Hats Off to Bacteria!

Overview

Our bodies contain more microbial cells than human cells. Bacteria live in our guts, in our mouths, and on our skin. Decades of cavalier overuse of antibiotics has disturbed this bacterial ecosystem, perhaps irreversibly, with ramifications that are only now being acknowledged and examined. On December 2, 2013, a panel convened at the New York Academy of Sciences to discuss microbiomics research. The panelists were Lawrence Brandt, a professor of medicine and surgery at the Albert Einstein College of Medicine; Martin Blaser, director of the Human Microbiome Program at the NYU School of Medicine; and Maria Gloria Dominguez-Bello, an associate professor of medicine at New York University Medical Center. Hats Off to Bacteria! was presented by Science & the City and the Sackler Institute for Nutrition Science and moderated by Christine Gorman, senior editor for health and medicine features at Scientific American.

Gorman began the evening by asking why there is such a heavy research focus in this field. Brandt attributed his interest to his success using the fecal transplant, a technique he first attempted in 1999 to help a patient combat diarrhea induced by Clostridium difficile. The patient developed diarrhea after taking a course of antibiotics for sinusitis; nothing could shake her resultant C. difficile infection. Brandt reasoned the initial antibiotic treatment had killed gut bacteria that promote digestive health; not knowing which strain to replace, he transplanted stool from her husband. That night she reported marked improvement—for the first time in six months. The procedure has helped other patients, but Brandt predicts that its days are numbered. In the future, doctors hope to be able to identify and administer the particular strain of bacteria that is needed, so that patients do not receive the thousands of others that are present in a stool sample.

Blaser and Dominguez-Bello focused on the innovations that have enabled study of the microbiome. We have known since the 17th century that bacteria live in our bodies: Anton van Leeuwenhoek saw bacteria when he examined saliva under an early microscope. Louis Pasteur thought that our normal flora are essential for health. But 99% of the bacteria we harbor are resistant to culture in the lab. It was thus almost impossible to study bacteria until the last decade or so, when DNA sequencing techniques allowed researchers to obtain gene sequences from as little as one bacterial cell. These techniques not only enabled examination of the microbiome but also demonstrated that such an examination is necessary, with the surprising finding that the bacterial cells in our bodies outnumber human cells.

Why are bacteria in the body? What do we, and the bacteria, gain from this arrangement? And who's in charge? "There is a dialogue," Dominguez-Bello said, "sometimes a fight, sometimes a good dialogue. We have evolved with them. The first form of life on Earth was bacteria. Whatever came after had to deal with bacteria, cope with bacteria, associate with bacteria ... None of our ancestors have ever existed without them." The first complex cells, both plant and animal, were symbionts that engulfed bacteria to outsource their energy production; the engulfed bacterial cells eventually became mitochondria and chloroplasts. Bacteria were later similarly exploited by organisms. "Part of the success of larger organisms like plants and animals," Blaser said, "is that we have learned how to harness bacteria to work with us, so that they can do some of our metabolic work and our immune work."

Human microbiota perform many essential functions, such as producing vitamin B12, digesting plant fibers, helping to train our immune system to distinguish self-molecules from nonself-molecules, and helping to fight off pathogens. It is increasingly clear that we cannot accomplish these functions alone, and in exchange the bacteria receive food and a warm, safe home. Blaser noted that some species are "obligate symbionts," meaning that our bodies are the only environment in which they can survive. If these strains are killed with antibiotics before they are transmitted to other people, especially to the next generation, the bacteria could disappear forever.

Brandt used this idea to introduce the hygiene hypothesis, which postulates the continued importance of bacterial exposure throughout our lifetimes. He pointed to evidence that the makeup of our microbiome is a major determinant of our wellbeing, thinking, and functioning, contributing to conditions such as diabetes, obesity, allergies, asthma, and atherosclerosis, as well as to anxiety and mood and cognition disorders. According to the hygiene hypothesis, these conditions have become more prominent because our obsession with sanitation has eliminated the exposure to bacteria humans used to routinely get through contact with soil, animals, and each other. The finding that children who grow up on farms have fewer allergies than those who grow up in cities lends credence to the idea.

But Blaser disagreed: "If the hygiene hypothesis is true," he said, "it may just be minor." He thinks it is not the organisms present in soil that prime our immune system but rather the specific bacterial strains that humans have always harbored. Many of these stains can be acquired only within a narrow window in our lifetimes. "The intactness of the normal microbiota provides important immunity," Blaser said. "The organisms that we've coevolved with since forever are important to us, especially if we acquire them early in life," he continued, explaining his "missing microbes" hypothesis. "If we no longer acquire them our microbiota is different, and there are a variety of consequences."

