Research into the microbiome and modulation of the community of bacteria in the human body continues to emerge at record rates. Whether evaluating prebiotics and fiber, live bacteria, or postbiotics (heat-killed microbes or their components which confer health benefits on the host), there is a great deal of science to unpack. At the same time, opportunities for product development in this complex and challenging market continue to emerge.

At the virtual Future of the Microbiome Summit, organized by Trust Transparency Center and held in December 2021, scientists discussed recent developments in substantiating benefits for “biotics” supplements. At the same time, market experts shared insights into successful commercialization in this segment, led by ties to digestive, immune, mood, sleep, and inflammation benefits.

“It’s important to remember where it all started. The microbiome is a collective of the genomes of all microorganisms, not just bacteria but also fungi, viruses, and their DNA, RNA, and proteins, all of which can affect the health outcomes and appearance of the host in areas such as oral, brain, thyroid, digestive, skin, and immune health,” said Sue Hewlings, director of scientific affairs for Nutrasource. “The microbiomes of the gut, the lungs, the skin, the mouth, the placenta, and the vagina are all becoming key areas of research focus, as are the microbiomes of animals for pet and animal health; and patterns of dysbiosis in these areas are being linked to specific health conditions.”

Fiber Fundamentals
Experts at the summit discussed fundamental elements of microbiome research, and new directions in which research is heading.

Thaisa Cantu-Jungles, a postdoctoral researcher at the Food Science Department of Purdue University, described key fiber sources designed to let beneficial bacteria populations flourish.

Once reserved for a handful of fiber classes, namely fructo-oligosaccharides, inulin, and galacto-oligosaccharides, “the definition today is broader than that,” Cantu-Jungles said. “There are so many different kinds of dietary fibers with prebiotic potential that are still not explored, with different sugar types, particle sizes, side chains, and chemical structures. Some are isolated, and some are found in insoluble matrices.”

Further, it’s important to determine if a prebiotic fiber is fermentable or non-fermentable, soluble or insoluble, and what the tolerability is, which largely depends on fermentation rate.

“Prebiotic fibers are such a complex and diverse category of molecules which can affect microbiome utilization, and which microbes end up utilizing the fiber change outcomes,” Cantu-Jungles said. She also noted that a major area of focus will be engineering dietary fibers to make them more available to beneficial strains, and less available to competing strains, for end goals such as butyrate production. However, it remains important for researchers to account for the differences between individual microbiomes.

“It’s very challenging to make a fiber that works similarly in all people regardless of who takes it,” Cantu-Jungles said. “But fibers more complex—physically and chemically—can produce more singular responses in people when precisely aligned to the specific bacteria we want to promote…. Feeding one bacteria in a targeted way can control which microbes are being fed, with more consistent and robust results.”

“We can use prebiotics to increase populations already naturally present in the gut,” she continued, “with promised stability unlike the latest generation of probiotics which are highly sensitive to oxygen. A mixture of fibers can provide a greater balance, supporting the whole core of beneficial species in the gut leading to multiple health benefits. The future of prebiotics will involve complex fibers that act more and more like probiotics, while others will be designed to match and more deeply promote the probiotics we ingest.”

Precision will Prevail
Leveraging data technologies to provide consumers with precise health recommendations based on genetics and other factors offers significant potential to increase product efficacy.

Eran Segal, computational biologist and professor at the Weizmann Institute of Science, discussed shifting the focus of phenotyping data collection seen to date toward the microbiome. “Genetics are a fixed component, but if we look at the environment and diet, deep phenotyping data can hopefully reverse trends [of disease rates] and lower the cost of drug development…. Focusing on what we’ve found in the microbiome area, we’re developing new techniques for analysis beyond composition of bacteria. We now record exact genetic variation of every single position across bacteria, and can associate the genetic variation of species with very significant signals, such as the BMI of the host at enough significance to explain one or two BMI points.”

Researchers working with Segal are developing a discovery pipeline for strains that work at the DNA level. Precision nutrition can help developers target the behaviors of fibers as well, said James DiNicolantonio, director of scientific affairs for AIDP. Fibers can be tailored to ferment in various regions of the digestive tract, and what makes precision nutrition important in the prebiotics fibers space is the end point of offering efficacy at lower doses, which entails less in-gut fermentation, resulting in fewer side effects.

“Typical fibers, on the other hand, often need to be administered in high doses for efficacy, and that means high levels of fermentation…. Typical fibers can often feed harmful bacteria as well as beneficial strains and make gut health issues worse. There are key needs that can be addressed through precision in prebiotics, such as selectively growing good gut bacteria, while simultaneously ensuring the prevention of gut dysbiosis.”

There is a lack of clarity as to what extent fibers can modulate a person’s gut microbiome, and whether addressing the variability of each person’s gut is feasible, noted Edward Deehan, senior R&D and quality scientist at Agrifiber Solutions. “The key issue is functional redundancy. Many species can use the same fiber substrate, or produce the same metabolite. Fiber degradation is a complex cross-feeding network, and many things need to be considered, along with individualized environmental factors such as pH, gut inflammation, and the presence or amount of nutrients.”

