by Katya Frazier
Graduate student in the Committee on Molecular Metabolism and Nutrition
If you’ve had strep throat or an ear infection, you likely have deep respect for antibiotics. They powerfully fight off bacteria—by damaging their DNA, disarming their protein-making machinery, or causing their cell walls to explode.
But what happens if antibiotics inadvertently target the “good” bacteria in our bodies? These are the micro-organisms that help us digest our food, make our vitamins, keep our skin moisturized, tune our immune system, and so much more.
For over a decade, scientists and physicians have noticed a connection between early use of antibiotics and inflammatory bowel diseases (IBD)—chronic, painful gastrointestinal conditions that are growing in incidence at an alarming rate. IBD, the umbrella term for Crohn’s disease and ulcerative colitis, affects over 1.5 million in the U.S. alone. As many people can attest, there are few effective therapies that provide lasting relief.
Recently, Eugene Chang, MD, and his team at the University of Chicago published a study aiming to understand the connection between antibiotics and IBD development. In this study, Jun Miyoshi, MD, PhD, and Alexandria Bobe, PhD, treated pregnant, genetically susceptible mice with antibiotics and then observed both the mothers and their new pups over time.
Mouse pups whose mothers were treated with antibiotics did, indeed, tend to develop IBD-like symptoms, but the evidence showed a more complicated story. Since the antibiotics were not transmitted from mother to pups, Miyoshi and Bobe could determine that it wasn’t the antibiotics themselves that triggered the IBD symptoms. Instead, the antibiotics disrupted the bacterial community in the mothers, and this unbalanced microbiota (dysbiosis) was transferred to the pups during pregnancy, delivery, and nursing. The gut dysbiosis skewed the pups’ immune system, priming them for inflammation and increased development of IBD-like symptoms, as compared to non-treated mice.
Interestingly, the mothers of these pups, as well as other adult mice given the same antibiotic exposure, tended not to develop symptoms, which include weight loss and diarrhea. It was as if their immune systems, which were fully mature before they were exposed to the antibiotics, kept them from developing symptoms—even though they were genetically primed.
These experiments seem to indicate a direct, causal link between gut dysbiosis—an imbalance of bacteria in the gut, which can be caused by antibiotic use—and later development of IBD, especially in those with both immature immune systems and a background of genetic susceptibility. This is not to say that we should stop using antibiotics, as they can be crucial, life-saving treatments. What this study does show is the powerful, complex effects of gut bacteria during early life on our health. And this may be true not just for IBD, but other inflammatory diseases as well, from allergies to certain types of arthritis.
This research and others suggest promising new avenues to improve health. What if the balance of bacteria in our gut could be used as a biomarker to diagnose or even predict IBD? And what if we could find a way to reset the microbiota in the gut and tame the inflammation that results in IBD?
Diving into the complex mechanisms of the gut microbiome
Although research has revealed so much, the mechanisms by which the microbes in our bodies affect disease are still cloudy. Microbial communities in the gut are not only complex, but thrive only in an air-free environment, which makes them particularly difficult to study. But the more we discover about the dynamics of the microbiome—in both healthy and sick individuals—the better chance we have to turn the dial towards health. The Duchossois Family Institute was established to advance these discoveries.
But that is only part of the Duchossois Family Institute mission. It will also drive translation of bench research on the microbiome more efficiently into the clinic and back again to the lab. We need to better understand how our current lifestyles and treatments affect the bacteria living within us, so we can help countless other people achieve a lifetime of vigor and good health.
Photo by Seweryn Olkowicz/WIKIMEDIA COMMONS
by Kristin Hoddy, PhD
Postdoctoral fellow in the Department of Medicine
Section of Pulmonary and Critical Care
A good night’s sleep is not always easy. Lack of sleep may serve as badge of honor, a sign of productivity, or, a necessity—to get a job done. The number of sleepless Americans seems to be steadily increasing.
