Gut Feelings

The microbiome, poised to transform modern medicine—perhaps even to alter our perception of what it is to be human—is still largely a mystery. But researchers at UB and elsewhere are on the path to solving it.

Story by Lauren Newkirk Maynard | Illustrations by Shaw Nielsen

“Our work at UB has grown exponentially, and it’s terrifically exciting. What’s happening here and elsewhere has the potential to rewrite the microbiology textbooks we all learned from. ”
Robert Genco

Much like the Earth itself, our bodies teem with life that is not, strictly speaking, our own. Trillions of tiny organisms, including bacteria, fungi, viruses and other one-celled microbes invisible to the naked eye, reside in and on us in specialized communities. Together they form what’s called the microbiome—our body’s complete ecosystem of microorganisms.

To illustrate just how prolific these little guys are, our microbes are estimated to outnumber the body’s cells 10 to 1; together they weigh between one and three pounds in an average-size adult. And they’re not just along for the ride. Many organisms making up the microbiome play well with their hosts and with each other, helping control and maintain our immune system, weight, hormone levels and other vital life functions. But balance is the key. All microbes are opportunistic and can flood our systems when competing microbes are absent; some, like the E. coli bacterium, can do quite a bit of harm as a result, causing serious illness or, if they succeed in overwhelming the microbial and bodily defenses, even killing their host.

Consequently, it’s the nastier microbes that often dominate headlines, as the medical community rushes to develop and prescribe ever more potent antibiotics to combat new strains. However, scientists, physicians and the public are starting to pay more attention to our body’s beneficial microbes, realizing the powerful, healing roles they play in human health and well-being.

Microbiologist David Relman, who co-directs the Center for International Security and Cooperation at Stanford University, is among those who are attempting to shift the focus of infectious disease research to include not just the pathogenic microbes but the “good guys” as well. Speaking about the microbiome at UB this past fall as part of President Tripathi’s Critical Conversations series, Relman, one of the country’s top researchers pursuing this relatively new field, seemed at times to be in awe of our dual biologies—that of our own cells and that of the cells of our microbial partners. “We are one type of life among many, many others. Nothing exists in isolation,” he said.

Indeed, human microbes have been around as long as we have, and thrive in different amounts and groups inside our body’s many habitats, including in our intestines and mouth, on our skin, and in our nostrils. These groups can be quite different from each other, but, as Relman described, there are also similarities among microbial communities around the world. For instance, a North American’s gut bacteria, or flora, may have more in common with the gut bacteria of someone in Japan than they do with the bacteria in that individual’s own gums.

Microbes, like our own genes, may also predict our future health. Bacteria found in a pregnant woman’s vagina are passed along to the baby’s underdeveloped gastrointestinal tract at birth and, along with breast milk, help seed the newborn’s gut flora with the right microbial mix to help it—and the child—develop normally. Some researchers suspect that birth by cesarean section and formula feeding may be linked to health issues later in life because the infant wasn’t exposed to that very specific combination of beneficial bacteria.

A new chapter for UB’s genomic experts

Before the microbiome, our bodies’ genes were another great medical mystery to be solved. While scientists have mapped the human genome—the DNA-driven genetic material common to all of us—our microbes are another story. Their genes, as well as their overall structures, functions and interactions with each other, and with us, are still greatly unknown.

UB has long held a pioneering role in genomics—the study of genes and their DNA building blocks. In the 1990s, UB geneticists, including J. Craig Venter (now with the J. Craig Venter Institute) and Norma Nowak (PhD ’86 & MS ’80), helped sequence and map the human body’s 23,000 genes in the landmark Human Genome Project. Encouraged by that achievement, in 2007 the National Institutes of Health launched the Human Microbiome Project (HMP) to study the genetic material of microbial communities found in 18 different sites within the body, including the oral cavity, lower intestine, skin and vagina. In total, they collected more than 11,000 specimens from 300 adults using cutting-edge genomic sequencing technology to spot the microbes’ presence.

A year before the HMP launch, a team of scientists from UB, Stanford, Washington University in St. Louis and what was then called The Institute for Genomic Research (now the J. Craig Venter Institute) published results of a milestone study on the human colon in the journal Science. It was the world’s first DNA sequencing of all the genes of an entire community of human microbes.

