Probiotics: Their Problems and Potential

Feb 23, 2018
ZBiotics

Buzzwords — “Cryptocurrency,” “GMOs,” “Machine Learning” — words with which most people are familiar but few fully understand. I want to add "Probiotics" to the list. For many of us, probiotics are things we see on a yogurt label in the grocery store. We loosely relate them to health with little knowledge of what they are or what they do. We hear the terms “pro” and “bio” together, and we say, “In favor of life… Fine, I'll put that in my body.” But in reality, we wouldn’t know a lactobacillus from an E. coli.

However, for the few that are familiar with them, probiotics can mean a great deal. For instance, many individuals suffering from serious digestive diseases like ulcerative colitis take probiotics to ease debilitating day-to-day pain. Among the healthy, “biohackers” and generally health-conscious people often supplement their diets with probiotics, testing different types and combinations to augment their daily health.

As a result, probiotics are big money. The global market is estimated to be worth over $40 billion, and it’s growing at 7% per year. All one needs to do is take a look at a supermarket shelf to see that major companies like Nestle, Unilever, and General Mills are betting big on probiotic-enhanced products.

But that all raises a few questions: What are they anyway? What are they supposed to do? Do they work? We’ll dive into these questions and see how, even though probiotics have been a part of the human experience for centuries, we are merely beginning to explore their potential.

What are Probiotics?

The first thing to know, is that the term “probiotic” itself is a catch-all. The official definition comes from a conference of scientists who met in 2001 in Cordoba, Argentina. They were there as part of a United Nations summit convened to help Argentina settle a trade dispute related to powdered milk. In that illustrious context, this group of experts arrived at a definition of probiotics that has held sway over the industry ever since:

"Live microorganisms which, when administered in adequate amounts, confer a health benefit on the host.” UN Report

What does that really mean? And what sins does this definition hide? Let’s break it down…

The first thing to notice is that even though we usually talk about gut probiotics you eat, there’s nothing gut-specific about them. Probiotics are used in skincare, mouthwash, foot cream, all sorts of things. We’ll talk about gut probiotics – which are the most familiar – but they are far broader than that. Now let's get to the definition.

“Live”

These things are alive, which matters more than one might think. To have an effect, gut probiotics need to be alive in the gut, which means they need to be strong enough to survive the stomach and reach the intestines. Stomach acid is harsh and can be quite deadly to microbes. This brings us to Sin #1 among probiotics manufacturers…

Some things labeled as probiotics actually may not survive the stomach acid. They might never get the gut! If a probiotic label says in vitro, all that means is that it has had an effect in a test tube. It does not mean that it will work in vivo, in the body, when it has to survive the stomach acid. Probiotic labels often play on this confusion. See if you can spot the "in vitro" in this probiotic's packaging:

 

“micro-organisms” 

Probiotics can be yeasts and other microbes, but the vast majority of commercial probiotics are bacteria, identified by name in 2 parts: the species and the strain.

Part 1 is the species. An example is “Lactocaucus lactis.” That’s a mouthful, so all of it gets abbreviated as “L. lactis,” which follows the naming convention of first letter of the genus abbreviated, then the species name.

Part 2 of identifying a probiotic is understanding that within a species, there are many different strains. A strain is a particular genetic variant of the species. Strain names are usually combinations of letters and numbers, like “O26.” The important thing to recognize is that within a species, each strain can be very different.

Let’s take, for example, the species E. coli. We hear a lot about E. coli outbreaks of foodborne illnesses. But some strains of E. coli are actually considered probiotics. Within the E. coli species, different strains show massive variation. One study analyzing E. coli DNA found that 80% of E. coli genes could vary from strain to strain! That means only 20% of all E. coli genes were considered core to the species. That’s how E. coli O26 could cause an infectious outbreak at Chipotle in 2016, while E. coli DSM 17252 can be sold as a probiotic.

This brings us to the Sin #2 of probiotics marketers: intentionally confusing species and strain. If you look online, you’ll see countless probiotics companies hawking what look like the same probiotics, but what really are only the same species, not the same strains. And as we saw, that means they can have very different effects.

Are these 2 L. Acidophilus products the same? Impossible to know.

“which when administered in adequate amounts

Whatever probiotics are supposed to do, it often depends on having enough of them there to do it. Probiotics are quantified in “Colony-Forming Units” (CFUs). Because probiotics are often intended to crowd out other microbes, it may takes billions of CFUs to hit that crowd-out threshold and see a desired effect.