Poor sleep is not just a problem for night-owls. Approximately 24 to 50 percent of middle aged men and 9 to 23 percent of middle aged women face the day with a poor night’s sleep due to sleep-disordered breathing, a catch-all term that includes conditions like sleep apnea. The risk is higher in certain populations, including the elderly, those with high blood pressure or obesity, and those with a family history.
When the airway is repeatedly restricted, sleep disordered breathing occurs, causing a drop in blood oxygen, blood pressure fluctuation, and widespread stress. The brain senses the change in oxygen level and triggers arousal, a “wake-up now!” response, which generally lasts three to fifteen seconds; longer arousals typically cause the person to awaken fully.
This condition can go undetected and persist for years, but those affected may feel poorly rested and have trouble remembering things. As few as five arousals an hour may be enough to cause a person to feel chronically sleepy; some people with severe cases experience an average of 30 arousals hourly. Left untreated, the combination of low blood oxygen levels and poor sleep can have a disastrous effect on health, wellbeing—and potentially the gut microbiome.
Both population studies and experimental studies have shown a provocative connection between inadequate sleep and increased risk of both obesity and diabetes. “Good sleep is important for maintaining optimal health, but people don’t always realize the impact that sleep has,” says Erin Hanlon, PhD, from the University of Chicago Sleep Research Center.
Seminal work led by UChicago researcher Eve Van Cauter, PhD, showed that sleep deprivation hinders the body’s ability to control blood sugar. In fact, after about a week of sleeping only four hours a night, study participants showed their first meal of the day elicited peak blood sugar responses akin to aging about 30-40 years.
Interrupted breathing presents a major barrier to sleep quality. Every time an arousal occurs, the sleeper goes back to stages of lighter sleep—problematic, because the brain needs to cycle through specific sleep stages each night. In just three nights where subjects’ deepest sleep was disrupted, researcher Esra Tasali, MD, found a 25 percent decline in insulin sensitivity—a hallmark of type two diabetes—similar to gaining between 17 and 27 pounds.
“The mechanisms between sleep loss, body weight, and blood sugar control are not well understood,” Hanlon says. “Sleep loss might be affecting the function of the microbiome which, in turn, influences body weight and glucose regulation. It could possibly be the other way around, or perhaps a multi-directional relationship.”
A recent paper published by a UChicago team with international collaborators provided some clarity. They compared two groups of mice for four weeks, repeatedly disrupting sleep every two minutes (as in severe sleep apnea) in one group while the other slept undisturbed. Mice with repeatedly disrupted sleep demonstrated increased appetite, diminished insulin sensitivity, and an accumulation of fat concentrated underneath the abdominal muscles and around the organs in the gut. This particular fat also showed indications of elevated inflammation. The researchers noted changes in both the type of bacteria and the metabolic products those bacteria produced. Despite these interesting relationships, the exact mechanisms were unclear.
The team went on to create a model with cells that mimicked intestinal barrier tissue, the tissue critical for keeping waste and bacteria in the intestine while letting nutrients pass through. They exposed the model tissue to intestinal contents from both mouse groups. The tissue grown from sleep-disrupted mice proved to be leaky; that from the well-rested mice held its own.
Next, the team inoculated germ-free mice with microbiota from each of the mouse groups. The germ-free mice given bacteria from the sleep-disrupted group increased their food intake and went on to develop tell-tale signs of inflammation and insulin resistance—despite no disruption to their sleep and no change in body weight or visceral fat.
This work provides some tantalizing clues to the consequences of disrupted sleep, which raises some practical questions. Would a healthy gut microbiome protect against the development of obesity or diabetes in the face of a sleep-deprived world? Perhaps the answer to sound sleep is waiting deep within our guts.
Photo by Adi Goldstein on Unsplash
by Elise Wachspress
Katie Harris came to the University of Chicago from Pittsburgh excited to apply her strong background in microbiology and immune signaling to advance the boundaries of science. She had found this post-doctoral opportunity—with eminent scientist Eugene Chang, MD—that would allow her to study how the microbiome contributes to inflammatory bowel disease, knowledge that someday might improve the lives of the 1.6 million people who suffer from this debilitating, often lifelong condition.
