Every practitioner knows about avoiding greens, a rich source of vitamin K1, when a patient is on warfarin.) Vitamin K2, however, is equally important and is an indispensable component of optimal bone and cardiac health. The science on vitamin K2 is robust and rapidly accumulating, and it is time for vitamin K2 to take its place on the list of essential supplements. Here is just a small fraction of what we already know and what exciting new research is soon to be published.

Vitamin K2 is part of the vitamin K family, a group of fat-soluble vitamins. This family is actually split into two groups: vitamin K1 and vitamin K2. The difference lies on a molecular level. Vitamin K1 has one molecule (phylloquinone), while the K2 group comprises multiple molecules (menaquinone).

Members of the vitamin K family have the same structure-they share a “quinone” ring. Members of the vitamin K2 group, however, have 

carbon-hydrogen atoms in their side-chain, called isoprenoid residues. The length of the side-chain dictates vitamin K2’s ability to reach different tissues within the body-the longer the side-chain, the more effective the form of vitamin K2. It will be absorbed better, stay in the blood longer, and will be more active in bone, arteries, and soft tissues.

Vitamin K2 has traditionally been available in supplements and functional foods as synthetic MK-4 and natural MK-7. In 2012, Sato et al. examined MK-4 versus MK-7, seeking to decipher which is more bioavailable.

In this study, single-dose administrations of MK-4 (420 µg; 945 nmol) or MK-7 (420 µg; 647 nmol) were administered to healthy Japanese women with a standardized breakfast. MK-7 was well-absorbed and reached maximum serum level at six hours after intake and was detected up to 48 hours after intake. MK-4 was not detectable in the serum of all subjects at any time point. Consecutive administration of MK-4 (60 µg; 135 nmol) or MK-7 (60 µg; 92 nmol) for seven days demonstrated that MK-4 supplementation did not increase serum MK-4 levels; however, consecutive administration of MK-7 increased serum MK-7 levels significantly in all subjects.

The researchers concluded that MK-4 does not contribute to vitamin K status as measured by serum vitamin K levels. MK-7, however, significantly increases serum MK-7 levels and, therefore, may be of particular importance for extra-hepatic tissues, or tissues beyond the liver.

Vitamin K2’s proven ability to activate osteocalcin makes it an invaluable nutrient in achieving optimal bone health. Osteocalcin (OC) is a protein produced by osteoblasts (bone-building cells) that, when activated, bind calcium to the bone mineral matrix. In a placebo-controlled, randomized clinical trial, Knapen et al. sought to demonstrate this benefit in apparently healthy postmenopausal women, with vitamin K2 as MK-7*. The team monitored the effect of a 180-µg MK-7 supplement on the bone quantity of 240 healthy postmenopausal women for three years.

The supplementation group significantly increased in circulating active OC (cOC), a well-established biomarker for bone and vitamin K status. In the MK-7 group, the inactive protein, undercarboxylated OC (ucOC), decreased by 51% +/- 21% as compared to the placebo group (+4% +/- 49%), indicating a positive MK-7 bone effect. After three years of supplementation, improvements in both bone mineral content and bone mineral density were statistically significant in the MK-7 group; moreover, bone strength was statistically improved.

A burgeoning area of research documents vitamin K2’s protective effect on cardiovascular health. This benefit is linked to the activation of the matrix Gla protein (MGP), a K-dependent protein that is one of the most powerful inhibitors of vascular calcification known today. By activating MGP, vitamin K2 helps the body shuttle calcium away from arteries so that it does not deposit in the artery walls.

in 2012, evaluated the dose-response effects of extra vitamin K2 (MK-7*) supplementation on the carboxylation (activation) of osteocalcin (OC) and MGP, and the effects on thrombin generation as an indicator of safety.

Forty-two healthy Dutch men and women aged 18–45 years were randomized into seven groups to receive either placebo capsules or vitamin K2 as MK-7* capsules at a daily dose of 10, 20, 45, 90, 180 or 360 µg. ucOC, cOC, and desphospho-uncarboxylated MGP (dp-uc-MGP) were measured. To increase the statistical power, the researchers collapsed the treatment groups into three dosage groups: 1) placebo, 2) low-dose supplementation (doses below the recommended dietary allowance, or RDA, per the European Union’s Commission Directive 2008/100/EC nutrition food-labeling rules), or 3) high-dose supplementation (doses around RDA, Commission Directive 2008/100/EC).