But here’s where we see Sin #3. More does not necessarily mean better. Probiotics makers often ignore this fact or fail to mention it in advertising, but taking too many probiotics can perturb the microbiome. This can lead to health problems and a condition known as dysbiosis.

“confer a health benefit”

What are probiotics supposed to be doing anyway? There are generally 3 ways probiotics are supposed to work:

  1. Crowd out bad microbes
  2. Help the body do something better
  3. Do something the body cannot do on its own

Here we have Sin #4. Manufacturers are not very clear about what the effect of a probiotic is supposed to be. Furthermore, there is often very little data to substantiate even general effects. To this day, no clinically tested probiotic has ever been approved by the U.S. Food and Drug Administration (FDA). Probiotics on the market now are compliant for safety, but none have been proven efficacious. This sin is the most significant, and we’ll dive deeper into this shortly.

“on the host”

One final fact of interest: probiotics are not just for humans. Some of the largest probiotics buyers are in the veterinary and agricultural industries, where probiotics are often fed to animals.

 

So, there it is! Probiotics defined. Feel satisfied? Neither do I. There is a huge amount of variability here. And with it, much room for confusion. But it’s not yet time to throw the baby out with the bathwater. Let’s dive deeper into what good probiotics are supposed to be doing, and, more importantly, whether they are actually doing it.

The Problem with Probiotics

Probiotics are supposed to confer a health benefit, but what is that health benefit? As mentioned, probiotics are generally supposed to do one of three things:

  1. ‍Crowd out bad microbes, the idea being that more “good” bacteria in your gut should out-compete the “bad” bacteria and thus help prevent or treat illness.
  2. ‍Help the body do something better, such as stimulating gut movement or breaking down toxins.
  3. Do something the body cannot do on its own, like fighting disease or and chemically altering our food to increase nutrient absorption. 

Commercial probiotics may promise all or some of these effects, but they all boil down to changing the gut microbiome in some beneficial way. Here is where we need to distinguish between 2 uses of probiotics: use by healthy people, and use by people with certain disorders. 

Probiotics for the Healthy

The number of healthy people who take probiotics is significant and growing every day. But is this supplementation making these people any healthier beyond placebo effect?

The answer, for no, looks to be no. A 2016 review by researchers at the University of Copenhagen looked at 7 randomized controlled trials investigating the effect of probiotics on fecal microbiota in healthy adults, seeking to answer the question: do probiotics in healthy adults cause any change to the gut microbiome? In all but one study, the researchers saw no effect, and in the one study where there was a statistically significant effect, that effect was not beneficial to human health. As it stands, there is practically no scientific evidence that probiotics are going to make healthy people healthier. But what about in sick people?

Probiotics for the Sick

Here, the feedback is mixed, but there is a growing body of preliminary evidence that probiotics can sometimes have a beneficial effect when it comes to addressing certain disorders. Examples of some conditions where probiotics have shown positive effects include:

  • Necrotizing Enterocolitis – a sometimes fatal gut disease in preterm babies
  • Side effects of people treated with antibiotics
  • Symptoms associated with irritable bowel syndrome

This makes more sense; if you think about these conditions as either being caused by or manifesting in some form of gut microbiome imbalance or distress, augmenting with beneficial replacement microbes could be very helpful. But it doesn’t stop there. Articles out there cite probiotics as a possible mitigating treatment related to a number of conditions, including:

  • Anxiety
  • Autism
  • Diarrhea
  • Eczema
  • The common cold
  • Allergies

To date however, the FDA has never approved any probiotics for preventing or treating a health problem.

Here’s where we have to ask “Why?”. Why is it so difficult to see beneficial effects of probiotics in humans – not just among healthy people but also among people with diseases? Why do certain probiotics regimes seem to work amazingly well for certain people? We hear about probiotics being effective, but nobody can discern a consistent effect in a randomized controlled trial. This is the scientific gold standard and a necessary condition for anything to get FDA-approved.

As I see it, the answer lies in the issue of consistency.

Our gut microbiomes are incredibly individualistic. From person to person, they are completely different. There are different collections, amounts, and proportions of microbes swirling around in our guts. Not only are they different; they are changing constantly over time, and not just year-to-year, but week-to-week. That means that a single strain of probiotic is going to have a hard time impacting you and I in the same way. Perhaps it can seed and survive in your gut, but does nothing in mine. Maybe it can survive in both of our guts, but to varying degrees.