But she found UChicago offered an opportunity she never expected, one with impact much more immediate than “someday.” Never did she think she would be going into business.
It just so happened that a more advanced post-doctoral colleague in her lab, Joe Pierre, had just recognized some interesting things about a fungus named Candida albicans.
Candida, which grow well only in the human body, usually cause fairly solvable problems, like vaginal “yeast” infections. But Candida are shapeshifters. Usually oval (in the “yeast” mode), they can also convert to a hyphal form—a filament with a point at one end. And minor changes in its environment can cause rapid switching.
The problem is, hyphae can wreak havoc in the gut. They use their tips to break out of the human digestive system and into the blood stream. The result, for those with cancer or HIV or otherwise compromised immune systems, is a potentially deadly infection.
On the other hand, Candida in yeast form are valuable members of the gut community. They stimulate the gut lining, significantly reducing our susceptibility to inflammatory bowel disease, influenza infections, and other conditions. So eradicating Candida is not a winning strategy.
Another complicating factor is that fungal cells, unlike bacteria, are structurally similar to our own. This makes finding agents that target them without attacking human cells very difficult.
What Joe, now on faculty at the University of Tennessee, noticed was that there were certain peptides—smaller versions of proteins—that specifically prevent Candida from going from yeast to hyphal form. They are like fairy dust that could keep your basically good children always on their best behavior.
Joe’s next move was to pull together a team to make this discovery useful to the greatest number of people. He enlisted Katie and Dr. Chang, and they looked to the Polsky Center for Entrepreneurship and Innovation to help get the discovery out of the lab and into clinics and homes. The goal: develop a safe, effective product that would help prevent dangerous Candida infections in immuno-compromised patients. They started building a company: AVnovum, named for the novel AVpeptides they were creating to maximize the “fairy-dust” effect Joe had discovered.
The AVnovum team entered the Innovation Fund competition run by the Polsky Center. They knew that in order to be competitive they would need a strong business pitch as well as a good scientific idea, so they enlisted Myles Minter, a post-doctoral scientist at UChicago with a degree in intellectual property and an aptitude for business.
A large, experienced panel of business experts heard their pitch and awarded the team $150,000 to develop and test improved AVpeptides. Monica Vajani, a Booth student also trained as a biomedical engineer, enthusiastically joined the team to help. With Joe off to his faculty position in Tennessee and Myles accepting a position at William Blair, she and Katie became the “boots on the ground” to move this fledgling business forward.
Katie redoubled her efforts in synthesizing a variety of AVpeptides, about 30 so far, to see which worked the best to keep Candida in line. She first tests the peptides “in vitro”—in a petri dish where the Candida is growing by itself—and will eventually test in various animal models. She has already demonstrated the new compounds can improve effectiveness.
Meanwhile, Monica is collaborating closely with the Polsky team to put AVnovum on solid commercial footing. She developed a business plan, with the help of advisors at MATTER, who have extensive drug development experience. Once Katie identifies the best peptide candidates, they will concentrate on finding the most cost-effective ways to produce these in bulk, perhaps in the lab, or maybe via a biologic, using living microorganisms, plants, or animal cells to manufacture the compounds. Next will come preclinical toxicology tests, clinical trials, etc.: a long road, but perhaps a profitable one. Candida poses a $3.5 billion burden to the health care system, and those with Candida bloodstream infections have mortality rates as high as 30 percent. There are currently no safe and specific treatments for this subset of immunocompromised patients.
The AVnovum team hopes to change that fact soon. The peptides can be given orally and are so specific to defanging Candida that demonstrating safety is likely a slam-dunk. For those at highest risk—those on high-dose corticosteroids or about to receive an organ transplant or being treated for cancer—the AVpeptides will likely be used prophylactically, to prevent infections in the first place.
Katie has surprised herself with her own involvement in this business venture. “Entrepreneurial science was something I never had an interest in,” she says. “I got involved with biological research because I find the natural world absolutely fascinating.