The researchers on that study included Relman and microbiologist Stephen Gill, who was then on faculty in the Department of Oral Biology in UB’s School of Dental Medicine. Today, researchers worldwide—including an increasing number at UB—study the microbiome using genetic blueprints from these previous projects. “Our work at UB has grown exponentially, and it’s terrifically exciting,” says Robert Genco (DDS ’63), SUNY Distinguished Professor in the departments of Oral Biology and Microbiology and Immunology—and a vocal proponent of microbiome research. “What’s happening here and elsewhere has the potential to rewrite the microbiology textbooks we all learned from.”

With its scientific rigor and public outreach, the HMP also brought gut bacteria into the mainstream, prompting best-selling food journalist Michael Pollan in 2013 to have his own gut microbiome tested. His results (and many others’) are proudly promoted by the “American Gut” initiative, a crowdsourced version of the HMP that aims to collect data on Americans’ fecal flora. In turn, that data will become part of the open-source Earth Microbiome Project, a massive, global study attempting to characterize all microbial life on the planet.

UB’s Microbiome Hunters

Jeffrey Lackner, professor of medicine and director of UB’s Behavioral Medicine Clinic.

The Gut: A new mind-body connection

“Most of the research being done regarding the effects of psychological stress on the microbiome has been preclinical, or at least not done on humans. ”
Jeffrey Lackner

In the past decade, microbiome research has spread into other fields beyond microbiology and genomics, including neurology and psychology. Most recently, researchers have found evidence that microbes and the brain can communicate, helping regulate how we think and feel. Many studies are underway to test whether our microbiomes play key roles in autism, anxiety, depression and other psychological disorders.

Jeffrey Lackner, professor of medicine and director of UB’s Behavioral Medicine Clinic, takes the mind-body connection even further; he has a hunch that it may be a two-way street. With funding from UB and the National Institutes of Health, and using stool samples collected from subjects enrolled in a much larger study he led to test how a behavioral treatment program could improve GI symptoms of irritable bowel syndrome (IBS), Lackner aims to explore the brain’s effects on the gut microbiome—an angle he says hasn’t been clinically studied before. “We know there’s a connection between the gut and the brain, but we don’t know how it works, or why,” he says. “Most of the research being done regarding the effects of psychological stress on the microbiome has been preclinical, or at least not done on humans.”

Joining him on this two-year pilot study are UCLA gastroenterologists Emeran Mayer, a noted microbiome expert, and Kirsten Tillisch, an expert on how the brain and microbiome interact in patients with functional gastrointestinal disorders. Both helped design the study, and they will play key roles in analyzing its data. The trio hopes to find evidence proving their hypothesis that the brain not only can receive messages from the gut microbiome, but can also send messages back, thereby changing the microbes and how they behave. If it succeeds, Lackner believes the research could one day lead to more effective self-management treatments for IBS and other common yet intractable gastrointestinal disorders influenced by the microbiome.

Jean Wactawski-Wende (PhD ’89, MS ’83), dean of the School of Public Health and Health Professions.  

The Mouth: An oral history

“There is no other prospective epidemiological study as large and rich as this that can address questions about the oral microbiome. ”
Jean Wactawski-Wende

UB researchers in the schools of medicine, dental medicine and public health have built a reputation for rigorous clinical research of the microbes in the mouth. The oral cavity, as it’s called, has a relatively complex microbiome, meaning it contains a high genetic diversity and distribution of many microbial species. Some of them, it’s believed, may be linked to systemic diseases outside the mouth, such as heart disease, stroke, diabetes and pneumonia.

The mouth is an ideal target, then, for a project led by Jean Wactawski-Wende (PhD ’89, MS ’83), dean of the School of Public Health and Health Professions. She and Genco, along with several other UB researchers, are conducting a five-year, $4 million study funded by the National Institute of Dental and Craniofacial Research to examine postmenopausal women and the possible connections between the communities of microbes living under their gums and the prevalence of periodontitis, a common and chronic inflammatory disorder also known as periodontal (gum) disease. “There is no other prospective epidemiological study as large and rich as this that can address questions about the oral microbiome,” she says.

Population health researchers use this kind of prospective study, Wactawski-Wende explains, to follow a group of individuals who have clear differences, like diet or weight, and then determine how these factors may affect long-term rates of a certain outcome, such as the development of a disease. Now, she says, the characteristics of these women’s oral microbiome can be set alongside these and other personal attributes, showing possible associations with and risk factors for disease—and perhaps avenues for prevention or treatment.