However, residual agricultural material, known colloquially as “upcycled” material, represents a cost-effective and sustainable means by which food manufacturers can isolate discrete fibers, compared to other more challenging approaches such as modifying existing carbohydrates with chemicals or enzymes, or by synthesizing fiber structures, Deehan said.


Mapping the Microbiome
Kristofer Cook, CEO of Carbiotix, concurred that understanding the individual nature of gut microbiomes is key to the development of precision fibers and bacterial strains. Carbiotix is a biotechnology company that aims to set a standard, at a reasonable cost, for consumer-oriented microbiome testing paired with dietary advice.

What began with an analysis of a few key strains following galactan supplementation developed into a “bridge between PCR and the current paradigm of testing: 16S. Everything is done in triplicate to ensure samples are more reliable,” Cook said.

The company recently introduced its consumer-facing LinkGut gut health testing service. “LinkGut is focused on food, beverage, and nutraceutical companies who don’t want to build up infrastructure or outsource tests to another party. It helps to build brand loyalty by marketing transparency to consumers, while we do everything we can to keep costs down by looking at the kits, shipping, and partners,” Cook said. “Predominantly, we want to reinforce transparency, personalization, and for consumers to be able to evaluate the efficacy of the products they use themselves and find the best dose or product. Instead of focusing on species diversity, we look for target species and metabolites. We believe in multiple and longitudinal samples, personalized intervention, and a broad disease and holistic focus, not just the microbiome itself.”

Tomasz Wilmanski, research scientist at the Hood-Price Lab for Systems Biomedicine at the Institute for Systems Biology, also emphasized the importance of metabolomics in furthering the definition of what a healthy microbiome means.

With a consumer-facing personalized wellness program called Arivale, Wilmanski and his team took to pooling data on bacterial phyla in various regions of the globe, accompanied with blood metabolomics tests, deep phenotyping, clinical evaluations, self-reported GI health outcomes, and 16S RNA sequencing. The goal was to bring swaths of data to light on the differences and similarities present in the gut microbiota of both healthy and unhealthy people.

The group determined that blood metabolomics were a strong predictor of gut microbial alpha-diversity, using a suite of 40 metabolites. “A validation cohort further backed up the conclusion that blood metabolites serve as a strong interface between the gut and health outcomes,” Wilmanski said, noting that metabolites produced directly within the gut, such as hippurate, cinnamoylglycine, and P-cresol sulfate, were the best predictors of alpha-diversity.

Additionally, a metabolite derived from the breakdown of testosterone in the gut was associated with alpha-diversity, emphasizing one of many mechanisms by which sex hormones can influence gut microbial populations. “The ultimate product of the gut microbiome that affects one’s physiology are blood metabolites,” Wilmanski noted. “They can be used as a potential screening in clinical settings, and should be emphasized more to give clinicians information they might need before sequencing a person’s entire gut microbiome. It’s also important to uncover the rest of the gut metabolites, and how they might influence health outcomes to fully explain the role that the gut plays in metabolomics.”

Psychobiotics
The field of psychobiotics, a small but emerging class of live bacteria tied to mental health benefits, have been a hot topic in recent years. Ted Dinan, medical director of Atlantia who coined the term “psychobiotic” in 2013, discussed investigation of what has become known as the gut-brain axis—a complex series of relationships between activities in the gut and in the brain.

Dinan broke down chemical assays, animal studies, and clinical trials in both healthy subjects and those with clinical mood disorders. Research has identified a number of rare bacteria shown to exert mental health benefits in self-reported assessments, markers of stress such as cortisol, and more. Additionally, there are substantial differences in the microbiota of clinically-depressed people compared to healthy populations, Dinan noted.

“The products of microbial activity get into the bloodstream and have an influence over organisms, and are epigenetic regulators which influence the ways that genes act and behave,” Dinan said. “The gut microbiome has a diverse range of actions which are undoubtedly important from a neurological perspective. For example, certain microbes can actually synthesize tryptophan, which the human brain can’t store and needs a constant supply of, which is converted into serotonin…. We can’t change the genes in ourselves, but can change the genes in the gut microbiota, which is like a pseudo-organ in that it behaves like one, and has a massive amount of DNA. This is an extremely important concept from a health perspective.”


Marketing the Science Responsibly
Microbiome science is complex and multi-faceted, requiring a certain level of understanding among consumers.

Experts said the marketplace will grow the most by engaging with consumers at their knowledge level so that they can make informed choices. Ensuring that consumers have realistic expectations about what microbiome-targeting products can do, and communicating with media to ensure the field of research is represented accurately, will be critical to legitimizing the marketplace.

According to Len Monheit, CEO of Trust Transparency Center, familiarity with probiotic ingredients skews toward younger audiences; the average probiotic user tends to be more concerned about lack of energy, anxiety, joint or other pain, insomnia, depression, and immune health than the average supplement user.

Key elements that consumers are looking for on labels include terms like prebiotic, contains fiber, contains a prebiotic and probiotic combination, contains at least 10% of the recommended daily intake of fiber, is symbiotic, and contains a resistant starch. According to Monheit, about 60% of consumers can accurately define a probiotic when given multiple definitions to choose from—less for the definitions of postbiotics, prebiotics, and symbiotics.

