We’ve been thinking about probiotics all wrong. Typical probiotic supplements attempt to “seed” the microbiome—to shift the population of bugs in our gut in a predictable, favorable direction. The problem is, that approach just doesn’t work. 

Fortunately, there are a handful of biotech companies who are thinking differently. Probiotics of the future will look very different. They’ll be thoughtfully selected or engineered strains clinically proven to deliver particular benefits. That future is coming soon. 

The Problem with Traditional Probiotics

Most probiotics on the market today are based on two fundamental assumptions:

1. We know what strain is going to be beneficial for every person at any time
2. That strain will impact the gut microbe population when taken as a supplement

Unfortunately, there is no strong evidence that either of these assumptions is true. 

First of all, the microbiome is very difficult to study. Many of the species that live in our gut can’t be cultured (grown in a lab), so most of our understanding comes from sequencing the microbiomes of different people and making inferences about how the differences might impact their health. 

From that work, we know that a diverse gut microbiome is preferable and that there are some strains more associated with positive health. But the probiotics industry actually predates much of that sequencing work. 

“The probiotics industry, by and large, started out of the dairy industry,” explained Arlene Fosmer, microbiologist and CSO of Infinant Health. We’ve known for a long time that yogurt is beneficial, and there was already a precedent and a mechanism for manufacturing microorganisms used in dairy and cheese. 

But eating yogurt, with all its nutritional complexity, is not the same as swallowing a capsule. Taking a probiotic supplement and expecting it to change your microbiome is like sprinkling grass seed into a bed of weeds and allowing a new lawn to grow. 

“The notion that you can wedge a species into the gut microbiome is difficult. Think about it like an ecosystem,” said Christoph Geisler, Founder of Unlocked Probiotics, “all of these things, like diet, impact it in ways that are pretty unpredictable.”

“Most probiotics are transient. They go right through the GI system,” echoed Fosmer. 

That’s the probiotics zeitgeist—generic strains taken as dry pills that have inconsistent effects at best. But there’s a baby in this bathwater. Just because traditional probiotics are underwhelming doesn’t mean that the field of probiotics isn’t promising. We just need to approach them differently.  

Next Generation Probiotics

The transient nature of most probiotics is not necessarily a nonstarter as long as the probiotic in question can have a positive impact while it’s passing through. 

Zbiotics is counting on it. Their aptly named “Sugar-to-Fiber” probiotic leverages an engineered strain of the naturally occurring probiotic B. subtilis to reorganize sugars into fiber in the gut. The strain does not take up residence, but when taken daily, it’s estimated to increase dietary fiber by about 10-15 grams. That amount is significant since 95% of Americans don’t get enough fiber, and most people fall about 15 grams short. 

“It’s very straightforward,” explained Zach Abbott, founder and CEO of Zbiotics, who will also be moderating a session entitled “Bridging the Gap Between Biotech Innovation and Consumer Acceptance” at this year's SynBioBeta: The Global Synthetic Biology Conference. “We verify in gut simulated conditions that it makes the enzyme, the enzyme is functional, and how much sugar to fiber we can create.” They’re working on human studies right now to analyze shifts in the microbiome that signal an increase in fiber digestion.

What’s really unique about the Zbiotics probiotic—aside from the fact that it’s engineered—is that it’s intended for a particular purpose and is being validated to confirm that it does that very specific job. 

Similarly, Unlocked Labs is engineering probiotics to break down oxalic acid, the precursor to kidney stones. There is currently no therapy for preventing kidney stones, which can be recurrent and are extraordinarily painful. 

And there’s an extra advantage to a probiotic therapeutic: “Probiotics stay in the gut, they don’t enter circulation unlike small molecules, so the potential for side effects is very limited,” explained Geisler. And since gut seeding doesn’t work—we know they flush out in a day or so. That leaves the door open to a host of other therapeutics. In addition to kidney stones, Unlocked is currently thinking about gout and cholesterol. 

But if probiotic therapeutics are so promising, why aren’t large pharmaceutical companies churning them out? 

“The interest from pharma in the microbiome space is past its peak,” explained Dirk Gevers. Gevers formerly oversaw the Data Analysis Working Group of the Human Microbiome Project and is now Chief Scientific Officer of Seed Health.

While the traditional probiotics industry has been focused on wellness products with little or no clinical evidence, pharma dabbled in probiotics as therapeutics but found the cost of bringing a complex cocktail of probiotics to market too high. 