In that high-variability context, randomized controlled trials are going to do a poor job of measuring effectiveness. These trials are designed to eliminate the individual differences between us and pull out consistent effects, precisely the types of effects probiotics are unlikely to have. As a result, some researchers see the future of probiotics as personalized: strain collections designed individually for every individual’s unique microbiome. However, this will be a long time coming and introduces a host of technical challenges that remain to be solved. Until then, finding a probiotic that works for you that also works for me is unlikely. 

Is this unsatisfying? Yes. Is it the final answer on probiotics? No.

Introducing ZBiotics

We believe in an alternative hypothesis: that with the right approach, probiotics can be made to work consistently across individuals. It’s a mindset behind much of what we do here at ZBiotics. To summarize, successful gut probiotics face two major challenges:

  1. Probiotic benefits are still too generic. We often don’t know what a probiotic is supposed to be doing, or how it’s supposed to be doing it.
  2. Every person’s gut microbiome is extremely different, meaning that even when you know the effect you’re trying to have, it is difficult to have that same effect consistently across multiple people using a single strain.

At ZBiotics, we have been working for over a year and a half to address these two challenges.

1: How do we get a probiotic bacteria to have a more specific effect? 

Our answer is bioengineering, also known as genetic engineering and, in our case, genetic recombination. We alter the genetic code of a safe bacteria so that the bacteria does something that we’ve designed, like producing an enzyme with a particular purpose.

Let’s use an example. Imagine that we used genetic engineering to alter the DNA of a safe bacteria so that as the bacteria goes about its regular life cycle it also produces a lactase enzyme. Lactase is the enzyme lacking in the bodies of people suffering from lactose intolerance. If everything checks out – the bio-chemical pathways of the body, the timing of enzyme production, etc. – we would have created a probiotic with a very specific purpose: to break down lactose and to allow people with lactose intolerance to consume dairy products.

A concern with this, as with any new product, is safety. How can we be sure that genetically engineered probiotics like this are safe? We would not only use the same FDA-compliant safety tests that ensure any new food ingredient is safe, but we would also make something that starts with a very good base. Taking a bacteria we know is safe, then engineering it to produce an enzyme that we know is also safe and extremely similar to an enzyme the body already produces.

This is what we mean when we say, “probiotics with purpose.” Genetic engineering allows us to design and build probiotics that have specific effects, a major improvement over the generic use case of conventional probiotics.

2: How do we ensure that that effect is consistent across different people?

The second challenge is consistency. Traditional probiotics try to alter the gut microbiome, counting on their ability to “seed” the gut. “Seeding” just means that the bacteria take up residence and become part of the gut microbiome and are still there long after the probiotic is ingested. But seeding is difficult. It requires that the probiotic isn’t out-competed by other microbes. It creates safety concerns if the probiotic messes with other gut microbiota. And it counts on the seeding to happen in the right location in the gut. Now, take all that complexity and multiply it by the differences in everybody’s individual microbiomes...

That is a massively complex problem. Counting on seeding drastically lowers the probability that a probiotic is effective in a single person. This makes it highly unlikely that a probiotic working in one person will have the same effect in another person.

Finally, here is where we get to the tactical insight behind ZBiotics. Instead of trying to tackle all that complexity head on, what if we sidestepped it? What if we decided our probiotic didn’t need to seed the gut to have an effect? Just have the probiotic pass through the gut and leave, having its desired effect on the way. That solves a few issues. First and most dramatically, one dose has one effect that is consistent across different people. Second, we avoid much of the risk that our probiotic perturbs the rest of the microbiome. Yes, the probiotic would have to be taken repeatedly to preserve the effect, but probiotics are inexpensive to make, and repeated dosing of probiotics is already commonplace in the market.

This is what we are working on at ZBiotics. A whole new kind of probiotic – built for a particular purpose and designed to be consistently effective across different people. We have been in the lab for over a year and a half and have made some exciting progress. If you are interested in learning more or staying up to date, feel free to sign up for our email list at ZBiotics.com.

Stephen Lamb

Stephen is co-founder and COO of ZBiotics. Insatiably curious, he is consistently awed by the power and potential of synthetic biology.

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