Kantha Shelke, a food scientist and founder of Corvus Blue LLC, noted that people don’t learn about the microbiome in school, but excitement has infected the public with information from journalists and magazines. “Scientists are discussing extinctions in the microbiome tied to antibiotics, and companies are offering microbiome analysis, but there’s so much variation in the microbiome based on the time of day, or the time of week, and we have to be careful about what we base the promises we’re making on,” she said.

Scientists have an important role in shaping how the public interprets their research, Shelke said, advising experts to convey clearly whether an experiment detected clinically significant differences, whether a study showed correlation or causation, what the mechanism of action might be, how well an experiment can be extrapolated to a general population, and other factors which may help explain results. “It doesn’t matter how much we know, what matters is how clearly people can understand it,” Shelke said.

Maria Pavlidou and Peter Wennstrom of the Healthy Marketing Team said that how a company markets its probiotic product largely hinges on the audience. “Different health concepts are at different places of familiarity in the consumer market,” Wennstrom said. “Some of the biggest concepts are digestion benefits, meeting fiber requirements, and cultures, while more of the specific probiotic and prebiotic concepts are still a bit more in the early mass market stages for lifestyle stakeholders.”

“It’s important that an early decision on language is made depending upon whether you’re addressing the pharmaceuticals industry, more technically minded consumers, the mass market, etc. The science is all the same, but the communication is different,” Pavlidou said.

Given constraints on making health claims, formulating probiotics with other ingredients may help offer more substantive communications with consumers. Further, differentiating in a category where consumers can easily muddle the science is critical through patents and branding.

While other product attributes may not be deal breakers, the credibility behind scientific claims could lead the probiotics category to exponential heights. But if trust among consumers erodes then the entire category will suffer, said Kevin Cencula, global marketing manager for Kerry.

“Often, people in the industry perceive a tension between the science arm and the marketing arm of a business,” he noted. “People believe that science stands on a foundation of credibility, while marketing tries to push the envelope and potentially stretch the truth behind health claims. But having a branded ingredient enables it to show up as unique; it prevents companies from hiding behind something generic, and a distinct name amplifies the uniqueness of an ingredient by highlighting the importance of strain specificity.”

Market Dynamics
Over the past decade, the amount of sequenced microbiome samples collected by researchers grew from 202 to 27,0000, said Denise Kelly, investment advisor at Seventure and former professor of immunology and microbiology. Understanding about how gut bacteria interact with drugs, the environment, and disease states has also grown exponentially.

“What we know now is that microbial ecology shifts throughout life stages, from nutrition and diet, and switching to either an urban or a rural lifestyle,” she said. “Developmental factors are a big predictor of disease, and we’re focusing on the microbiomes of near-centenarians. We know that antibiotics and sanitary practices are removing very important organisms from the environment that are key to maintaining health, and their use seems to correlate with the skyrocketing incidence rates of several immune-related disorders. We know that diets which target the gut microbiota alter human immune status.”

Kelly noted that the first microbiome-based drug, a treatment for skin psoriasis, has cleared a phase 3 clinical trial, signifying that the pharmaceuticals industry is also on the cusp of innovating with microbial-based therapy. “The FDA has been incredibly supportive and the pharmaceuticals industry is extremely excited about the therapeutic opportunities within this space,” Kelly said, noting that this could differentiate between one-size-fits-all products and precision medicine.

“The field was once dominated by infectious disease and GI issues solutions, but is much more wide open now to include oncology, neurodevelopmental and neurodegenerative diseases, and the oral microbiome. It’s seen a lot of investment, IPOs, and mergers and acquisitions activity since the pandemic which shows that the field is beginning to progress in a very significant way,” Kelly said.

She predicted groundbreaking approaches will include big data integration, diversifying the focus to include potentially beneficial viruses and fungi, machine learning, basing products at various life stages, and a growth in engineered bacteria.

“From 2015 to 2020, the functional foods industry saw a 30% growth in products making probiotic claims,” said Cencula, from Kerry. “Venture capitalists are more and more interested in where probiotics fit in the supplements space. While some companies want a commodity supplier, others don’t just see it as a raw material. They want something with extra care and expertise to understand its incorporation into a finished product, and they want to take on more of a partner role.”

As microbiome research continues to develop, a clearer picture of the role that overall diet and fermentation play in metabolic diseases will continue to develop. “There is a whole landscape of what’s contributing to metabolic disease: calorie density, sedentary lifestyle, insomnia, stress, and medications. The development of literature surrounding ultra-processed foods is also relevant. UHP foods lack whole food ingredients and contain artificial colors, flavors, and stabilizers. Epidemiological data is linking these foods to a rise in diseases, both involving obesity and in terms of all-cause mortality,” said Chris Damman, MD, chief scientific and medical officer for UR Labs. “At the same time, improvements have been noted in whole food, high-fiber diets. Processed foods with fiber added could be a missing part of the solution, emphasizing convenience and consumer preference.”  

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Mike Montemarano has been the Associate Editor of Nutraceuticals World since February 2020. He can be reached at MMontemarano@RodmanMedia.com.