Prebiotic research is expanding health applications and formulations

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The prebiotics market is expanding both within and beyond digestive health. Researchers are uncovering new routes by which prebiotics can act on both the gut and the brain, creating new opportunities for prebiotic products that target different pathways.

Product formulators are starting to view prebiotics as an ingredient category in its own right rather than an extension of the probiotics category. This, in turn, is spurring interest in some exciting applications.

Mental Health

One growing area of prebiotic research is mental health. Consumer interest in natural remedies for stress and anxiety skyrocketed during the COVID-19 pandemic. This inspired research on mental health prebiotics, says Linda Peek, senior marketing manager for Biotis GOS by FrieslandCampina Ingredients (Amersfoort, The Netherlands).

“The gut-brain axis is a really hot topic right now,” Peek says. “Last year, 42% of consumers reported a desire to improve their mental well-being, and 50% said their stress led to bad moods and issues sleeping. Although interest is at an all-time high, the gut-brain axis is still an emerging area of science. Research has only just begun in recent years to shed light on the role a healthy gut microbiome plays in facilitating mental well-being.”

One recent randomized, double-blind, placebo-controlled clinical trial¹ sought to determine whether FrieslandCampina’s branded prebiotic galacto-oligosaccharide product Biotis GOS could reduce anxiety and improve gut bacteria composition in healthy women aged 18 to 25 with no history of mental or gastrointestinal disorders. At the start of the study, the subjects were assessed for baseline anxiety level on subscale 44 of the State-Trait Anxiety Inventory and were then assigned to either a high-anxiety (n=25) or low-anxiety (n=23) group. These groups were further subdivided into groups: 1) high-anxiety plus placebo (n=13), 2) high-anxiety plus Biotis GOS (n=12), 3) low-anxiety plus placebo (n=12), and 4) low-anxiety plus Biotis GOS (n=11). Participants in all groups gave a stool sample and completed a four-day food diary at baseline. They were also assessed at baseline for IQ and emotional processing via the Wechsler Abbreviated Scale of Intelligence and the attentional dot-probe task, and completed a series of self-report questionnaires on mood, anxiety, sleep, and emotional regulation. The subjects repeated the entire battery of tests after study conclusion.

The participants received 7.5 g of Biotis GOS powder per day, or a matching placebo, for 28 days. Forty-eight participants completed the study. After four weeks, the high-anxiety-plus-GOS group exhibited a statistically significant reduction in self-reported anxiety scores relative to placebo, while the low-anxiety-plus-GOS group did not. The high-anxiety-plus-GOS group also saw an increase in gut microbiota diversity and reduced bias toward negative stimuli on the attentional dot-probe task. While the effect size was small, the study authors concluded that GOS “may be effective in influencing the expression of anxiety” and that further research is warranted.

Immune Health

The gut-brain axis is only one pathway for prebiotics. Prebiotic ingredients are also leveraging the connection between gut health and immune health, creating potential market opportunities for prebiotic products that reduce inflammation and help regulate immune function.

Immune health has been a high-priority research focus over the last year, says Frederic Narbel, DBA, vice president of B2B sales at Clasado Biosciences (Jersey, UK). “When we think ‘immune system,’ we tend to picture white blood cells attacking foreign bodies,” Narbel says. “However, around 70% of the immune system resides in the gut, so that’s naturally the focal point.”

Clasado’s branded galacto-oligosaccharide ingredient Bimuno has shown a positive effect on immune function in various studies, Narbel notes. Recent research, he says, demonstrated that Bimuno positively impacted markers of immune resilience in the elderly and improved inflammatory markers in asthmatic and overweight sample groups.

Bimuno is one of the ingredients included in Procter & Gamble’s Align Fast-Acting Biotic Gummies. This new gummy product is a great example of a synbiotic, a product that combines a prebiotic with a probiotic to provide the benefits of both, says Per Rehné, CEO of Clasado Biosciences.

Infant Health

One recent European study² performed as part of the Early Nutrition Programming Project (EARNEST) revealed the benefits of prebiotic supplementation for infants.

The study, a prospective, randomized, double-blind, placebo-controlled, multisite trial, followed 160 healthy, full-term, exclusively-formula-fed infants from age four months or younger to age 12 months. The infants were randomly assigned to receive either 0.8 g/dL of Beneo’s (Parsippany, NJ) Orafti-brand Synergy1 (n=81) or a control formula (n=79) every day until their first birthday. A pediatrician examined the infants at baseline and at ages two months, four months, six months, nine months, and 12 months. Infants were assessed on various dimensions of health, including sleeping habits, crying habits, stool frequency and consistency, digestion, weight, length, and the frequency and duration of any infections or fevers. Stool samples were collected at ages two months, six months, and 12 months, and were analyzed for concentration of Bifidobacterium, Enterobacteriaceae, Bacteroides, C. leptum, and C. coccoides.