The results showed that extra MK-7 intake at nutritional doses around the RDA improved activation of the extra-hepatic vitamin K–dependent proteins; moreover, no adverse effects on thrombin generation were observed. Given the fact that, in the West, typical total vitamin K intake amounts to 100–150 µg/day-and that in this study, the MK-7 intervention supplemented a regular diet-this study demonstrates the high potency of this vitamin even at remarkably low intake levels. In conclusion, vitamin K2 as MK-7 is safe with respect to the hemostatic system and results in measurable changes in circulating inactive OC and inactive MGP that should be beneficial for bone and cardiovascular health.

Another study of note was conducted by Caluwe et al. and published in 

 Hemodialysis patients suffer from accelerated vascular calcification, and as previously stated, the vitamin K–dependent MGP is one of the most powerful inhibitors of vascular calcification. Hemodialysis patients have high levels of inactive MGP (dp-uc-MGP), and researchers hypothesized that these patients may benefit from pharmacological doses of vitamin K2 to improve the calcification-inhibitory activity of MGP.

To determine the optimal dose of vitamin K2 as MK-7 for MGP activation, 200 chronic hemodialysis patients randomly received 360, 720, or 1080 µg of MK-7* three times weekly for eight weeks. Dp-uc-MGP was measured at baseline and after eight weeks.

At baseline, dp-uc-MGP correlated inversely with vitamin K2 intake (P = 0.023). MK-7 supplementation dose-dependently reduced dp-uc-MGP. The levels decreased by 17%, 33%, and 46% in the respective groups. The researchers concluded that pharmacological doses of vitamin K2 supplementation might be a novel approach to prevent vascular calcifications in chronic hemodialysis patients.

 “Breakthrough” Vitamin K2 MK-7 Study Confirms Heart Benefits

Vitamin K’s current recommended dietary allowance is based on the liver’s requirement for blood clotting, but substantial concentrations of inactive, extra-hepatic Gla-proteins are found in the circulation of non-supplemented individuals. This suggests that vitamin K intake above the RDA is required for an optimal, extra-hepatic vitamin K status.

To that end, Theuwissen et al. measured circulating ucOC and dp-uc-MGP in 896 samples of healthy volunteers and defined target groups for vitamin K supplementation based on increased levels indicative of tissue-specific vitamin K deficiency.

 They studied the response to supplements by measuring the circulating dp-uc-MGP level in samples from two short-term trials of vitamin K2 as MK-7* supplementation in 42 children and 68 adults.

According to the researchers, children and adults with more-pronounced vitamin K deficiency had the highest responses to MK-7 supplementation; therefore, children and adults above 40 years of age showed the largest tissue-specific vitamin deficiency and, accordingly, may benefit from MK-7 supplementation to improve their extra-hepatic vitamin K status.

With proven safety and efficacy, vitamin K2 is an essential nutrient to consider in the pursuit of bone and cardiovascular health for young and old. I also have it on good authority there is more extraordinary research to come, and we are likely to see even more evidence to support the need for this essential supplement.

* NattoPharma’s branded MenaQ7 vitamin K2 as MK-7 was used as the source 

Sato T et al., “Comparison of menaquinone-4 and menaquinone-7 bioavailability in healthy women,” 

Knapen MH et al., ”Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women,” 

 vol. 24, no. 9 (September 2013): :2499-2507

Theuwissen E et al., “Low-dose menaquinone-7 supplementation improved extra-hepatic vitamin K status, but had no effect on thrombin generation in healthy subjects,” 

vol. 108, no. 9 (November 14, 2012):1652-1657.

CaluwÃ© R et al., “Vitamin K2 supplementation in haemodialysis patients: a randomized dose-finding study,” 

Theuwissen E et al., “Vitamin K status in healthy volunteers,” 

New vitamin K2 research on bone and heart health, and the significant differences between MK-4 and MK-7

Vitamin K2 for Bone, Heart Health: Just the Tip of the Research Iceberg?

With nine in 10 Americans deficient in choline and the Institute of Medicine (IOM) identifying choline as a high-priority nutrient in 2014, choline may well represent one of the largest untapped nutritional opportunities of recent times.

