The good, the bad and the ugly side of using bacteria to improve human health.
Humans are terrified of bacteria. Throughout history, hostile microscopic organisms have swept through villages, cities and continents. The plague. Salmonella. It's estimated that cholera alone causes over 120,000 deaths per year. Deadly bacterial diseases continue to rack up an enormous body count.
It's easy to think of bacteria as our enemy.
But when a black-and-white box about the size of a book slid across my desk in early August, I was confronted by a different narrative. Inside the box, three tiny vials of murky liquid were neatly packed, resting face up. They were labeled "probiotic drink," and inside them were millions of genetically modified organisms which, I'd read, could help cure a hangover.
Scientists have long recognized the potential of probiotics -- live micro-organisms that benefit their host -- for improving human health. Researchers believe we could use these good bacteria to do almost anything, from treating eczema and UTIs to, yes, even curing a hangover. Some scientists are even transplanting human poo, full of bacteria, directly into the gut of sick patients and, remarkably, beating back infectious disease.
It's highly likely you've seen probiotics on a supermarket shelf or you're already ingesting them on a regular basis. If you're into certain yogurts or cheese, you're eating them. If you've tried kombucha, you're drinking them. Some dietary supplements contain live bacteria, too.
That's flipped the bacteria-as-enemies narrative on its head. As we come to understand more about the human microbiome -- the universe of bacteria, fungi and viruses that dwell within us -- we're beginning to learn that bacteria are not enemies, but allies. As a result, the probiotics industry is flourishing.
The number of research papers on probiotics has steadily risen in the past decade. Dozens of clinical trials are underway in universities and hospitals across the world. And some estimates suggest the market size of the probiotics industry will swell to almost $74 billion by 2024, a third the size of the vitamin supplements market. It's clear consumers are buying into the hype.
But as the hype builds, so do the questions. Scientists are cautious, trying to navigate a sea of low-quality studies. Why do some probiotics work while others have no effect? How are they affecting the microbiome? And how can we understand them better?
Holding the tiny probiotic drink in my hand and studying the murky liquid inside, I had those same questions. And an even more pressing one: Should I drink it?
The world's first genetically engineered probiotic comes in a thumb-sized glass bottle, a Silicon Valley facsimile of Alice in Wonderland's "drink me" potion. Designed to make you feel better after a night of drunken debauchery, it's already been dubbed by some as a "hangover cure."
The truth is more complex.
Unlike Lewis Carroll's imagined drink, this bottle is full of living organisms bumping against one other. The trillions of microbes inside the vial have never existed on Earth before. Under a microscope, they look like tiny, pink pills.
The fuzzballs in the potion, dubbed ZB183, are genetically modified bacteria, created by San Francisco startup ZBiotics and specially engineered to alleviate the awful after-effects of a big night out.
Zack Abbott, microbiologist and co-founder of ZBiotics, spent three years tinkering in a laboratory to develop the new microbe strain. Abbott and his team started with a common bacteria found on fruit and vegetables known as Bacillus subtilis and took advantage of a quirk of bacterial evolution: The microbes can detect DNA in their environment and incorporate it into their genes.
"It's a really simple process that bacteria have refined over the last 3 billion years, and they do naturally all the time," Abbott says.
They handed the bacteria a gene from a different bacterial species and, after a little coaxing, the bacteria incorporated it into its DNA.
"The only changes we made were to add in this gene and to change some of the genetic regulatory mechanisms of the bacteria to get enhanced expression of the gene," Abbott explains.
The genetic additions allow B. subtilis to break down a toxic byproduct of alcohol known as acetaldehyde, which is believed to cause nasty hangover symptoms like nausea and headaches.
Abbott's creation is less Frankenstein's monster and more Frankenstein's janitor. In essence, he's created an acetaldehyde mop that passes through the body, helping scrub the gut. It doesn't affect how drunk you'll get. The probiotic is designed to be taken before drinking, allowing time for the microbe-cleaners to get into the digestive tract and ready themselves for work, complementing the body's ability to break down acetaldehyde.
Read more: This beer was made from Berlin's recycled wastewater
Can this genetically engineered clean-up crew "cure" a hangover? Abbott doesn't make those claims.
"This is not your 'get-out-of-jail-free card' hangover cure because that doesn't exist," he says. "Anybody who's telling you that is really selling snake oil, because a hangover is a very complex set of symptoms that is caused by a lot of different things."
"This is science and not science fiction."
The science, as it stands, is sound. In a test tube, ZB183 was able to reduce acetaldehyde concentrations. When ZBiotics tested it in rodents, they didn't see any adverse effects on gut health. That work is as yet unpublished, but has been submitted to a peer-reviewed journal and is publicly available at bioRxiv.
Consumers still harbor concerns about genetically modified foods and therefore might be frightened by the contents of ZBiotics' drink, Abbott notes. But this bacteria has a long history when it comes to human consumption. It's a prominent feature of the Japanese food natto, a dish containing soybeans fermented by B. subtilis. Abbott is confident it will do no harm, but he'd like to evaluate the new strain's effects more specifically.