While there was no difference in the raw number of infections between the control and experimental groups, the infants who received Synergy1 experienced a shorter average duration of infections. The supplementation group also exhibited a lower total daily crying time than the control group on four out of the five visits. The study authors concluded that Synergy1 supplementation was associated with a shorter duration of infections and a slight improvement in infant well-being.

Prebiotic fibers are an important area of research that will continue to grow, says Kyle Krause, regional product manager of functional carbohydrates for Beneo North America. He predicts future research will explore their cognitive health implications. “We expect that there will be continuing research on the effects of prebiotic fibers as they relate to immune health and strengthening inner defense mechanisms and the gut-brain axis. While there is much research on the benefits of prebiotic fibers on physical health, we expect to see more investigative research into impact of the microbiome on cognitive health.”

Weight Management

Could prebiotics be the next big thing in weight supplements? René Kamminga, CEO of OptiBiotix Ltd., a subsidiary of OptiBiotix Health PLC (York, UK), says weight and metabolic health are among the most interesting areas of emerging prebiotic research. In particular, he says the intersection between prebiotics, the gut microbiome, and mood is leading to exciting studies.

“New research³ conducted at the University of Illinois has shown that consuming avocado, a natural prebiotic high in fiber, may help improve gut health,” Kamminga says. “Elsewhere, researchers at the Indiana University School of Medicine have discovered⁴ that the stomach-specific protein gastrokine-1 (GKN1) may play a major role in the progression of obesity as it interacts with microbes in the gut. While more evidence is required around the role of GKN1, it could be another avenue for microbiome modulators and prebiotic formulations to explore.”

A 2020 study⁵ examined the effects of OptiBiotix’s branded weight-management ingredient SlimBiome, a blend of agglomerated glucomannan, fructooligosaccharide, and chromium picolinate, on body weight, body fat, and waist-to-hip ratio in 12 women between the ages of 18 and 65 with a BMI ranging between 25 and 35. The study, a single-group, prospective, open-label pilot human trial, followed the volunteers for four weeks. All 12 subjects replaced their usual breakfast and lunch with one 206-kcal GoFigure shake per meal. Each GoFigure shake delivered 3 g of SlimBiome. The subjects also ate two 112-kcal snack bars per day, with each bar containing 1.5 g of SlimBiome. For dinner, the subjects were permitted to eat a healthy meal of their choosing provided they did not exceed 1,500 kcal/day.

The subjects’ waist-to-hip ratio and blood pressure were measured at baseline and on study conclusion, and they completed the Control of Eating Questionnaire once per week. Their blood pressure, gut microbiome diversity, resting metabolic rate, and body composition were also assessed via bioelectrical impedance analysis at baseline and on study conclusion.

After four weeks, the subjects lost an average of 1.9 kg in body weight. The group’s average BMI fell from 29.3 to 28.6, and average waist and hip circumference decreased by 3.5% and 2.7%, respectively. Average body fat percentage fell by 1.2%, while average fat mass decreased by 1.7 kg. The group also exhibited a statistically significant reduction in systolic blood pressure. The study authors concluded that SlimBiome may help reduce body weight and fat mass while improving mood and gut microbiome composition.

Formulation Opportunities

Historically, the prebiotics market has primarily consisted of dietary fibers and ingredients that indirectly support GI health by acting on various pathways. Now, formulators are creating a new type of prebiotic that can directly promote healthy digestive function by acting on bacterial strains themselves.

John Deaton, vice president of science and technology for Deerland Probiotics & Enzymes (Kennesaw, GA), says an emerging class of prebiotics known as bacteriophages is demonstrating an ability to support digestive health and has opened the door to synergistic blends. Bacteriophages, Deaton says, are distinct in their composition and mechanism of action.

“Bacteriophages, or phages, are tiny bundles of RNA encased in a protein shell,” Deaton says. “Their innate role is to overpower a specific bacterial strain. Consuming phages that are known to target pathogenic or irrelevant strains residing in the microbiota will shift it away from dysbiosis to a healthier, sturdier bacterial composition. Phages work by destabilizing cell walls and taking over metabolic processes of the targeted bacteria.”

The emergence of phages as a prebiotic class has expanded opportunities for formulators by providing a non-fiber alternative, Deaton explains. Fiber-based prebiotics, he says, can often cause unpleasant side effects like gastrointestinal discomfort and bloating. In contrast, phages can reduce GI discomfort and provide synergistic benefits when combined with probiotics.

