In April, the U.S. Food and Drug Administration approved Seres Therapeutics’ Vowst—the world’s first prescription microbiome-based therapy.

Indicated for the prevention of recurrent Clostridioides difficile (aka “C diff”) infection in adults, Vowst contains live microbial spores derived from healthy human feces. In essence, it’s a fecal microbiome transplant in capsule form. The approval was supported by two clinical studies—one placebo-controlled, the other open-label—involving a total of 346 patients with severe recurrent C. difficile.

In the placebo-controlled trial, the Vowst-treated patients had markedly lower 8-week recurrence rates—12.4% vs. 39.8%—compared with the placebo group (Feuerstadt P, et al. N Engl J Med. 2022). Both groups had been previously treated with standard antibiotic drugs for C. difficile.

Though there were some unwanted effects associated with Vowst (abdominal bloating, fatigue, constipation, chills, and diarrhea), it was generally safe and well-tolerated. According to the FDA, its potential benefits far outweigh its drawbacks.

The approved clinical indication for Vowst is quite narrow: prevention of C. difficile recurrences in adults previously treated with antibiotics. Seres stresses that the product is not intended as a primary treatment for acute infections.

But in approving Vowst, the FDA has quietly unlocked the door to an entirely new and potentially vast category: prescription microbiota-based drugs. And this begs a big question with significant implications for the dietary supplement industry: Are Rx probiotics on the horizon? For the next year or two, the answer is “probably not.” But longer term, it is a very real possibility.

Market Players to Watch

According to market research firm Global Data, there are more than 130 different companies across the pharmaceutical, biotech, and food/beverage sectors currently working on patented probiotics and microbiome-based therapies.

Global Data claims that in the past three years, pharmaceutical companies have filed more than 633,000 microbiome-related patent applications.

For now, Nestlé appears to be in the lead in terms of total number of patents and partnerships.

Seres is partnering with Nestlé Health Science to launch Vowst in the U.S. and Canadian medical markets. A press release following the approval noted that Nestlé is investing $125 million in the launch, and will play the lead role in channeling Vowst into North American clinics.

Aside from the recent Vowst deal, Nestlé is currently working on a Lactobacillus-based weight management product. Whether that will ultimately come to market as a supplement, food in-gredient, or approved medical food remains to be seen.

Nestlé is not a drug company, per se. But over the last decade, it sure has started to behave like one, as STAT business writer Rebecca Robbins pointed out in her 2018 article on the company.

Nestlé has made a strong shift away from the candy, ice cream, and dairy products for which it is best known, and toward a stronger position as a healthcare company.

Robbins noted that Greg Behar, Nestlé Health Science’s CEO since 2014, has an extensive pharma background, having spent years in top roles at Boehringer Ingelheim. Since Behar took the helm, Nestlé has acquired or partnered with a number of innovative biotech startups. In 2018 the company took a major position in the practitioner supplements channel by acquiring the Atrium Innovations portfolio of companies. Nestlé’s investment in Seres and the product that ultimately became Vowst, began in 2016.

In September, Nestlé announced Behar will leave the company at the end of 2023. Anna Mohl, currently head of international business at Nestlé Health Science, will become CEO beginning in 2024.

Other global pharma players have also been venturing into microbiome-based therapies. According to Global Data, Pfizer, Novo Nordisk, and DuPont de Nemours all have products in the works. 

Biotech industry consultant Jean François Denault, in a 2021 article for Genetic Engineering & Biotechnology News, stated that other international pharma titans including Boehringer, Takeda, Gilead, Novozymes, and Merck all have deals—large and small—with probiotic/microbiome-focused biotech companies. 

Johnson & Johnson is definitely in the game, via its Swiss subsidiary, Cilag GmbH. In 2018, Cilag announced a long-term agreement with Probi—a Swedish probiotics manufacturer—to develop new microbiome modulation products based on Probi’s cornerstone Lactobacillus plantarum LP299V strain. 

OptiBiotix Health, a microbiome-focused biotech company based in York, UK, is also accelerating its efforts to develop L. plantarum-derived products targeting specific clinical conditions, including hypertension, dyslipidemia, and cardiovascular disease. Several years ago, OptiBiotix announced a partnership with an unnamed U.S. pharmaceutical company to bring its branded strains into the U.S. market, and to potentially develop therapeutic products outside the food and dietary supplements categories.

AstraZeneca, the UK pharma giant, and an early-stage investor in Seres, has its own Microbiome Discovery lab, dedicated to “Unlocking the microbiome to discover new drugs within you.”

On its website, AstraZeneca acknowledges the relationship between microbiome changes and a wide range of human respiratory, metabolic, neoplastic, and inflammatory diseases. And this opens entirely new possibilities for microbiome-based treatments.