“But I am thrilled to know that my work can actually improve lives. If this treatment ends up available to patients, my work in the lab would contribute to preventing fungal infections in a safe and effective way. I still love performing research in basic biological concepts, but I now have a greater appreciation for how that research can be used to improve human health.”
As sources of government and corporate funding flow and (mostly) ebb, capturing the monetary value of scientific discovery may be essential to advancing the boundaries of knowledge. Good science is expensive, but it is the surest road to progress.
That is why the growing partnership between the University of Chicago Medicine and the Polsky Center for Entrepreneurship and Innovation may be one of the most critical facets of the Duchossois Family Institute.
Photo above (cropped): Candida albicans in both yeast and hyphal forms. The rough-surfaced cell at the center is a neutrophil, one of the immune system’s “first-responders” to infection or environmental toxins. (Kernien, John F.; Johnson, Chad J.; Nett, Jeniel E., CC BY 4.0)
Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office
by Katharine Harris, PhD
Postdoctoral fellow in the Department of Medicine
Section of Gastroenterology, Hepatology & Nutrition
Katya Frazier, a second-year graduate student at the University of Chicago, arrived home at 3 a.m. again. It took her three minutes to jog from the lab back to her apartment; living close to work is a big perk when you are collecting microbial samples from mice at 2 a.m. Katya wants to know what microbes are doing in the middle of the night, and so she routinely gives up sleep to collect samples.
For years, scientists have observed that our bodies function differently throughout the course of a day. Body temperatures, hormone levels, immune function, and metabolism all exhibit daily rhythms, oscillating over the course of 24 hours. In fact, this year’s Nobel Prize in Physiology or Medicine was awarded to researchers for their discovery of the biological underpinnings of this circadian clock, now known as a powerful influence in maintaining health.
Researchers at the University of Chicago are investigating how the vast community of microbes that live in and on the human body participate in this daily dance, and Katya is an important member of this team. In 2015 Vanessa Leone, PhD, and Eugene Chang, MD, published some breakthrough research on the circadian rhythms of the microbial community in the gut using mice as their model system. Their work showed that the abundance and function of microbial species living in the guts of mice differs depending on the time of day and that these fluctuations influence whether or not the mice became obese.
How does this happen? The major biological clocks in our body are set by light/dark cues. But the microbes that live in the gastrointestinal tract never see the sun, so how could they know the time of day? One part of the answer is the diet of their host. What, when, and how much the mice eat directly affects what nutrition is available to their microbes.
Leone and Chang’s 2015 experiments fed one set of mice a regular, low-fat, high-fiber mouse chow and another set a high-fat diet. Perhaps not too surprisingly, the mice on the high-fat diet gained much more weight.
When the team examined both the mouse fecal matter and contents of their digestive systems, they found starkly different microbial composition between the two groups. Surprisingly, in the mice fed the low-fat diet, the types of bacteria changed in abundance and function over the course of 24 hours, and so did the waste products they put out, with levels rising and falling depending on the time of day. In the mice on the high-fat diet, the bacterial balance varied much less, as did their waste products, sending a steady stream out to the liver, one of the main organs involved in metabolizing fat.
Perhaps the microbes on the high-fat diet lost track of time and confused the rhythm of the liver? Or was it the liver that was somehow telling the microbes what time it was? And how do the oscillations in microbial populations influence metabolic diseases, such as obesity and type 2 diabetes? These are the questions that Katya and Dr. Leone’s team are seeking to answer.
Modern life—with its electric lights, shift work, constantly available food, and quick and easy international travel—assault our biological rhythmicity, the sleep/wake cycles developed over eons of evolution. Circadian disruptions are associated with higher rates of metabolic disorders, increased blood pressure, high blood sugar, abnormal cholesterol levels, obesity, and elevated risk for heart disease, stroke, diabetes, and even some cancers. Maybe understanding and being able to manipulate the 24-hour variations of our microbial tenants can help prevent some of these outcomes.