Wactawski-Wende’s team is looking at the severity and progression of gum disease in a unique way. Unlike most microbiome studies to date, UB has access to an unprecedented amount of data from the Buffalo OsteoPerio study, one arm of a massive, nationally funded project called the Women’s Health Initiative (WHI) conducted here for more than 15 years—an extremely long time in terms of human scientific studies. The larger WHI has tracked the lifestyle, diet and many other health-related factors of more than 162,000 postmenopausal women over the past 23 years.

Robert Genco (DDS ’63), SUNY Distinguished Professor in the departments of Oral Biology and Microbiology and Immunology.

Microbes on multiple fronts

These are exciting times at UB as its work on the human genome and microbiome matures, says Wactawski-Wende. Encouraged by better genetic sequencing technologies and increased funding from the federal government for personalized medicine, UB is investing in a wide range of multidisciplinary studies, mostly in the sciences and medicine, but also in fields ranging from engineering to art.

In addition to the studies led by Lackner and Wactawski-Wende, several teams of public health researchers, microbiologists and biostatisticians have joined forces to investigate bacteria’s role in health, and many are doing it with data from the WHI. Last year, Michael LaMonte, a UB epidemiologist and co-investigator on Wactawski-Wende’s periodontal study, began assessing a proposed study that would look at the gut microbiome’s role in cardiovascular disease in older women. His UB colleague Jo Freudenheim, an epidemiologist and breast cancer expert, just published data from another study ancillary to the WHI, indicating that there appears to be an increased risk of breast cancer in postmenopausal women who have periodontal disease (oral microbes have been found in cancerous tumors), while another research group is about to test its theory that the lack of diversity of gut flora collected from newborn babies in Kenya could be linked to a risk for stunted growth later in life. Similarly, Frank Scannapieco (PhD ’91, PMCRT ’89), chair of UB’s Department of Oral Biology, has been investigating connections between the oral microbiome and lung disease, while Genco has conducted and presented research on its associations with diabetes.

The laboratory of Timothy Murphy, SUNY Distinguished Professor in the Jacobs School of Medicine and Biomedical Sciences, has been studying the bacterial species that are present—and periodically cause flare-ups—in people with chronic obstructive pulmonary disease, or COPD, which restricts the amount of air entering the lungs. Murphy also helps direct UB’s new Genome, Environment and Microbiome Community of Excellence, or GEM for short (see sidebar below).

Students as well as faculty are taking part in UB’s cutting-edge microbiome work. At the Coalesce Center for Biological Art, a hybrid “bio-art” laboratory facility on the North Campus sponsored by the GEM working group, faculty, students, visiting researchers, artists-in-residence and the general public are exploring ideas about our relationship to the unseen living world through hands-on creative engagement. In the Honors College, biochemistry undergraduates, genomics and bioinformatics experts, and computer science faculty have used next-generation genetic sequencing to analyze human gut bacteria before and after gastric bypass surgery. Other students have assisted on studies of the gut microbiome of marine mammals and prehistoric polar bears.

Wactawski-Wende sees her school’s various projects as parts of a greater whole regarding microbiome research at UB, and says the work has provided her with a fresh injection of professional fulfillment and focus. “As a longtime researcher and administrator, it’s not often that I get to work with people outside my field,” she says. Genco agrees. “We’re all talking and working together in ways we never have before. Who knows what we’ll uncover?”

Lauren Newkirk Maynard is a section editor for At Buffalo.

The Genome, the Environment and the Microbiome (GEM)

One of UB’s three Communities of Excellence, the Genome, the Environment and the Microbiome (GEM) is a research, education and engagement group working to advance our understanding of the genome, the microbiome and their interactions with the environment. Co-led by Timothy Murphy, director of UB’s Clinical and Translational Research Center, pioneering genomic scientist Norma Nowak (PhD ’86 & MS ’80) and Associate Professor of Biochemistry Jennifer Surtees, GEM has spent the last year or so gathering a powerhouse team of faculty, including scientists, lawyers, educators, biostatisticians, philosophers, historians, artists and other relevant experts across the university.

    GEM will collaborate with students, and with the public, to develop models for personalized medicine, educate individuals about their health, and accelerate vital public policy discussions about the ethical, legal and social implications of genome sequencing. It’s not just about better medicine, says Surtees, but a deeper understanding of ourselves and our place in the world. “There’s a huge gap between what scientists know about genetics and the microbiome, and what the public knows,” she says. “Especially about how it all relates to their own health.”