In mid-November 2010, Alex O. wondered for the first time if he might be dying.
For six weeks, the 27-year-old had been suffering from a digestive disease as horrific as it was mysterious. Shortly after breaking up with his girlfriend in late September that year, he’d started experiencing bouts of diarrhoea, which he initially thought might be due to the stress month, however, his diarrhoea hadn’t improved and was now flecked with blood. Stabs of gut pain had begun to wake him up at night. “The persistence of the diarrhoea,” he recalls, “kind of told me it wasn’t due to my mental landscape.”
Alex, a freelance graphic designer who works part-time at a food co-op in Minneapolis, had long described himself as “100% average” – 178cm, 77kg, brown hair, brown eyes. But his illness was making him look and feel anything but average. He could see in the mirror how quickly his face was turning gaunt and pale. He could feel his vitality draining too, almost as if someone had tapped a vein with an IV line and forgotten to cap the other end. A passionate, lifelong skateboarder, he no longer had the energy for his favourite recreation. He could barely make it through a day of work.
Alex’s family doctor had tried everything he could think of, including diet changes and a weeklong course of antibiotics. Nothing worked. The doctor finally referred Alex to a gastroenterologist, who ordered tests for three potential culprits: cancer, HIV/AIDS and a gut infection caused by a bacterium called Clostridium difficile, or C. diff, for short. First identified as a cause of intestinal infection in the 1970s, this rod-shaped bacterium inhabits the digestive tracts of up to eight percent of healthy people without producing symptoms. It can be harmless, provided its population remains under control.
Considering the alternatives, Alex found himself hoping his problem was an overgrowth of C. diff. “When the gastroenterologist explained what he was testing for, he didn’t rate one possibility as more likely than the others because he didn’t want to give me false hope. I remember waiting for the HIV/AIDS test, in particular, which he’d ordered because I was so anaemic. There was one night when I thought that it probably was HIV and that I might die from it. It’s really awful to say, but physically and mentally I was in so much pain I almost wished I were dead.”
Eventually the doctors ruled out cancer and HIV. Alex was so relieved when the tests came back positive for an infection that the news struck him as more curious than dire. What he didn’t know then was that eliminating this stomach bug is one of the most difficult battles faced by infectious-disease specialists today – and one they often lose.
Each year, C. diff kills more Americans than HIV does – 45 000 people died from the infection between 1999 and 2009 in the States, according to the Centre of Disease Control. That’s a lot.
Take a quick look at yourself in a full-length mirror. What stares back is first and foremost a human being: a massive assortment of human cells organised into human tissues and human organs.
If this conventional description seems reasonable to you, brace yourself for a fundamental shift in self-concept: for every one cell in our bodies, at least 10 microbes – from bacteria to fungi to viruses – piggyback atop and within us. Thanks to powerful new investigative tools such as next-generation gene sequencers, scientists continue to uncover an astonishing diversity of species. To date they’ve been concentrating on bacteria. This is partly because these are our most common fellow travelers, and partly because technologies for sampling viruses, fungi and other such organisms are still being refined.
The figures are nothing short of flabbergasting. Up to 100 000 000 000 000 (that’s 100 trillion) individual bacterial cells from thousands of different species colonise everything from the mucous membranes of your nostrils to the lining of your urethra – and a myriad of body niches in between. An infinitesimal pittance of these bacteria consists of hostile invaders; their numbers, for the most part, are held in check. A slightly larger share is made up of transients – bugs whose populations rise and fall depending on your environmental exposure. The vast majority, however, are permanent residents called “commensals,” which are beneficial bugs whose lives have coevolved with ours since ancient times. This collective assortment is known as the human microbiome.
A single square centimetre of skin, for example, hosts 10 000 bacteria perched just on the outside surface. Lightly scrape your fingernail across the same small area and you’ll unearth 50 000 more.