In 1998, the IOM recognized choline as an essential nutrient needed by humans and critical for proper fetal and child development. The adequate intake (AI) recommendation for choline is 550 mg/day for men, 425 mg/day for women, 450 mg/day for pregnant women, and 550 mg/day for lactating women.

While the need for choline is great, data from the 2007–2008 National Health and Nutrition Examination Survey (NHANES) evaluation showed that only 10% or less of the U.S. population across all age groups had a usual choline intake at or above the AI. Only young children are generally meeting AI levels.

Liver, eggs, egg yolks, and a variety of meats are the richest sources of choline, but their consumption has decreased in recent years. Supplementing the diet with choline is almost essential in order to ensure adequate consumption for optimal health.

The opportunity exists to promote choline for all ages. The U.S. FDA recently proposed adding choline to the list of nutrients permitted to be listed voluntarily on the Nutrition Facts panel on food labels. FDA has also mandated choline as an ingredient in infant formula.

Because the IOM has documented choline’s functionality in health promotion and disease prevention, robust health claims are possible for this nutrient.

Choline is associated with cognitive function, including development of the memory center. It has been shown to help prevent neural tube defects (NTDs) during pregnancy, support liver health and help prevent fatty liver disease, support heart health, and aid in sports performance.

Choline, an essential nutrient that is functionally complementary to B vitamins and omega-3 fatty acids, is critical to overall health and healthy cognitive function. Choline is a critical component of the building blocks of the nervous system, including neurotransmitters that form the mechanistic basis for memory. Choline is part of the brain’s messaging system and functions directly and indirectly in brain activities and in cognitive development of the fetus and infant.

Specifically, choline is a precursor to the neurotransmitter acetylcholine. Choline also functions as part of phosphatidylcholine, a structural component of the phospholipid membrane of all cells, including glial and neuronal cells. Choline supports the communication between neurons in the brain and promotes better availability of neurotransmitters for signaling within the brain. The availability of choline at different stages of human development and aging appears to be a significant determinant in improving the density and branching of dendrites, which results in more contact points for neurotransmission,

 thereby affecting the strength of neuronal response to stimulation in the parts of the brain responsible for memory.

The level of choline in the brain is directly affected by its levels in plasma, which is supported through dietary intake and supplementation.

 Oral intake of choline affects blood levels of both choline and acetylcholine.

Cognitive decline in aging is due in part to oxidative events. Such oxidative events occur when high levels of homocysteine are present. Homocysteine is a metabolically generated amino acid that is directly and inversely associated with choline intake.

Homocysteine may play a role in cognitive decline in normal aging and may atrophy parts of the brain hippocampus and cortex.

 Increasing choline intake may help to maintain cognitive function in the otherwise healthy, aging individual.

The opportunities for choline in the brain health market are great. In 2013, U.S. consumers spent $660 million on brain health supplements.

 Just under half (45%) of supplement users took a supplement to keep their heart healthy, while 28% took a supplement to boost their brain function/memory.

 According to survey data from HealthFocus International, maintaining mental sharpness as we age is the number one consumer concern, while lack of mental sharpness is also among the top 10 concerns.

 Mental/aging and aging/memory are both strong nutraceutical mass markets, on a par with vitamin D or omega-3s.

Strong evidence indicates that adequate choline intake supports normal liver functions and helps to prevent nonalcoholic fatty liver disease (NAFLD) and fatty liver, conditions that result either from choline deficiency or alcohol consumption.

Choline’s role as part of the phospholipid phosphatidylcholine is critical in healthy liver function. As mentioned, phosphatidylcholine is a primary structural component of the phospholipid membrane of all cells. This phospholipid is also needed in the construction of very-low-density lipoprotein (VLDL), which functions in fat transport.

The effect of choline on preventing fatty liver has been evident for some time. Research published in 1958 reported the positive effects of choline on liver health. A single dose of choline administered to choline-deficient animals increased the oxidation of liver fat as well as the synthesis of liver phosphatide P

NAFLD affects one-third of U.S. adults, including one-half of obese men as well as 11% of adolescents. One in 10 adults has liver disease. While liver health is still a relatively small supplement category, sales of liver/detox supplements topped $115 million in 2013, up 7.2% from 2012. The side effects of prescription medications, especially statins, are also raising concerns for liver health.

Choline affects heart health through a variety of mechanisms. First, choline helps lower levels of homocysteine, which otherwise causes oxidative stress and damage to LDL cholesterol, leading to plaque formation.