One 2020 randomized, parallel-arm, double-blind, placebo-controlled clinical trial⁶ funded by Deerland investigated whether Deerland’s branded PreforPro bacteriophage cocktail could exert a synergistic effect when administered in combination with Bifidobacterium animalis subsp. lactis BL04 (B. lactis). The participants, men and women aged 18 to 65 with a BMI between 20 and 34.9, were randomly assigned to receive either 1) a placebo consisting of 15 mg of rice maltodextrin (n = 21), 2) 1 x 10⁹ colony forming units (CFU) of B. lactis BL04 (n=23), or 3) 1 x 10⁹ CFU of B. lactis BL04 in combination with 1 x 10⁶ plaque forming units (PFUs) of PreforPro, containing LH01-Myoviridae, LL5-Siphoviridae, T4D-Myoviridae, and LL12-Myoviridae bacteriophages (n=22). The active ingredient was administered in the form of a 15-mg capsule once per day for four weeks.

The subjects were instructed to fast for eight hours, avoid exercise for 12 hours, and avoid any medications or supplements for 24 hours prior to study visits. Participants kept to their normal diets and completed two-day diet records at the start and end of the intervention period. All subjects provided blood samples at study visits and completed digestive health questionnaires at baseline and after four weeks. Subjects self-reported their bowel movements on the Bristol Stool Scale and also provided stool samples for analysis.

The PreforPro group reported an improvement in colon pain and a minor improvement in GI inflammation relative to the other two groups. The PreforPro group also experienced a significant increase in E. coli-targeting phages over the study period. PreforPro consumption also caused a reduction in concentrations of bacteria that are associated with gut inflammation. While the study authors list several caveats, including the fact that the subjects’ diets were uncontrolled, they nonetheless conclude that PreforPro may help manage occasional gastrointestinal symptoms and may help enhance the GI effects of B. lactis.

Evidence is emerging to suggest that prebiotics are more than just food for probiotics, Deaton notes. He says the PreforPro study demonstrates that prebiotics like phages can help support a healthy microflora balance.

Personalized Prebiotics on the Horizon?

As prebiotic research evolves, experts predict personalization will begin to emerge as a prominent research domain. Emerging research will focus on the individual differences in microbiota and how they might influence how prebiotics behave in certain individuals, says Len Monheit, executive director of the Global Prebiotics Association (Spring, TX).

“We know that we have responder and non-responder populations,” Monheit says. “We also know that everyone is so unique in their microbiota. Overall, diversity is good, but certain strains correlate with overall health. If you umbrella these fundamental concepts, we can see that the ability to have a ‘diversity measure’ as well as diagnostics around certain species and strain combinations [can enable one to] pinpoint areas where prebiotics will be maximally beneficial.”

Chemical Research Drives Prebiotics Forward

Some of the recent research advances in prebiotics have less to do with clinical trials and more to do with the physical and chemical properties of prebiotic ingredients. Research on the chemical properties of different soluble fibers is enabling more targeted, more personalized ingredient development, says Kavita Karnik, global head of nutrition and regulatory affairs at Tate & Lyle (Chicago).

“Soluble fibers have strong prebiotic properties, but not all fibers are the same,” Karnik says. “Properties like molecular weight and bond linkages have an impact on their fermentation profile by modulating the speed, location, and extent of fermentation. This, in turn, causes different effects on various biomarkers and health parameters.”

The prebiotic industry is not far from a future where specific prebiotic fibers can be designed to target a particular species of gut microbiota, Karnik says. Developments like this could open up new opportunities in the area of personalized nutrition.

Precision Prebiotics

In addition to personalization, there is significant research activity in precision and synergistic prebiotics. Research on precision microbiome modulation is investigating if and how specific prebiotic fiber structures can induce predictable, repeatable changes in the microbiome that can result in targeted health benefits, says Anne Franck, global COE leader, nutrition, for the food technology division of Cargill (Minneapolis).

“As research into the microbiome progresses, the beneficial impact of selected prebiotics throughout life stages is being explored,” Franck says. “With strong interest especially in early life nutrition and healthy aging, there is a significant window of opportunity to impact health through selective gut microbiota modulation.”

Another emerging area of interest is prebiotic blends consisting of different prebiotics, each of which has a different modulatory effect on specific gut microbiota. Franck says these blends contribute to a more diverse and resilient microbiome.

Whole-Food Ingredients Grow

The global prebiotics market has seen impressive growth, with some market researchers forecasting 7% compound annual growth through to 2030.⁷ This growth is inviting market disruption.