Skin, of course, is an ecological dessert compared with your body’s truly prime real estate. “Most microbes prefer rich environments where there’s a lot of food,” says Dr George Weinstock, associate director of the Genome Institute at Washington University in St Louis. “And the gut is obviously where the nutrients are.” Some estimates suggest that up to four kilograms of micro-organisms colonise the food highway that begins at the average guy’s mouth and ends at his butt. Revolting, yes, but also crucial.
“The more we learn, the more we recognize how many vital contributions our
commensals provide,” says Dr Lita Proctor, project director of the R1.4-billion
Human Microbiome Project, which was launched in 2007 by the National Institutes of Health.
Start with the role they play in activating, training and maintaining our immune systems. For example, when skin commensals detect harmful bacteria, they trigger their human host to recruit inflammatory and immune cells to aid in the defence. Likewise, new research on mice suggests that when commensals in the gut detect flu viruses, they may use white blood cells to send warning signals to the lungs, sparking a counter attack from respiratory immune cells.
Our microbiome also helps us digest components of plant-based foods, such as dietary fibre and polysaccharides (the long-chain carbohydrates in starch) that we can’t break down on our own. Researchers have even discovered that the intestines of Japanese people carry bacteria that help digest seaweed. In the ultimate example of human-bacterial symbiosis, each cell in our bodies contains mitochondria, organelles that take energy stored in simple sugars, fatty acids and amino acids and release it in a form that powers everything we do. Our mitochondria are so essential that you might think they’ve always been absolutely, 100% human. But in fact, ancestors of today’s mitochondria were once bacteria that were living independent lives. Serendipitous infection of the ancestors of humans led eventually to the merger of invader and host. We’ve remained inseparable ever since.
Another contribution comes courtesy of the extraordinary number of metabolic by-products our microbiome produces. Bacteroides in the colon produce vitamin K. One common skin resident, Propionibacterium acnes, breaks down sebum, an oily substance produced by our sebaceous glands, creating a natural skin moisturizer. Other commensals alter the acid levels of their preferred habitat, making these areas less hospitable to destructive microbes.
When pathogens do attempt a hostile takeover, our good bugs release natural antibiotics known as bacteriocins to halt their advance. Lactobacillus salivarius in our mouths, for example, secretes a toxin lethal to Listeria monocytogenes – the bug behind deadly food-borne infections. Another bodyguard, the skin commensal Staphylococcus epidermidis, produces a peptide that can kill other dangerous staph germs.
Finally, the sheer enormity of friendly bacteria guard us against dangerous bugs by way of a process known as “colonisation resistance”. It’s analogous to an apartment complex that’s jam-packed with good tenants who don’t ask for much and always pay their rent on time. When microbial thugs – C. diff, for example – come looking for a place to grow, those tenants help ensure they don’t find any vacancies.
At least not usually – and not without help.
In New Year’s Day 2011, Alex called his father to ask for a lift to the hospital. A week before, he’d completed his fifth course of antibiotics, this time with a more powerful, broad-spectrum drug. For 10 days he’d religiously swallowed four pills a day, in the process killing virtually everything inside his digestive tract.
Once the pill supply ended, his gastroenterologist prescribed probiotic capsules, which contain several strains of live bacteria common in a healthy gut. The hope was that these bugs might jumpstart the re-population of a more normal gut microbiome. And this, in turn, could prevent C. diff from running wild again.
Alex realised within a few days that this latest strategy, like all of those preceding it, was failing. By New Year’s Day he was in a world of hurt. “As a skateboarder,” he says, “I’d developed a pretty high threshold for pain. Over the years, I’ve broken fingers, an ankle, a wrist and my arm.” But these injuries were nothing compared with the agony now stabbing his core.
The diarrhoea was also the worst he’d ever experienced. What his body was producing, Alex recalls, had no resemblance whatsoever to normal human waste. “It was bright red and completely liquified,” he says. “It looked like exorcism blood.” By the time his father got him to the hospital, he was so anaemic the ER docs debated giving him a full blood transfusion. In three months he’d lost 12kg. He was gaunt to the point of emaciation, and the pain had kept him awake for days.