Choline also works to support a strong heart muscle with regular contractions, leading to a controlled and lower heart rate with less stress to the heart over time. Acetylcholine is a neurotransmitter used by nerve cells that control the heart, muscles, and lungs. Acetylcholine supports communication between nerves and the heart muscle. Acetylcholine is released at the junction between nerve and muscle cells, called the motor end-plate. This release signals calcium ions to begin muscle contraction.

As the heart health market shifts from targeting prevention to targeting risk factor reduction, there are great opportunities for supplements that help reduce the risk of blood plaque formation, especially considering that one in five consumers recognize that atherosclerosis is an important health concern and that 32% of women and 53% of men have high levels of blood plaque.

Folate, choline, and betaine serve as hydroxymethyl group donors, and are all important in the prevention of NTDs that result in birth defects, including anencephaly and spina bifida. These birth defects occur early in pregnancy, between the 21

 days after conception, when many women do not realize that they are pregnant.

 Pregnant and lactating women are among the many shown to have suboptimal intakes of choline.

The benefits of adequate choline intake are invaluable. Human studies show that women in the highest quartile of choline intake had a 72% lower risk of NTD-affected pregnancy, and those with the lowest levels of serum choline had 2.4-fold greater risk of an NTD-affected pregnancy.

Large amounts of choline are delivered to the fetus across the placenta; choline concentration in amniotic fluid is 10-fold greater than that present in maternal blood.

Plasma or serum choline concentrations are significantly higher in pregnant women than non-pregnant women and are six- to seven-fold higher in the fetus and newborn than in adults.

 Human milk is rich in choline; therefore, the need for choline in lactation is greatest, and maternal stores are generally depleted for extended periods of time.

In the women and children’s supplements market, choline should be of prime consideration. Half (46%) of children younger than age four take a supplement, while 70% of children aged 4-6 take a supplement.

 In 2012, 3.8 million women in the United States used prenatal supplements, while four of the top 10 bestselling women’s supplements were prenatal.

Through its activity at a cellular level, choline can enhance muscle performance during exercise and improve stamina. Choline supports communication with muscle fibers and promotes muscle recovery following repetitive motion, resulting in better overall output during training. Choline also protects the body’s natural pool of nitric oxide. Nitric oxide expands arterial walls, increasing oxygen-rich blood flow to exercising muscles; however, nitric oxide is a molecule that lasts for only a second in the bloodstream and then has to be replaced. Choline supports optimal nitric oxide functions in the body, which is good for all athletes, especially body builders.

With sales of sports nutrition supplements reaching $4.5 billion in 2013 (up 13% from 2012), this category remains among the fastest-growing supplement sectors.

In December 2013, Gallup research found that just 15% of Americans are aware of choline. But awareness is growing. New choline supplements nearly doubled to 555 in the global marketplace in 2012, up from 292 in 2011.

According to Sloan Trends’ TrendSense Model, choline quietly became a mass-market opportunity in 2009–2010 and has continued to accelerate in terms of its marketability ever since.

 SupplySide West: Is Choline Destined for a Breakthrough?

Catherine Adams Hutt, PhD, RD, CFS, is chief science and regulatory officer for Sloan Trends Inc. (Aubrey, TX). Adams Hutt is a registered dietitian and certified food scientist, and supports companies with strategic business direction and regulatory compliance.

Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline.

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McCann JC, Hudes M, Ames BN (2006) An overview of evidence for a causal relationship between dietary availability of choline during development and cognitive function in offspring. Neurosc Behav Rev 30:696-712

Glen MJ, Gibson EM, Kirby ED, Mellott TJ, Blusztajn JK, Williams CL (2007) Prenatal choline availability modulates hippocampal neurogenesis and neurogenic responses to enriching experiences in adult female rats. Eur J Neurosci 25:473-82

Jones III JP, Mech WH, Williams CL, Wilson WA, Swartzwelder HS (1999) Choline availability to the developing rat fetus alters adult hippocampal long-term potentiation. Dev Brain Res 118:159-67

Li Q, Guo-Ross S, Lewis DV, Turner D, White AM, Wilson WA (2004) Dietary prenatal choline supplementation alters postnatal hippocampal structure and function. J Neurophysiol 91:1545-55

Wurtman RJ, Cansev M, Ulus IH. (2009) Choline and its products acetylcholine and phosphotidylcholine. In: Tettamani G, Goracci G editors. 