And so Katya continues to visit the lab at all hours of the day and night, observing how microbial populations are expanding and contracting, digesting their host’s food and spitting out waste products, in an effort to communicate with the host that provides their habitat. Each time Katya’s alarm sounds in the middle of the night and she flips on the lights, perhaps her own microbes are startled out of rhythm in reaction to their host’s strange and unexpected behavior, altering their own behavior in response.
Katya says she knew what she was signing up for when she chose this research, but she finds working on such a fascinating problem worth the stress on her own circadian rhythms. Her hope is that studying these mice and their bacteria carefully may provide powerful knowledge that will help us restore and maintain circadian rhythms and promote wellness.
by Elise Wachspress
Peripheral artery disease (PAD), the narrowing of the blood vessels in the body outside the heart and brain, affects more than 2 million adults in the United States.
PAD occurs when plaque—an amalgam of fat, cholesterol, calcium, and other substances—builds up on the walls of the arteries to the arms and legs. These corroded “pipes” can restrict or even stop blood flow, particularly in the legs and feet.
The person with PAD may feel no symptoms, but many begin to notice that walking or climbing stairs causes leg pain or numbness which stops on resting. The skin on their feet and legs may look pale, blue, or shiny, and nail and hair growth often slows or stops completely—all indications that oxygen and nourishment are not getting where they need to go.
Over time, people with PAD have increasing difficulty with walking; they are more likely to lose their independence, with major impact on quality of life. Those with very advanced disease may develop sores on the feet and legs, which often heal slowly, or not at all. They are also at risk for problems in the arteries in the heart (coronary artery disease) and in the brain (cerebrovascular disease). Because of the strong connection between plaque in the legs and other parts of the body, PAD is one of the largest risk factors for both heart attack and stroke.
While the disease can start as early as age 40, incidence increases significantly with age. By age 70, more than ten percent of men and nearly as many women are dealing with PAD. For African Americans, the numbers are nearly twice as high.
Clinicians know that smoking, high blood pressure, high cholesterol, and diabetes can set up PAD, but not everyone with these risk factors develop the disease. Physician-scientists are beginning to understand that inflammation—the body’s complex immune response developed to protect against microbial pathogens or other irritants—is also a major player, causing plaque to develop inside the artery walls. But how to pinpoint the irritants that invoke this response? There are millions of kinds of microbes in, on, and around us that could be causing this immune response, but the vast majority—especially those in our gut—are essential for keeping us healthy.
University of Chicago scientists engaged in the fight against PAD are now focusing on the complex interplay of the immune system, inflammation, and the microbiome. Better understanding of the mechanisms involved may yield new tools and strategies against the disease and the heart attacks and strokes that can follow.
The researchers are coming at this problem from three angles: in the lab, in the clinic, and in the broader population.
- In the lab, they are feeding mice high-cholesterol diets to see how the microbial balance in each mouse affects the development of plaque in the arteries. By then transplanting fecal matter from healthy humans into mice with PAD, the team can see if changing the bacterial balance in these mice slows or stops disease progression.
- In the clinic, the team is tracking patients with serious PAD, those with wounds so severe they must have surgery to improve blood flow in hopes of preventing amputations. The team will track how the balance of bacteria, both in the patients’ gut and on their skin, affects blood flow to damaged tissues. By pairing extensive clinical data about these patients—including measures of inflammation in the blood and studies of genetic information —with information on the microbial populations present in each patient, the team aims to identify the balance of bacteria that promotes healing.
- In the wider population, the investigators aim to track 100 patients with PAD over two years. In this much broader group, they hope to discover the connections among each patient’s microbiome, immunological markers, imaging tests that measure arterial health, and, importantly, functional status—through a walking test—to gauge how the microbiome affects not only disease progress but also quality of life. The investigators will also track the participants’ diet and physical activity, two factors well known to influence the microbiome and PAD. Because UChicago Medicine has developed relationships with patients of such diverse ethnic, racial, and economic backgrounds, this study can yield findings to suggest new treatment strategies for a wide spectrum of individuals.