The ER docs prescribed oxycodone and administered multiple units of saline. As soon as the gastroenterologist arrived, he immediately started yet another round of antibiotics, this time using vancomycin, the most powerful agent yet. For the next month, Alex rarely left home.
“I could go to work for maybe three hours,” he says. “I was so sick at many points that I couldn’t do much more than immediately return home and lie around. I’d get these occasional survival pangs of hunger, and then I’d eat a little.”
Vancomycin in pill form, alas, proved no more effective than the other antibiotics Alex had taken. His doctor next tried liquid vancomycin, which he hoped might work better. This had to be refrigerated, which bound Alex even closer to home. He began despairing that he’d never lead a normal life again.
The liquid drug failed too. His gastroenterologist searched the medical literature, desperate to find something – anything – that might give his young patient a chance against the relentless enemy ruining him from within. The search led to Dr Alexander Khoruts, a gastroenterologist who’d reported nearly too-good-to-be-true success at treating recurrent C. diff infection. The intervention sounded both bizarre and, frankly, disgusting. But it had worked for dozens of patients.
What’s more, a referral to Dr Khoruts wouldn’t even require Alex to leave Minneapolis. An associate professor of medicine at the University of Minnesota, Dr Khoruts’s office was just blocks away from Alex’s apartment.
The only time in our lives when our bodies are thought to be completely sterile is during the nine months we spend in the womb. Throughout gestation, researchers have found, the composition of microbes in the mother’s vagina undergoes dramatic changes in preparation for the newcomer’s passage through the birth canal.
“Infants are like microbe magnets,” says Proctor, “and we know babies pick up a huge part of their microbiome during vaginal delivery.” Researchers refer to this as vertical transmission because it’s handed down from one generation to the next.
But birth is only the start. In the first two to three years of life, we continue to add and subtract new populations in many ways. We pick up some new germs through skin-to-skin contact with parents and siblings. We add others during the transition to solid foods, crawling explorations of the natural world, taste testing virtually anything we can cram into our baby mouths, encounters with animals and insects and increased exposure to more and more humans and their microbes.
“Your immune system needs to be educated,” says Dr Julia Segre, a skin researcher at the National Human Genome Research Institute, “and the best way to do this is to be exposed to lots of different microbes that can do the teaching.”
What’s worrisome is that we may be failing ourselves. Evidence continues to mount that the younger we are when our antibiotic exposure starts, the more serious and lasting are the problems caused to the “good bug” populations in our bodies.
“The average child in the US has received 10 to 20 courses of antibiotics by the time he or she is 18 years old,” says Dr Martin Blaser, a professor of medicine and microbiology at New York University’s Langone Medical Center. Typically the drugs are prescribed for ear infections, bad colds, sore throats, and the like. And antibiotics can sometimes prevent serious escalation of an illness – stopping strep throat, for example, from turning into rheumatic fever. Still, experts believe, the drugs are wildly overprescribed, and may be dispensed more to palliate worried parents than to help their kids.
Patients have long assumed that antibiotics may not always help, but they’re unlikely to hurt either – in other words, “better safe than sorry.”
But is this true? Of course, one well-known consequence is the emergence of antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), which made its first US appearance in a Boston hospital in 1968. In 2005, the CDC estimated that MRSA caused 278 000 hospitalisations and contributed to 17 000 deaths. Its targets aren’t limited to the sick and immune compromised: news accounts nation wide have documented athletes in peak shape succumbing to MRSA through skin exposure and contact sports.
Another deadly germ, E. coli O157:H7, has followed an eerily similar trajectory. It was first identified as a food-borne pathogen in 1982, after contaminated hamburger triggered severe bloody diarrhoea in dozens of diners. Since then, this virulent cousin of our “normal” E. coli intestinal residents has led to deaths and high-profile recalls of tainted foods – from last year’s 10-state outbreak linked to lettuce to 2009’s 30-state swath of contagion traced to cookie dough.