“The microbiome represents a new, untapped frontier for biomarker identification and drug discovery. Utilising technological advances which enable analysis of large datasets and the dis-ease area expertise present across our organisation, we are unlocking the potential of the microbiome to identify actionable biomarkers and bring novel therapies to patients,” says Taylor Cohen, director of microbiome discovery, on the AstraZeneca site.

AstraZeneca has not yet brought a prescription probiotic to market, nor have any of the myriad other pharma and biotech players currently prospecting the microbiome. But Cohen’s statement does make it sound like that’s where the company could be heading.

AstraZeneca and other Big Pharma players are also exploring possibilities for new drugs that modulate specific aspects of the microbiome to obtain distinct clinical outcomes. Such products would not be “probiotics” in the sense that we use the word in the supplements sector. But they would certainly qualify as microbiome-modulating therapeutics.

Microbiome Pathways

Leaving aside the question of Rx probiotics, it is clear that microbiome research has paved a way for pharma and biotech to gain entry into the more leniently regulated dietary supplements space.

Meanwhile, on the supplements side, many probiotic brands (and their raw material suppliers) have become more pharma-esque in the ways they develop and market products. Condition specificity is the new watchword, and strain specificity is the key to achieving it.

The simple, old narrative about “Bad Bugs and Good Bugs” that endeared probiotics to the general public and drove explosive sales for the last two decades, has given way to a much more complex and nuanced picture.

Microbiologists have shown us there’s not just one microbiome in the gut; there are many microbial ecosystems within the body—in the mouth, the lungs, the biliary tract, the mammary glands, the skin, even the conjunctiva of the eyes. These systems are interrelated and they affect almost every aspect of human physiology.

Commensal microbes can affect an astonishing range of human functions including appetite, sleep cycles, glucose metabolism, hormone regulation, mood, cognitive function, immunity, fertility, and even bone metabolism. They do this directly and indirectly via the myriad metabolites and cell signaling molecules they produce.

While the intestinal microbiome remains central to the story, we now have many other sub-plots centered on the various “axes.” There’s a Gut-Brain Axis, a Gut-Liver Axis, a Gut-Vaginal Axis, a Gut-Lung Axis, and likely several others.

This means that probiotics and microbiome-modulating substances have relevance far beyond gut health. Whether they reach the market as supplements, OTC products, or formal prescription drugs, they have potential as treatments for a very wide range of clinical conditions. And that glowing possibility has drawn intense interest from all sectors: food and beverage, pharma, supplement, and cosmetics and personal care. 

Condition-Specific Models

Many probiotic supplement brands are shifting from general health and gut health, toward much more organ- and condition-specific marketing positions.

For example, Seed Health—a Los Angeles based brand exclusively focused on strain-specific probiotics—recently built upon its flagship DS-01 Daily Synbiotic for overall gut health by launching new probiotic blends promising dermatologic, cardiovascular, and immunologic benefits.

Seed has research partnerships and projects with mainstream institutions, including the National Institutes of Health, Massachusetts General Hospital, University of California Los Angeles, Imperial College of London, Baylor College of Medicine, and the Cleveland Clinic.

The company’s website displays a notable shift away from typical dietary supplement language, describing some of Seed’s products as Live Biotherapeutic Products (LBPs), which are “regulated as drugs by the FDA and range from single microbes with defined pharmacological properties to entire ecosystems that can prevent and treat infection.”

The statement goes on to say that, “Our ‘living medicines’ have extensive safety data in a human population, target conditions that impact large global communities, and can be clinically validated at a fraction of the cost of a small molecule.”

In 2020, Seed spun off Luca Biologics, a company focused on live biotherapeutic drugs to prevent and treat vaginal dysbiosis and other women’s health conditions. Drawing largely on the work of University of Maryland microbiologist Jacques Revel, Luca’s development pipeline includes products to treat urinary tract infections and bacterial vaginosis, and even something that could potentially prevent preterm births.

On Luca’s website, Dr. Revel states: “Living medicines will disrupt the way we approach many diseases—and in some cases, may even replace the primary standard of care. By targeting these pervasive, unmet medical needs, especially in areas that have experienced little to no innovation, we can move toward a new future in global women’s health.”

ResBiotic, another relatively new and innovative brand, has developed an oral probiotic/botanical formula called ResB that can effectively modulate the gut-lung microbial axis, to improve the health of people with asthma and other respiratory conditions. That’s in addition to its general gastrointestinal and immune health benefits.

The product contains three trademarked strains of Lactobacillus (Lactiplantibacillus plantarum RSB11, L. acidophilus RSB12, and L. rhamnosus RSB13) combined with three synergetic botanicals for lung support: vasaka (Adhatoda vasica) leaf, Holy Basil (Ocimum sanctum) leaf, and turmeric (Curcuma longa) root.