Samantha Ford, MS, director of business development for AIDP Inc. (City of Industry, CA), says consumer-led trends like plant-based and clean-label ingredients are already inspiring consumers to embrace whole-food solutions.

“We’re already seeing new concepts disrupt the market,” Ford says. “We’re seeing prebiotics being used in new concepts such as skin formulations, detox and cleanse regimens, as well as a complement to probiotic products. But consumers aren’t only looking for clean and simple ingredients; they want to feel a difference.”

Future prebiotic research will focus on combination products and new studies on brain health, immunity, and metabolism, Ford says. Whole-food sources, though, will remain a significant trend. AIDP’s branded Actazin and Livaux ingredients, for instance, are derived from different varieties of kiwi fruit. In January 2021, AIDP secured a patent for the combination of Actazin, a kiwi extract powder rich in the digestive enzyme actinidin, and its branded PreticX xylooligosaccharide (XOS), a prebiotic.

A recent double-blind, placebo-controlled, multicenter study⁸ conducted by AIDP examined the effects of the combination of Actazin and PreticX on bowel function as measured via the Bristol Stool Scale and in number of complete spontaneous bowel movements. Participants were randomized to receive either 1) a placebo, 2) 600 mg of Actazin, or 3) 600 mg of Actazin plus 1.4 g of 70% PreticX, per day for 28 days. The not-yet-published study found that when administered together, Actazin and PreticX significantly improved stool form normality.

Xylooligosaccharides Validated

One ingredient that’s attracting attention from researchers is xylooligosaccharides (XOS). A 2020 in vitro study⁹ consisting of two different experiments examined the effects of varying dosages of XOS on gut microbiota composition and short-chain fatty acids in a TIM-2 simulated colon inoculated with human microbiota. In the first experiment, the researchers administered Prenexos brand of sugarcane-derived XOS manufactured by Prenexus Health (Gilbert, AZ) in either a 1.5 g/day or 3 g/day dose. In the second experiment, the simulated colon was inoculated with different microbiota, and a 1 g/day dose of XOS was administered. The researchers took samples after 0, 24, 48, and 72 hours and compared the results to microbiota grown in the standard medium, SIEM.

Relative to the standard medium, XOS increased lactate production, both at the 1.5-g and 3-g doses, and in both microbiota environments. XOS also increased bifidobacteria. While the authors caution that human clinical trials are needed to establish the potential health benefits of XOS, the study did validate that XOS has potential prebiotic effects.

Prenexus Health CEO Michael Bush says the most exciting new development in prebiotics involves managing serving sizes. Low-inclusion-rate prebiotics, he explains, are the future.

“The emergence of low-inclusion-rate prebiotics allows for full efficacious servings to be included in virtually any formulation, from foods to beverages to supplements,” Bush says. “By including full, studied servings, consumers will be able to [experience] the benefits of the ingredient [which will] support the growth of the space.”

Synbiotic Food and Drinks

While prebiotics on their own have been shown in clinical trials to have a variety of benefits, some ingredient suppliers are seeing growing opportunity in blended products that combine prebiotics with probiotics to create a synergistic effect. These synbiotics are well positioned to meet consumer demand for more tailored products, says June Lin, global vice president of marketing for health & wellness at ADM (Chicago).

“Synbiotics as emerging microbiome-supporting solutions are gaining traction,” Lin says, noting that an ADM Outside Voice survey found that 49% of respondents believe each person needs his or her own unique, customized diet. “As research on synbiotics expands, we expect synbiotics will also be incorporated into food and beverage formulations to fortify and tailor products for consumers’ distinctive needs.”

Synbiotics are ideal for inclusion in functional foods and drinks for a variety of reasons. Sarah Diedrich, marketing director for sweetening solutions & fibers at ADM, says ADM’s branded Fibersol is a low-viscosity, highly soluble ingredient that can maintain the structural integrity of reduced-sugar food products. ADM offers a synbiotic Fibersol ingredient blend designed to support healthy digestion that can be incorporated in a wide array of functional food and drink recipes like baked goods, beverages, yogurts, nutrition bars, cereals, trail mixes, and salad dressings.

Prebiotics to Break into Various Categories

The prebiotics market is no longer just about digestive health. With new research validating the role of prebiotics in everything from weight loss to immune function to children’s health and more, formulators and brands have a variety of opportunities to create and position prebiotics for a diverse array of functions.

As research into areas like skin health and brain health continues, the prebiotics market will continue to evolve into a multifunctional arena that’s rich in opportunities for innovation.

References

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