Bugs As Drugs

Let’s say you want to buy things with germs in them. There’s yogurt, of course, but there’s so much else.

You can buy pills for your gut, creams for your face, tablets for your breath. You can buy blueberry juice with germs, and pizza with germs. And a lot of these products make big promises about the benefits their germs will bring you. “Fungal Defense is specially formulated with ingredients that help maintain a balanced, healthy digestive environment,” for example. Natren Natasha’s Probiotic Face Cream “is enriched with DNA fragments of beneficial bacterial cells, which speed up the skins own natural renewal process.”

Did that last statement make not so much sense to you? Are you struggling to find the results of the clinical trials that demonstrated that Fungal Defense really will make you healthy? Relax! Somewhere on the labeling for the germ-laden product you just bought, you’ll probably find these words: “This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.”

There’s ample evidence that the 100 trillion microbes that call us home–the microbiome–exert important influences on our biology. While some of them can make us ill, for the most part they help maintain our health–nurturing our immune system, moisturizing our skin, breaking down food and toxic compounds. (Here are a couple pieces I’ve written for the New York Times for a sampling of this field.)  For the most part, though, the research has been fairly remote from the doctor’s office.

A huge amount of research has been carried out on mice rather than humans, for example. That’s because scientists can rear the rodents without any bacteria in their bodies and then observe what happens when they add in certain species to their microbiome. Scientists have also carried out a lot of research on humans, but it’s mostly been observations, not manipulation–what does someone’s microbiome look like before and after a gastric bypass, for example?

Actual experiments on people have been a lot rarer, not surprisingly. (Any parents willing to put their newborns in a plastic bubble to keep them germ free for the first five years of life? Hello? Anyone?) That’s not to say there are no such experiments. Scientists will sometimes test out bacteria on people to see if it can help their disorders. Some of these experiments are promising. The remarkable results with fecal transplants for people with dangerous gut infections have become a veritable poster-child for the microbiome’s application to medicine. But none of them have been the subject of exhaustive research that’s been given to an FDA-approved drug like, say, the cancer-fighting compound Gleevec.

There are many reasons for this shortfall. Scientists have only been able to study the microbiome with much clarity in the past couple decades, so they’ve got a late start. Another reason is that the microbiome is different from our own cells and organs. It’s an ecosystem made up of hundreds of species, with lots of diffuse, interlinked effects on our bodies.

Making matters worse (or a more exciting challenge, if you’re of a sunny disposition) is the fact that there isn’t any one microbiome. While the microbiomes of humans are similar to one another, each of us has a mix of species and strains that’s unique–a mix that also changes from day to day. That variability makes it hard to say that adding in one particular species is going to make a difference to anyone who’s sick with a particular disease. Even an exquisitely rare microbe might play a crucial part in the overall ecosystem.

None of these hurdles has blocked the growth of the business of the microbiome. But the $8.7 billion industry has thrived because the microbiome occupies a fuzzy middle ground in the regulatory landscape. Purveyors of germ-loaded products can vaguely hint that their wares will bring you medical benefits. But to the U.S. government, their products are not, officially speaking, medicine. They’re food or cosmetics.

It’s possible that the bottle of probiotics you buy in the drug store really will help your digestion, or your immune system, or your bad breath. But it’s also possible that the bacteria you’re buying will get annihilated in the ruthless jungle that is your body. A lot of species you’ll find in probiotic products do not actually belong to the dominant groups of species in the human microbiome. Stop eating them, and they’ll disappear from your body.

The fact that you feel better after taking probiotics might be due to entirely different reasons. Who knows–maybe the very notion that a pill can “restore your ecosystem” will have a powerful placebo effect. As long as companies don’t make any specific drug-like claims about their germs, they can say whatever they want. (Dannon got nailed in 2010 for claiming Activia yogurt can cure colds.) Such is no longer the case in Europe, however; at the end of 2012, companies were no longer able to tout health benefits of the germs in their products.

While these products may not harm you, they can’t stand in for medical treatment. If you’ve got a serious case of diabetes, you shouldn’t just randomly start popping probiotic pills because you’ve heard that your microbiome influences insulin signaling. That’s not to say that someday there might not be clinically proven microbiome treatments for diabetes. We’re just not there yet.

According to Nature Biotechnology, however, we’re getting there. The current issue has a special focus on the microbiome (behind a paywall, alas). As reporter Charles Schmidt notes in an article for the journal, biotech startups are setting out on the drug-approval road in order to prove that some bacteria are indeed safe and effective. Enterologics in Minnesota is testing out a strain of E. coli as a treatment for a type of gut inflammation called pouchitis. Bernat Olle, the co-founder of Vedanta Biosciences in Boston, also contributes an essay to Nature Biotechnology, in which he mentions that his company is testing out a cocktail of species that can restore gut ecosystems degraded by diseases.

All well and good, but the fact is that the bacteria that these companies are studying have been known for a long time. That’s because they were comfortable enough in laboratories to thrive. Most microbes in our bodies require much more exotic conditions. As a result, scientists are just starting to discover them by fishing out their DNA from our bodies. Some companies are trying to mine this newly discovered diversity for keystone species that could have important effects on our health. These new species could also serve as diagnostic tests for diseases. Certain microbes in the mouth are associated with a risk of heart disease, for example. Frederik Bäckhed of the University of Gothenburg in Sweden and his colleagues have patented a way to assess that risk by examining the bacteria in your spit.