Each of these three studies will inform the others. This three-pronged approach is a classic example of how academic research drives better medicine: 1) find ways to get at the underlying biological mechanisms of health and disease; 2) translate that understanding to address the critical problems of the sickest patients, and 3) develop the knowledge that can help the broader population achieve wellness and the most satisfying life possible.
Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office
by Maggie Zhang
Graduate student in the Committee on Microbiology
Food allergies constitute a major public health concern. For an estimated 15 million Americans, exposure to common foods such as peanuts and milk causes negative, even deadly, immune responses. In recent years, food allergy rates among children have risen sharply, increasing approximately 50 percent between 1997 and 2011.
Why is the problem growing?
Let’s go back to the nineteenth century, when the findings of Louis Pasteur, Joseph Lister, and many others were converging on an essential function of the human body: immunity. The immune system was so named because it seemed to “exempt” the body from attack by microorganisms.
Given that microbial infection was thought to be the primary cause of immune reactions, it seems counterintuitive that people today—more free from infectious disease than ever—would be so heavily crippled by inflammation, the quintessential immune response. But decades of research reveal that a hyper-reactive immune system underlies autoimmune and allergic diseases, leading to severe conditions such as anaphylaxis.
Anaphylaxis can be life-threatening. In the same way that a healthy immune system reacts robustly to the intrusion of foreign toxins and microbes, a hyper-reactive one can respond just as dramatically to certain foods.
Despite the increasing prevalence of food allergies, current treatment options are problematic. Searching for new solutions, scientists have turned to the gut microbiome, the teeming ecosystem of microscopic organisms occupying our gastrointestinal system.
For some 800 million years, we have been building mutually beneficial relationships with the microbes that dwell within our gut. But over the past few decades we have drastically altered the environment that they call home, thanks to widespread antibiotic administration, extreme sanitary practices, and especially a high-fat, low-fiber diet.
Our dietary choices affect the species of bacteria that live within us. Our microbes eat what we eat, taking a small cut of our food in exchange for synthesizing nutrients that we need but cannot make ourselves. Many bacteria ferment what we cannot digest, such as the soluble fibers in vegetables, fruits, grains, and legumes. As a byproduct, they produce anti-inflammatory molecules called short-chain fatty acids.
Bacteria known as Clostridia are star performers. Cathryn Nagler, PhD, and her team have pinpointed Clostridia as key peacekeepers in the gut microbiome. Using mice born and raised in a microbe-free environment, Nagler’s group has demonstrated that introducing Clostridia blocks sensitization to food allergens. The microbes foster an anti-inflammatory environment within the gut in multiple ways, promoting the secretion of mucus along the gastrointestinal lining and producing a short-chain fatty acid called butyrate, which nourishes cells in the colon. These help to create a protective barrier in the gut, which prevents allergens—like peanuts and milk—from encountering pro-inflammatory immune cells.
These findings might soon change how we treat allergies. Nagler has teamed up with Jeffrey Hubbell, PhD, of the University of Chicago’s Institute for Molecular Engineering, to launch the start-up ClostraBio in order to commercialize novel food allergy remedies. Their aim is to develop novel, targeted treatments to restore the protective barrier naturally provided by peacekeeper microbes.
For centuries, we have appreciated the protective functions of the immune system against microbial attack. We have memorialized the contributions of Pasteur and Lister in everyday words like pasteurization and Listerine®, concentrating on the harmful bacteria that we must eliminate to remain healthy.
But in fact, only about 2 percent of all microbes are pathogenic—the rest are neutral, beneficial, or even essential to our well-being. While there is no doubt that modern sanitary practices have reduced the scourge of infectious disease, we have come to understand that though “bad” microbes can cause disease, “good” bacteria can also prevent it.
Just as plants depend on microbes to extract vital nutrients from the soil, scientists now hypothesize that animals only achieved mobility when we learned to carry within our bodies the microbes necessary for our survival. Maybe it’s high time for us to appreciate the importance of our symbiotic pact with the microbes that helped make us who we are today.