Jan 26, 2018 | Microbiome
by Maggie Zhang
Graduate student in the Committee on Microbiology
About one1 in 10 people will develop a kidney stone during their lifetime. The risk is even higher for those suffering from high blood pressure, diabetes, and obesity. And the incidence of forming kidney stones—a process known as nephrolithiasis—is on the rise: from 3.8 percent to 8.8 percent over the last four decades.
The problem is not new. Kidney stones were found in an Egyptian mummy dating back to 4800 BC. Indian texts from around 600 BC recommend a vegetarian diet and urethral syringe of medicated milk, clarified butter, and alkalis. If these failed, surgery was the final treatment.
In a broad sense, our approach to treating kidney stones has remained unchanged over two thousand years later. Even now, patients who develop stones will be advised lifestyle interventions, such as drinking more water and changing to a special diet.
But these changes are often unsustainable and sometimes simply insufficient. Patients who develop one stone have a 50 percent chance of forming another within five to seven years, as well as increased risk of chronic kidney disease, which can eventually lead to kidney failure and the need for dialysis or transplantation. Although advances now allow for less painful and invasive surgeries to remove kidney stones, we’re still not much better at preventing them in the first place.
Hatim Hassan, MD, PhD, and his team at Oxalo Therapeutics, a University of Chicago-based startup, plan to prevent kidney stones in the first place.
The source of these painful deposits is oxalate, a chemical naturally present in the human body and found in many foods, such as spinach, beets, and nuts. Though it is normally eliminated as waste through the kidneys, when too much oxalate enters the urine, it can combine with calcium to form the stones.
Research from Hassan’s group has shown that factors secreted by the intestinal bacterium Oxalobacter formigenes can provide a natural solution. The bacteria consume the oxalate in the large intestine and thus reduce what is passed on to the kidneys, reducing the risk of stone formation. Introducing live bacteria directly into the intestines and maintaining them there, however, remains problematic. The team at Oxalo Therapeutics is working on proteins and peptides generated by Oxalobacter that can help transport oxalate from blood into the large intestine and thus reduce the amount entering the urine.
Last December Oxalo presented their ideas at the University of Chicago Innovation Fund finals, managed by the Polsky Center for Entrepreneurship and Innovation. The team—Hassan and Chicago Booth student Yang Zheng—won $250,000 in venture funding to develop a first-in-class therapeutic to treat kidney stones. The Innovation Fund provides critical early capital to push groundbreaking ideas out of the lab and into solutions that can improve the lives of many.
Hassan’s group had already shown that substances derived from Oxalobacter could stimulate oxalate transport by human intestinal cells grown in culture. They had also demonstrated that these substances could decrease urinary oxalate levels in mice with high levels. Thanks to Innovation Fund support, Oxalo Therapeutics will now develop promising Oxalobacter-derived proteins and peptides aimed at reducing oxalate levels in human urine.
The hope is that a daily oral pill made from optimized versions of these proteins and/or peptides will eliminate the problems involved in administering live bacteria. This preventive drug offers significant advantages over treatments, not the least of which is a much more natural method of helping people stay free of kidney stones.
Long before ancient Indians first described their remedies, trillions of bacteria lived in harmony with the human body, providing countless indispensable functions to support human health. Our co-existence with them predates medicine by over two million years. For millennia, the microbes inside us have been experimenting with the best ways to survive, which depends on keeping their homes—us—healthy as well.
Greater understanding of our internal microbial community can help us treat and more importantly prevent disease. Part of the job of the Duchossois Family Institute is to get the right microbes and their products into the people who need them.
Oxalo Therapeutics is on their way to doing just that.
Photo (cropped) by Jakupica/Wikimedia Commons
Jan 4, 2018 | Medicine, Microbiome, Uncategorized
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
Dec 20, 2017 | Microbiome
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
Nov 29, 2017 | Microbiome
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.
Nov 15, 2017 | Food Allergies, Microbiome
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.