Olle also notes that some companies are engineering bacteria that we could consume.  This year marks the fortieth anniversary of the first insertion of an animal gene into E. coli. Today, E. coli and other engineered microbes pump out vast amounts of medicine and other products. But they do so in giant fermentation tanks, not in our guts. People with diabetes must wait for companies to harvest insulin from E. coli, purify the molecule, and sell it in vials which they can then inject into their bloodstream. (For more, see my book Microcosm.) Imagine, instead, that people could swallow bacteria that could take up residence in the gut and produce a life-saving drug right where it’s needed.

A company called Actogenix is trying to do that. They’ve carried our early human trials on a species called Lactococcus lactis they’ve engineered to carry a gene that encodes an anti-inflammatory protein. Another company, Osel, has engineered Lactobacillus jensenii to carry a gene for cyanovirin N, a protein that may help prevent HIV infection. They’re in preclinical trials.

This wave of efforts will not change medicine in the short-term. But in the medium-term it may. Nature Biotechnology surveyed experts on the microbiome about its future in medicine.  “The potential for gut microbiota manipulation is enormous, and so is the market,” declared Jeroen Raes of Vrije Universiteit in Brussels. “In 15 years, we will all be drinking specific, personalized probiotic cocktails. I suggest that every healthy person freezes a fecal sample now so they will be able to treat themselves in the future.”

14 thoughts on “Bugs As Drugs

  1. While many/most peopleknow about the gut flora, there’s some really interesting work being done where I work, at UCSF by Dr. Andrew Goldberg and his colleagues. This group is looking at the microbiome of the sinus–what’s it like in healthy tissue, and how the composition changes in sinusitis. Not only are they checking to see what’s there, they’re also exploring the mechanics of what’s going on–what are the bugs (friendly and no so much) up to? Earlier this year, the New Yorker wrote a piece on this work–the issue # eludes me at the moment, but it’s interesting stuff!

  2. so…how are genetically modified microbes any better for us than any other genetically engineered organism? or are gmos completely innocuous?

  3. That frozen fecal sample might raise some eyebrows should it be discovered by guests in the freezer next to the meatloaf … Otherwise, no argument here.

  4. Keep up the drumbeat Carl, I think this and the piece about phages that can potentially control Cholera are groundbreaking. The problem is fitting these treatments into our current framework.

  5. Great article. You mentioned once that you edited this column yourself and that pointing out errors was welcome, so:

    “…one particular species is going to make a different to anyone….”

    I assume that should be “make a difference”.

    [CZ: Thanks-fixed!]

  6. My mother suffered from many things. Some symptoms multiple doctors have not been able to justify. They’ve put her through so many courses of antibiotics over the last 20+ years. My guess is her micro biome is in an awful state of disarray. I love the research comin out. I wish I could get her in some trials.

  7. Ahah. Just today I am working on an assignment, and i mention using genetically modified bacteria to fight disease. I look for a source, and this is sitting there, being all useful.

    Thanks CZ! As always, interesting and helpful

  8. To date, too much microbiota research has just been expensive description, but I’m hopeful for the impact of public awareness on prudent use of antibiotics. People and their doctors may not give a damn whether drug overuse is selecting for the evolution of resistance, but if it might damage their precious personal microbiome, well, that’s a different matter.

  9. Thanks for the article. One thing you don’t mention is a disease which can kill premature babies and which can be prevented (up to 60% of the time) by giving probiotics. That disease is necrotizing enterocolitis, an inflammatory condition of the bowel which has a high mortality and long term morbidities. There are now 24 randomized controlled clinical trials which have enrolled over 4000 babies with a uniformly positive result. There are no known adverse effects in these trials and the cost is just pennies a day.
    A number of neonatal units are now giving premature babies probiotics on a routine basis. I have a few posts about this on my blog neonatalresearch.org

  10. Bacteriolytic therapy can generate a potent immune response against experimental tumors.

    Agrawal N, Bettegowda C, Cheong I, Geschwind JF, Drake CG, Hipkiss EL, Tatsumi M, Dang LH, Diaz LA Jr, Pomper M, Abusedera M, Wahl RL, Kinzler KW, Zhou S, Huso DL, Vogelstein B.


    Howard Hughes Medical Institute, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.


    When spores of the anaerobic bacterium Clostridium novyi-NT are systemically injected into animals, they germinate exclusively within the hypoxic regions of cancers. The germinated bacteria destroy adjacent tumor cells but spare a rim of well oxygenated tumor cells that subsequently expand. Surprisingly, we found that approximately 30% of mice treated with such spores were cured of their cancers despite the viable tumor rim initially remaining after spore germination. The mechanism underlying this effect was shown to be immune-mediated, because cured animals rejected a subsequent challenge of the same tumor. Similar effects were observed in rabbits with intrahepatic tumors. It was particularly notable that the induced immune response, when combined with the bacteriolytic effects of C. novyi-NT, could eradicate large established tumors.

  11. Bugs as drugs not only includes the use of probiotics, but also a lot of other therapeutic strategies, including helminth therapy for autoimmune diseases and infusion of donor faeces for recurrent Clostridium difficile infections – for more, please visit the Blastocystis Parasite Blog @ blastocystis.net

  12. Science is just in the beginning faze of research into the effects of the other then us that lives within us! it seems that this is the Century that we learn that other living things have value!

  13. I really love how you cite the names of people doing research in your articles! Its so nice to actually be able to find the studies you base your articles on and read more in depth!!

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