ResB’s main mechanism of action centers on the ability of these organisms to produce specific short-chain fatty acids that are absorbed from the gut into blood circulation, and enter the lungs where they influence lung and immune function and clearing of mucus.

The company’s founder, C. Vivek Lal, MD, is a neonatal intensive care physician, who also heads the pulmonology microbiome lab at the University of Alabama, Birmingham. In addition to Resbiotic, Lal also owns Alveolus Bio, a company that develops inhaled biotherapeutics for serious lung diseases like chronic obstructive pulmonary disorder (COPD). 

Though ResBiotic is playing squarely on the supplement side of the regulatory divide, Dr. Lal’s conventional medical training, scientific experience, and commitment to research shape everything about the company, and give the products a quasi-pharma pedigree.

After years of preclinical research, ResBiotic recently published its first open-label human safety trial involving 11 healthy individuals and 11 asthmatic patients treated with the ResB formula for one month. The asthmatic patients showed significant improvements in standard measures of lung function (FEV1) compared with baseline, an effect not seen with the healthy non-asthmatic subset. There were no significant adverse effects associated with ResB and further clinical trials are underway.

Seed and ResBiotic are just two examples of microbiome-based companies that are focusing their efforts on condition-specific targets. There are many others. And as this trend continues, the line between probiotic supplements and “living biotherapeutics” will become increasingly blurred—unless regulatory agencies step in and sharpen the boundary via enforcement actions.

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"Will a prescription probiotic emerge in the next 10 years? It’s hard to say. The reality is, the process of bringing a drug to market is long, arduous, and expensive ... More likely, we’ll see a lot more companies entering into the 'microbiome-modulation' and 'living biological therapies' space. 

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Agents of Change

It’s a scientific given, at this point, that changes in the microbiome correlate with many disease conditions, and vice versa. What’s less clear is whether that relationship is causal, and whether microbiome-based treatments will have meaningful life-changing impacts. 

Dan Merenstein, MD, professor of family medicine, Georgetown University, and director of the university’s research programs in family medicine, has headed 10 probiotic studies since 2006. He said there are many big questions about the directionality of the correlations between disease states and microbiome changes.

“It’s possible that people with ulcerative colitis get the disease and then their microbiome changes, or it’s possible that the microbiome changes and then they get the disease. We haven’t figured that out … yet,” said Merenstein. “But there’s a lot of interest in this because if we can change peoples’ microbiomes, we could potentially treat things like ulcerative colitis, or obesity.”

That sort of ambiguity doesn’t fit well into the neat “single cause, single effect, single solution” model that underpins a lot of pharmaceutical thinking.

Adding to the complexity, many commensal bacteria seem to have bivalent or even polyvalent effects on humans. For example, in the context of antibiotic-associated diarrhea—one of the most common conditions for which people take probiotics—the B. lactis HN019 strain of Bifidobacterium from Howaru has been shown to reduce bowel movement frequency, thus reducing diarrhea. Yet in the context of constipation, that same organism can increase bowel movement frequency.

From a pharmaceutical perspective, where a drug has a discrete and one-directional mechanism of action, this seems paradoxical. But it makes sense considering that probiotics really are not drugs. Rather, they’re change-agents that cause shifts in microbial ecosystems.

“Probiotics tend to normalize things,” said Arthur Ouwehand, PhD, adjunct professor of microbiology at the University of Turku, Finland, and one of the world’s experts on probiotics and their impact on human health. Dr. Ouwehand is a member of the scientific advisory team for Howaru, International Flavors & Fragrances’ (IFF) line of proprietary probiotic strains.

“It’s about balancing back to a normal state. Probiotics are not like drugs that push only in one direction. A laxative is always a laxative. It always pushes in the same direction whether necessary or not. But probiotics push toward the middle, toward balance.”

That line of reasoning likely won’t stop pharmaceutical companies—or supplement brands, for that matter—from experimenting with probiotics and other microbiome-focused biologicals in a drug-like way.

The idea of effectively treating debilitating disorders with something as simple and relatively inexpensive as commensal bacteria (or their metabolites) is quite compelling.

Will a prescription probiotic emerge in the next 10 years? It’s hard to say. The reality is, the process of bringing a drug to market is long, arduous, and expensive. We haven’t seen an Rx probiotic yet, and there don’t appear to be any imminent candidates on the near horizon.

More likely, we’ll see a lot more companies entering into the “microbiome-modulation” and “living biological therapies” space. That’s a bit of a marketing and regulatory gray zone, and it’s probably not a significant threat to the probiotic supplements segment, for the moment. But give it another few years, and a few billion dollars more in global investments, and it could be a very different picture.

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About the Author: Erik Goldman is co-founder and editor of Holistic Primary Care: News for Health & Healing, a quarterly medical publication reaching about 60,000 physicians and other healthcare professionals nationwide.