But even if you eat that cookie dough and don’t get sick, there’s a good chance you will gain weight ¬– and believe it or not, antibiotics may be one of the culprits here too.
Since at least the early 1950s, low-dose antibiotics have been a routine additive in livestock feed, a practice known by the acronym STAT, for subtherapeutic antibiotic therapy. “Most non-farmers assume that this is to prevent some disease in the herd,” says Dr Khoruts. “It’s not. The real reason is the discovery that antibiotics make animals fatten up more quickly.”
By 1954, researchers at the Naval Medical Research Unit had heard about STAT. They also knew of several small human studies that showed that antibiotics helped premature infants and undernourished children gain weight. Very little, however, had been published on weight effects in adults.
Strep infections can quickly spread through military ranks, and Navy researchers had demonstrated that giving antibiotics prophylactically at the first sign of an outbreak could reduce the number of people sickened. Might these drugs also be boosting the weight of robustly healthy young men?
To find out, they randomized six 55-man companies of Navy recruits into three groups. At reveille every morning for the next seven weeks, each man was given a yellow capsule containing either an antibiotic (penicillin or Aureomycin) or a placebo; he didn’t know which one he was taking.
By the end of week seven, all three groups had gained weight. But those on antibiotics had gained significantly more – on average, about 1.8 kilograms from Aureomycin and 2.2 kilograms from penicillin, versus only 0.9 kilograms from the placebo. This antibiotic enhanced fattening may not have reached the level seen in antibiotic-fed farm animals, but then again, most men of that era hadn’t received their first antibiotic doses as young as weaned calves and piglets had – a distinction that’s no longer true today. “Can using antibiotics to treat our kids for ear infections be setting them up for obesity in adulthood?” asks microbiologist Weinstock. “And if so, how?”
One intriguing possibility centres on the gut bacteria Helicobacter pylori. This bug hit the medical radar big time after two Australian doctors proved that it caused most stomach ulcers; the doctors won Nobel Prizes for their work. But H. pylori isn’t all bad – quite the opposite, actually. When it’s present in healthy numbers, H. pylori reduces the stomach’s production of ghrelin, the so-called hunger hormone. In so doing, H. pylori may not only dampen appetite signals in the brain but also decrease fat storage in adipose tissue. So H. pylori could be a natural ally against gluttony.
Until the beginning of the 20th century, researchers believe, H. pylori was the single most common bacterial species in the human stomach. But then, suddenly and without warning, it began disappearing. “By the turn of the 21st century,” says Dr Blaser, “fewer than six percent of children in the United States, Sweden and Germany were carrying the organism.” Many factors, he concedes, could be playing a role in H. pylori’s rapid demise, but antibiotics are his prime suspects. A single course of the antibiotic given for ear infections, for instance, could wipe out the entire H. pylori population in up to half of young patients.
Emerging research suggests that damage to the gut microbiome may be partly to blame for metabolic syndrome, a cluster of conditions including high blood sugar, high triglycerides and a large waist circumference. Left untreated, the syndrome increases the risk of heart disease, stroke, and type 2 diabetes. In a fascinating study published last year in the Diabetologia, French researchers showed that the blood concentrations of a specific bacterial gene accurately predicted which of 3 000-plus people would go on to develop diabetes six to nine years later. The same gene concentrations also predicted which normal-weight patients would go on to develop abdominal obesity.
Another component of metabolic syndrome is inflammation in fat cells. For reasons not yet understood, inflammation appears to change the way these cells store and mobilise fat. “This is the basis for one leading hypothesis about a microbiome role in metabolic syndrome,” says Weinstock. “Certain bacteria overgrowing in the gut may increase an inflammatory response in adipose tissue, ramping up fat storage and weight gain.”