One of the hallmarks of mammals is birth through a birth canal. The birth canal is rife with bacteria; as babies travel down it, they are inoculated with lactic acid bacteria that accumulate during the last trimester of pregnancy. These bacteria are the initial educators of the baby's naïve immune system, which must learn to "tolerate our microbiota and attack microbes." Babies born by cesarean section—approximately 50% of babies in New York City—miss out on this natural initial exposure and instead are first inoculated with bacteria floating around the operating room. These bacteria are comprised predominantly of human skin bacteria not from the mother but from the doctors, nurses, and previous patients in the room. We do not yet know the health consequences of this alternate initial exposure. "[Cesarean sections] are breaking a natural law," Dominguez-Bello said, "and there are consequences." Already, studies have shown that children born by C-section have a slightly higher risk of obesity, although differences in the composition of their microbiomes were not examined. Importantly, only babies born via elective C-section miss out on the inoculum; those born by emergency C-section, after their mother's water has broken, are exposed to the bacteria in the birth canal.

"What antibiotics have in common with C-sections is ... abuse," Dominguez-Bello said. Both are medically necessary in some cases, but overused. "What we're starting to do," Brandt claimed, "is look at something that we took for granted for a long period of time, and now analyze the consequences of those actions. Antibiotics are so indiscriminately used, and that's not a good thing." While both C-sections and antibiotics are valuable tools, we can no longer pretend that they do not have some detrimental outcomes. Research has found the colon microbiome of Americans is half as diverse as that of hunter-gatherer populations, such as Amerindians in the Amazon jungle and African populations living a traditional lifestyle. There is also less diversity in Americans' skin and mouth microbiomes. Thus antibiotics, while necessary in emergencies, should not be used in every infection. Some species of bacteria never recover after an antibiotic exposure, and others can only colonize us during a specific time in our lives; if we miss this chance, we can never recover it. Current antibiotics are "like atomic bombs," Dominguez-Bello said, obliterating every bug they encounter. In the future, genomic data could be used to generate antibiotics that target specific bacterial species and leave the extant commensal bacterial ecosystem undisturbed.

Questions from the audience ranged in topic from genetically modified organisms to cyborgs. No studies have been published on the effect GMOs might have on the composition of the microbiome, but diet has been shown to impact our bacteria. Vegans and carnivores have different species of gut bacteria. Japanese people harbor bacteria that can degrade marine algae, hunter-gatherers have strains for digesting carbohydrates, and Americans have strains that prefer lipids and proteins. One participant asked if the next generation of antibiotics might attenuate bacteria by inhibiting important processes such as quorum sensing rather than killing the colonies outright. Blaser noted that quorum sensing has only been studied in pure cultures, not in a diverse ecosystem such as our bodies, so the ramifications of disturbing it in that setting are unknown. Another participant wondered whether the external ostomy bag that now must be used to collect waste after a colectomy might one day be replaced with an artificial colon that contains the bacteria necessary for optimal function.

The panelists expressed diverse hopes for the future. When an audience member asked, "What is a healthy diet?" Brandt responded that we do not know yet; he anticipates that one day an individual could have her microbiome sequenced to get her ideal personalized diet. Blaser hopes that eventually his "missing microbes" could be replaced; he predicts that they will be administered to children in the same way today's children get vaccines. Helicobacter pylori is a prime candidate. It must be attained in the first few years of life, and in childhood it protects against asthma. Its disappearance has been implicated in the high rates of asthma in modern urban youth. In adulthood, however, it causes ulcers and stomach cancer, so Blaser suggested inoculating babies and then eradicating the bacteria from adults at age thirty. Dominguez-Bello is conducting a study in Puerto Rico in which babies born via C-section are immediately swabbed with their mother's vaginal secretions; these babies will be followed for years, and compared to those born vaginally and those born via C-section without swabbing. If significant differences between the babies are detected, she hopes that swabbing will one day become mainstream practice, or that more women will learn about the importance of the human microbiome and opt for vaginal birth when possible.

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Presentations available from:
Martin Blaser, MD (New York University)
Lawrence Brandt, MD (Albert Einstein College of Medicine)
Maria Gloria Dominguez-Bello, PhD (New York University)
Moderator: Christine Gorman (Scientific American)

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