"There are so many more questions you want to ask, in terms of seeing how the bacteria functions in the human gut," he says.
ZBiotics' first bacterial cocktail is just the beginning. Genetically engineering B. subtilis to inherit other genes, Abbott maintains, will allow his company to tackle a slew of everyday health problems. For instance, the team could splice in a gene that breaks down dangerous heavy metals or one that enhances the ability of the gut to absorb minerals.
"We want to engineer products that can help your body deal with those sort of toxic byproducts of everyday living."
One of the biggest challenges facing ZBiotics is getting a product to market that consumers will consider credible. Scientists aren't sure probiotics are particularly beneficial for healthy people, even though the marketplace is overflowing with wonder supplements.
"The hypothesis around probiotics is not very good," Abbott says. The term "probiotic" appears on the ZBiotics label, but "I certainly wouldn't classify us as a probiotics company," he says. "We're using probiotics as a way to really make enzymes that are beneficial for you, and have a very specific purpose."
If your heart is failing, you need a heart transplant. Same goes for your liver or kidneys. But if there's a problem with the colony of micro-organisms that live in your gut? Well, then you need a fecal microbiota transplant, or FMT.
A poo transplant.
It is what it sounds like: A healthy person's stool, which contains thousands of different bacteria, is transplanted into another person -- via either a colonoscopy, tubing through the nose or a poo capsule -- to treat debilitating conditions that affect gut health. The procedure might not immediately seem like a probiotic, but the current, confusing definition sees FMT fall under the same banner.
"I guess the difference in a fecal transplant and a probiotic is that a fecal transplant is a much more complex version of a probiotic," explains Hannah Wardill, a gut health researcher at the University of Adelaide.
Other researchers suggest a subtle, important distinction. Probiotics are specifically formulated mixes of bacteria, according to Sam Forster, a microbiologist at the Hudson Institute of Medical Research in Australia, but in an FMT a random mix of bacteria is transplanted between patients.
Though the definition of a FMT may be confusing, the procedure is one of the most promising treatment options for a nasty infection by the "superbug" known as Clostridioides difficile, or "C. diff." C. diff routinely takes up residence in the colon of patients who have undergone a course of antibiotics, causing gut inflammation and persistent diarrhea.
It's notoriously hardy and difficult to eradicate once it has taken hold, and current treatment options are to put patients on more antibiotics to clear the infection.
"As soon as you come off that antibiotic treatment, they relapse and the infection comes back," Forster says. The elderly are particularly vulnerable, and around 30,000 people die from the infection each year.
The key to fighting back is human feces.
In 2013, a small, randomized clinical trial demonstrated how effective FMT was at resolving C. diff infections. The treatment has since become something of a medical wonder. Medical practitioners are slowly coming around to using FMT as a C. diff fix, and, buoyed by the positive press, DIY poo transplants have become so commonplace you can find examples of people attempting them at home with a quick Google search. (Note: Please don't try this.)
Scientists hypothesize that the immigrant microbes from someone else's poo help crowd out the C. diff superbug, plugging the gaps and hoovering up valuable resources so the bacteria can't settle in. However, the reality is that scientists aren't sure exactly how FMTs work.
Because of their success in treating the chronic diarrheal infection, FMTs are becoming more common, even though the US Food and Drug Administration hasn't approved them for any use. Classed as an "investigational drug," FMTs are only available as a last-resort treatment for C. diff patients no longer responding to antibiotics.
Every year, around 15,000 Americans suffer through recurrent infection. That means there's a huge demand for human poo.
Rising to meet that demand are a handful of nonprofit "stool banks." OpenBiome, the first public stool bank in the US, was launched in 2013 in Medford, Massachusetts, led by MIT doctoral student Mark Smith. It allows people to donate their excrement at $40 per dump after passing a rigorous health screening that involves blood samples, a long questionnaire, a clinical interview and multiple test sample dropoffs over 60 days.
Whether they're regarded as a probiotic or not, FMTs highlight the pace of progress in using bacteria to improve health. Their promise extends beyond C. diff infections, too. The experimental treatment has been proposed as a fix for urinary tract infections, multiple sclerosis and diabetes.
"We're going to have a lot of evidence in the next five to 10 years on which conditions definitely benefit from fecal transplant and which don't," says Forster.
There aren't any standardized procedures for administering the treatment. It's not a regulated therapeutic, and it's not an exact science, either. There's so much variation of bacteria in any one person's stool that it becomes difficult to know why the treatment is working and what concoction of bacteria might cause the change.
Adverse events have been seen in some patients, and in June a patient with a compromised immune system died after receiving an FMT, which contained an antibiotic-resistant strain of Escherichia coli (E. coli). Another patient, who was inoculated with the same donor's stool, also developed an infection.