The troubling extinction of H. pylori in so many people has been impossible for scientists to miss. But what about other, less visible members of our microbial ecology? Researchers continue to discover never-before-seen genes with each successive round of sequencing. Could the tag team of modern hygiene and indiscriminate antibiotic use be eradicating critical commensals before we even learn of their existence, let alone what roles they serve?
“The most important factor in modern allergic and metabolic diseases might not be the decreased sampling of microorganisms in the food, air, water and soil,” says Dr Blaser, “but instead could reflect the loss of our ancestral microorganisms. Antibiotics kill the bacteria we do want as well as those we don’t.”
Dr Khoruts did not invent the fecal transplant, which was first described in the medical literature in 1958. But over the past three years, he has become one of the most accomplished practitioners and enthusiastic proponents of the procedure. Also known euphemistically as “human probiotic infusion,” or HPI, Dr Khoruts concedes that regardless of nomenclature, most people greet the concept with disgust.
The notable exceptions are those who are too sick to care.
Such was the case with Dr Khoruts’s first fecal transplant patient, a 63-year-old woman infected with C. diff who came to him as her last hope. “By this point,” he says, “her life was ruined. She’d lost 27kg, and I knew she was going to die. I gave her every antibiotic combination I could think of, and not one of them helped.”
If anything, her condition worsened, and Dr Khoruts suspected he knew why.
One of the unique traits of C. diff is its ability to hunker down during hard times. It does this by forming seedlike spores that place it in near-suspended animation. Because of this, any antibiotic treatment has an inherent limitation: it effectively kills off active C. diff as well as most of the “good guy” commensal species active in the gut. But C. diff spores aren’t doing anything active, so antibiotics have no target to attack. As soon as a patient stops taking the drugs, the spores “hatch” and C. diff returns in overwhelming numbers.
“Our first and best barrier against C. diff is our natural bacteria,” says Dr Khoruts. “As long as that microbial world is balanced and intact, it’s very difficult to become infected. But when antibiotics suppress or disrupt our natural bacteria, it creates room for C. diff to proliferate.”
Normally, if you need to restore the balance of good bacteria in your gut, you can pop probiotic capsules. This wasn’t really an option for Dr Khoruts’s first HPI patient. A single probiotic capsule contains, at most, billions of live bacteria from only a handful of species; she needed trillions of individual microbes from hundreds of species.
To date, doctors have found only one way to accomplish this: after approval by the university’s institutional review board, Dr Khoruts secured a 85g sample of feces from the patient’s husband, placed it in a blender with saline solution, and created a “special smoothie.” After filtering and screening this for transmissible diseases, it was ready for transplant by colonoscope.
Based on the scattered case reports he’d read, Dr Khoruts was guardedly optimistic that the transplant would help. What he didn’t expect was how much it helped – and how quickly. Within a matter of days, the horrible affliction that had tormented the woman for a year was gone.
Not everyone responds that quickly, and sometimes it takes more than one try for the microbial “graft” to take.
Alas, this is exactly what happened with Alex. Dr Khoruts offered two options. Alex could go back on vancomycin to again exterminate everything in his gut, and then try a second transplant. Or he could opt for a stalemate: to remain on vancomycin “essentially forever”. The C. diff would stay dormant, but his natural gut microbiome would be permanently wiped out.
“I told Dr Khoruts that I absolutely did not want to be on antibiotics for the rest of my life,” Alex says. “I said I was willing to have as many transplants as I needed to eliminate this bug.”
Luckily, he needed only one more. Within two days of the second transplant, Alex sensed that something truly different was happening inside him. By the 10th day, he had his first solid elimination in nearly nine months, which he now jokingly refers to as his “proud father’s stool.”
“I wanted to take pictures,” he recalls, “and send them to my parents, saying, ‘Look what I did!’”
Alex, who feels “insanely lucky” to have received such innovative medical care, has suffered no recurrent symptoms in the half year since the graft “took”. If anything, he feels even better than before, in large part because he now takes his health – and that of his microbiome – to heart.