Handbook of Neurochemistry and Molecular Neurobiology: Neural Lipids. 3 ed.

Babb SM, Ke Y, Lange N, Kaufman MJ, Renshaw PF, Cohen BM (2004) Oral choline increased choline metabolites in human brain. Psych Res Neuroimag 130:1-9

Hirsch MJ, Growdon JH, Wurtman RJ (1978) Relations between dietary choline or lecithin intake, serum choline levels, and various metabolic indices. Metabolism 27(8):953-60

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Olthof MR, Brink EJ, Katan MB, Verhoef P (2005) Choline supplemented as phosphotidylcholine decreases fasting and postmethionine-loading plasma homocysteine concentrations in healthy men. Am J Clin Nutr 82:111-7

Garcia A and Zanibbi K (2004) Homocysteine and cognitive function in elderly people. Can Med Assoc J 171(8):897-904

Nutrition Business Journal (2014) Condition Specific Supplement Data Sheets

Mintel, Vitamins, Minerals and Supplements - US - December 2013

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Sloan, A.E. 2014. TrendSense(TM) predictive model report. Sloan Trends Inc., Escondido, Calif. 

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Hartman Group, 2013. Reimagining Health & Wellness. The Hartman Group, Bellevue, Wash. 

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 (2012) Nutritional Supplements in the U.S, 5th Edition, September 2012

Widespread deficiency and a diversity of high-demand health benefits are moving choline into the spotlight in 2015. 

Choline Opportunities Are Ripe: Brain, Sports, and More

By now we’ve all read the jaw-dropping statistic: a healthy human body plays host to about 10 times as many microbial cells as it does to cells of…well, of itself. Which raises the almost existential question: Where does “self” end and “non-self” begin? And if we contain more of the latter than the former, what 

It’s heavy stuff. And yet it captures only in broadest outline the mysteries that researchers are untangling under the aegis of the Human Microbiome Project (HMP), the National Institutes of Health (NIH) effort charged with generating studies and data from which to characterize the human microbiome-that’s the collection of microbes that live in, on, and with us-and to analyze how it influences our health, or lack thereof.

While it’s still early days for the project, it’s no overstatement to call its potential revolutionary. As Donald. J. Brown, ND, managing director, Natural Product Research Consultants (NPRC; Seattle, WA), told an audience at the 2014 Council for Responsible Nutrition (CRN) Day of Science in November, “In the next couple of years, our worlds may be rocked” not just by what the HMP and allied investigations reveal, but by the findings’ power to shape public health and probiotic supplement research.

Brown, a naturopathic physician with a keen interest in probiotics, spoke at CRN’s Day of Science and in a subsequent interview with 

about good gut bugs and the emerging science concerning them. “The really interesting thing that’s coming up that we’re all sort of holding our breath for” is what we stand to learn when researchers start correlating data about the microbiome to specific wellness and disease endpoints, he says.

 as offering “a snapshot of what we might expect” when those correlations start surfacing. Researchers who studied the microbial composition of 123 non-obese and 169 obese subjects found that those with “low bacterial richness”-a group comprising 23% of the study population-exhibited more overall adiposity, insulin resistance, dyslipidemia, and pronounced inflammatory markers than those with greater bacterial richness.

The takeaway is that when it comes to health, more microbial diversity is better. And while the study is new, we might have drawn a similar conclusion by examining the guts of our forebears. Why? As Brown explains, “What we’re talking about is not fast-forwarding but going back in time to understand why, when people did more hunting and gathering and were exposed to soil in their food, that created a situation that led to more diversity” in their microbiomes.

The challenge for HMP researchers and the public health community-not to mention the dietary supplement industry-is to encourage that long-gone microbial diversity in a population not of hunters and gatherers, but of contemporary cube dwellers and consumers. And the solution, at least in part, may lie in probiotic supplements.

This realization comes at an already dynamic time for the segment, which continues to grow domestically and abroad. The Natural Marketing Institute (NMI) estimates that the category will reach a value of $44.9 billion by 2018, representing a compound annual growth rate of 6.8% from 2013.