The tragedy forced clinical trials to be put on hold as researchers worked to ensure their stool preparations were safe for use and free of the superbug. Peter Marks, FDA director of the center for biologics evaluation and research, said at the time that "while we support this area of scientific discovery, it's important to note that fecal microbiota for transplantation does not come without risk."
Those risks have some worried that the field is moving quicker than the science. FMTs have shaken the probiotics stigma and feature in dozens of clinical trials to assess their safety and efficacy. But probiotics as a whole have not been examined in humans with such rigor, leading to alarmist headlines and overly exaggerated claims of their health benefits.
Microbiome research has exploded in the past five years, and probiotics research is just starting to catch up. Wardill notes there's now renewed interest, calling probiotics "a little bit sexy" but she believes the field is being investigated with "a little bit too much haste."
Pluck a bottle of probiotics off a pharmacy shelf and your head will spin with multisyllable words you've likely never seen before. Lactobacillus. Bifidobacterium. Streptococcus. These species of bacteria are found commonly in probiotic supplements you can buy today. However, each brand and each bottle contains differing amounts of the bacteria, differing species and differing strains -- and we're really taking a shot in the dark as to what effect they have on our guts.
"We still have no good idea how probiotics work," says Elisabeth Bik, a science consultant and former Stanford microbiome researcher. "Although researchers have some idea which strains or combinations of strains might work, they still are not sure why."
The vast majority of scientific reviews published on probiotics are consistently inconsistent. Sometimes you get a protective effect. Sometimes you find none at all. Rarely do you see extreme adverse effects, but highly beneficial ones? They're few and far between.
There's also no indication the beneficial bacteria file for permanent residency in the gut. Perhaps they're just using it like an Airbnb. A recent study investigated 11 common probiotic strains and their passage through the gastrointestinal tract, finding the bacteria rarely colonized the gut and, even if they did, the response was different for each person tested.
"Like many other things, probiotics is also personalized in terms of the response," Eran Segal, one of the co-authors on the paper, says. "Some people will not get colonization, and others will get colonization, and [it] will be very specific, depending on the microbiome composition."
Wardill says current research approaches aren't sophisticated enough to really pull apart the relationships between health and the diversity of microbes inside us. For instance, studies might look at a concoction of probiotics or an FMT, full of a random assortment of bacteria, and record how it does -- or doesn't -- improve the health of sick patients. Others throw a mix into the gut of healthy people and see next to nothing.
"I think that it's really important that we almost just take a step back and have a look at exactly what microbial features and characteristics are associated with different things," says Wardill.
With interest in probiotics surging, there's an obvious need to ensure safety and standardization -- and that need comes into greater focus as companies begin to genetically modify bacteria to prevent hangovers or transplant poo cocktails from one human to another.
After the three vials of ZBiotics' purported hangover fix hit my desk, I began investigating the genetically modified strain of B. subtilis created by the team.Abbott, the company's co-founder, assured me the bacteria within the vial was in a state of dormancy and would germinate or "wake up" when it reached my gut. The genetically modified organism reached my office in Sydney via snail mail from the US.
I was surprised. Australia's Office of the Gene Technology Regulator usually conducts an exhaustive process before GMOs can be shipped into the country. In fact, importing GMOs is illegal under Australia's Gene Technology Act 2000. But listed as a "probiotic drink," this vial of never-before-seen bacteria landed directly on my desk.
A spokesperson for the Australian Government Department of Health assures me there is nothing wrong with importing this particular organism -- Bacillus subtilis is classified as an "exempt dealing" and considered low-risk -- but it still raises questions about regulation and safety within the probiotics industry. Yes, the bacteria in our yogurt, and Yakult probiotic drinks have been around for decades and haven't caused any health problems. But future probiotics are taking another step forward, becoming more complex, and even genetically altered, as our understanding of the microbiome improves. Sturdier regulations and a standard approval process will be required, particularly in the medical field.
"It's a space where the research needs to be leading in terms of understanding what's going on before we make mistakes that might not be possible to reverse," Forster says.
Then there's the booming probiotics industry, selling pills off the shelf which haven't been carefully vetted or overstating the health benefits of the probiotic mixtures in their supplements and bacteria-filled drinks. It's a marketer's dream -- they can slap whatever label they like on the bottle without specifically identifying what bacterial strain it contains. It's the consumer who becomes a guinea pig, guzzling down a concoction without any idea of what microbes are inside and whether they confer any health effects.
Yet there's an obvious allure in being able to transform your health by repopulating your gut with an entirely new Wonderland. I'm keen to dive down the rabbit hole and give the ZBiotics hangover remedy a try. Even knowing all I do about its safety, how it was created and being pro-genetic modification, I'm also ever-so-slightly paranoid I could somehow wreck my gut in the process.
I tell Sam Forster, the microbiome researcher from Melbourne's Hudson Institute, that I'm nervous, that I'm not sure I should give it a crack, secretly hoping he'll give me a scientifically valid reason not to. But he doesn't. A hangover remedy is pretty hard to pass up.
"If it was me," he says, "I'd drink it."