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What's Wrong with Probiotics? Part 2

What are probiotics supposed to do? And do they do it?

 

This is a 2-part post. In Part 1, we looked at how probiotics have historically been defined, and that over-broad definition provides cover for some pretty dicey behavior within the probiotics industry. Check out Part 1 if you haven't read it yet.

Here, in Part 2, we dive deeper into one of the central issues with probiotics – one that spans practically the entire industry: the lack of a specific, consistent health benefit. 

The Problem with Probiotics

Probiotics are supposed to confer a health benefit, but what is that health benefit? As touched on in Part 1, 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 sick people

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 now, 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 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 probiotic regimens 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 we 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 me 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 genetic engineering, also known as bioengineering 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.

Here’s 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 used to break down lactose – the sugar in dairy products that gives many people so much discomfort. If everything checks out – the biochemical 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 help people with these issues comfortably 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 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 “enhanced probiotics.” 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 an 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” (or “colonizing”) 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 to be effective, seeding needs 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.

Here is where we get to the tactical insight we had at 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 serving has one effect – an 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 repeated dosing of probiotics is already commonplace in the market.

This is what we are working on at ZBiotics. A whole new kind of enhanced probiotic – built for a particular purpose and designed to be consistently effective across different people. 

We’ve been in the lab for over three years working on it. And we’re so excited to share what we’ve created.

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