But thus far, consumer interest in probiotics has centered mainly on how the organisms improve gut health and regularity-for good reason, as overwhelming evidence supports their beneficial role in fostering healthy digestion. But where research into the human microbiome promises to expand this picture is in sketching how the “spokes coming off the gut-health wheel,” as Brown puts it, intersect with other facets of health.

Take, for instance, the relationship between probiotics and pediatric health. Brown points out that humans essentially have no microbiome prior to birth; only once an infant ingests vaginal fluid during delivery do microbes begin colonizing the body, and only afterward does gut-associated lymphoid tissue (GALT) begin to develop the bacterial richness necessary to mucosal immunity.

But with almost one-third (32.8%) of American infants delivered via Cesarean section in 2012, per Centers for Disease Control and Prevention (CDC) numbers

, and with many mothers still unable to breastfeed as much as they’d like, some children may be missing an opportunity to maximize their microbial diversity. As evidence, a 2013 study

 found that infants delivered by Cesarean had especially low levels of bacterial richness and diversity at four months, while formula-fed infants displayed not only decreased species richness but an overrepresentation of 

Such findings make it worth asking whether probiotics might set these infants on a bacterially richer start. One 2013 meta-analysis

 of 25 studies involving some 4,031 children found that not only did probiotic administration lower total levels of immunoglobulin E (IgE), an antibody that triggers allergic reactions, but that the reduction grew stronger with longer probiotic follow-up. The analysis also showed that probiotics significantly reduced the risk of atopic sensitization when administered both prenatally and following delivery.

On the matter of attenuating symptoms of asthma and wheeze, probiotics proved less effective-a result arrived at not just in the aforementioned meta-analysis but in another

. Nevertheless, Brown is quick to note that “there’s some really wonderful work” going on in the field, and he believes it’s time for major players in probiotic research to establish large studies that examine how probiotics-either administered directly or through the breast milk of a supplement-taking mom-affect the development of atopic diseases like eczema and asthma in Cesarean infants. “Are the outcomes better?” he asks. If they are, “That’s huge. That’s a big public health message.”

Another big public health issue concerns the consequences of widespread antibiotic use. While no one disputes the utility of these lifesaving drugs, antibiotics, by definition, lay waste to microbial diversity, and the costs go beyond a worrying increase in antibiotic resistance (more on that shortly) to encompass the general microbial imbalance known as dysbiosis and its attendant disturbances.

The effects of even routine antibiotic treatment can be stark. One small study published in the 

Proceedings of the National Academy of Sciences

found “profound and rapid” changes in the distal gut microbiota of the three subjects after only three days’ treatment with ciprofloxacin. After one week, microbial populations had partially returned to normal, but as far as 10 months out, the final composition of all study subjects’ gut microbiomes differed from that at the start. And per the results of another study

, clarithromycin and metronidazole appeared to reduce numbers of 

-normal constituents of the microbiome-dramatically and immediately following treatment. Four years after treatment, some subjects’ microbiomes remained “perturbed” and their levels of antibiotic resistance high.

While greater restraint in prescribing antibiotics might help reverse these trends, probiotic supplementation might offer another strategy. In one double-blind, placebo-controlled trial

 involving 30 patients undergoing a seven-day course of amoxicillin, metronidazole, and lansoprazole for 

infection, researchers examined probiotics’ effect on the patients’ populations of facultative anaerobes-a category of bacteria that includes pathogens like 

We're heading into a new era of understanding how probiotics benefit many facets of health.

Nutritional Outlook Vol. 18 No. 1

Immune-Health Supplements: Supporting Innate and Adaptive Immunity

The Utility of Hemp Seeds

Vitamin K2 for Bone, Heart Health: Just the Tip of the Research Iceberg?

Choline Opportunities Are Ripe: Brain, Sports, and More

Microbiome and Emerging Research to Unlock Probiotic Mysteries?

Folic Acid in the U.S. Threatened by Proposed Nutrition Label Changes?

FSMA: What's Happening in 2015?

Dietary Supplement Industry Issues in 2015

2015 Ingredients to Watch for Food, Beverage, Supplements

Why Some States Will Have a Head Start on Hemp

Lawmakers Move to Legalize U.S. Industrial Hemp Industry

How Does EFSA’s Caffeine Assessment Match Up with Other Global Standards?

EFSA Says Caffeine Safe for EU Adults at 400 mg Daily or 200 mg in Single Dose

2015 Flavor Trends for Food and Beverage