Seed is bridging the gap by bringing clinical evidence to wellness. “That’s one of the key differentiators for Seed,” said Gevers. “We're really bringing scientific rigor and clinical validation towards our product.” 

Seed’s DS-01™ Daily Synbiotic is a clinically validated probiotic and prebiotic supplement designed with whole-genome sequencing and gut simulation to ensure strain viability and targeted effectiveness. [Image courtesy of Seed Health]

Seed couples a genomic approach to strain selection (including whole genome sequencing for strain validation) with a gut simulation model to ensure strains remain viable when they reach their target site. On top of that, they’re one of the only companies that validate their products in randomized control trials (the gold standard for product testing). 

Seed’s flagship gut health product includes 24 strains not commonly found in probiotic products and is formulated to include prebiotics as well—so it’s more like applying new turf to that weed bed instead of just sprinkling seeds. But like Zbiotics and Unlocked, their daily gut health product has an impact without shifting the gut microbiome ecology permanently.  

Next-Generation Probiotics Beyond the Gut

The gut microbiome isn’t our only microbiome, and the bacterial communities on our faces, pits, privates, and more are much simpler. 

“A lot more is known about the skin microbiome than the gut microbiome,” explained Yug Varma, microbiologist and founder of Phyla. “It would be a lot more predictive to disrupt a key species in the skin microbiome.”

That’s exactly what Phyla does, using a unique category of probiotics—bacteriophages. Their serum leverages phage viruses that target the species of bacteria responsible for acne. What’s great about bacteriophages is their specificity. 

Varma likes to use a lawn analogy: “If there was a weed in your yard, you wouldn’t light your lawn on fire,” but that’s exactly what you’re doing when you use an antibiotic acne treatment or an antibacterial cream or soap. 

For more traditional, non-phage probiotics, skincare also poses a unique challenge: you can’t apply a dehydrated capsule to your skin.

Formulations for skin need to be liquid, and liquid cosmetics provide an opportunity for contaminants to grow. “For skincare, the FDA requires preservatives…those [preservatives] are extremely effective against everything, including probiotics,” explained Farzaneh Rezaei, fermentation expert and founder of Fafabiotics.

For this reason, “probiotic” skincare products currently on the market generally do not contain live cultures. 

Fafabiotics solves this problem by introducing a “blooming” step. The stable dry probiotic is mixed with a serum and then a lotion just before use.

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And remember Seed Health? They’ve got an evidence-based probiotic for vaginal health. In the case of the vaginal microbiome, we know a lot more about what species are beneficial, and the Seed probiotic provides a true ecological shift that persists. 

Next-Generation Probiotics for Infants

The infant microbiome is also a unique case for several reasons. 

For one, they are a blank slate. Babies in the womb have no microbiome. They acquire their microbiome from their environment through the process of birth and early life. This is particularly true for babies born via cesarean section—since infants get most of their microbiome from the birth canal—or when antibiotics are administered before birth. Additionally, babies typically have one food source, and their microbiome is far less diverse.  

For these reasons, it is actually feasible to “seed” the infant microbiome using probiotics. 

“It’s easiest to seed the microbiome in the first month of life or right after antibiotic treatment,” explained Fosmer, “it becomes harder and harder to change the microbiome as time goes by.” 

Her company, Infinant Health, is focused on a particularly interesting strain called B. infantis. As the name implies, B. infantis is unique to babies and small children. It was discovered for its distinctive ability to break down certain sugars found in breast milk. What’s fascinating and disturbing is that this strain—while commonly found in more traditional communities with low rates of C-sections and antibiotics—has been all but eradicated among modern, urban, western children. 

Seed Health also has a symbiotic (probiotic plus prebiotic) specifically formulated for kids. 

The Future of Probiotics

Most of the probiotics mentioned in this article are available online and in select stores now (Zbiotic’s Sugar-to-Fiber, Infanant’s infant probiotic Evivo, Seed Health’s gut, vaginal, and pediatric synbiotics, and Phyla’s anti-acne phage serum). Fafabiotic’s probiotic skin cream is launching this month, and Unlocked Labs expects to make their kidney health probiotic available commercially next year. 

What all of these probiotics have in common is that they are built on a foundation of rigorous microbiome research. They also acknowledge and account for the challenges and limitations of traditional probiotics—by targeting particular clinical endpoints, not relying on microbiome seeding, or focusing on areas of the body with simpler microbial ecology. 

In other words, traditional probiotics don’t really work, but you should give these new ones a try and keep an eye out for more evidence-based probiotics in the future.

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