Mar 26, 2018 | Food Allergies, Microbiome
by Elise Wachspress
There was a time when many people thought that unlocking the genetic code would help us easily identify how diseases arose and better strategies for treating or preventing them.
And that was true for the very few diseases precipitated by individual genes, like cystic fibrosis. Single-gene diseases, however, are fairly uncommon, because over time, especially when they interfere with reproduction, natural selection has been pretty effective in weeding them out of the “gene pool.”
Most diseases are “complex,” involving the contribution and interactions of many genes. An explosion of genetic studies over the past couple of decades suggests most genes contribute only a small degree of disease risk. Thanks to the redundancy built into the human body through eons of evolution, those who carried one or even several “disease genes” would likely never develop the disease.
And even those at very high genetic risk were often disease-free. Researchers began to suspect that some kind of environmental trigger was necessary to activate some disease mechanisms—putting us right back at a (much more complicated) version of the “nature vs. nurture” dilemma.
Environmental triggers can be hard to recognize or assess. Methods for evaluating air and water quality, better food labeling, even sophisticated wearable trackers are helping us identify some potential environmental factors, but there are many others we might not even have considered.
Disease caused by microbes: The other side of the coin
Long before genetic testing, we knew that exposure to certain viruses and bacteria also caused diseases, often independent of our genetic makeup. Polio, measles, rubella, and others were shown to be caused by a single type of microbe, like some diseases were caused by single genes. Again, this simplified the strategy for solving these: scientists developed vaccines, a major medical success story.
Now it is clear that some diseases arise from combinations of bacteria—or combinations of genes and bacteria. Like any puzzle, the more “unknowns” involved, the more complex the problem becomes.
Celiac disease is one very complex problem.
A (painful) gut reaction
Estimated to affect one in 100 people worldwide—two-and-a-half million in the U.S. alone—celiac is a serious autoimmune disorder that damages the small intestine, causing diarrhea, fatigue, weight loss, anemia, and sometimes an itchy, blistering rash. With celiac, the gut can no longer effectively absorb nutrients; in children, the condition can significantly retard growth.
Initially, celiac causes this damage only in the presence of gluten, found in wheat, rye, and barley. Unfortunately, since these grains have sustained humans for millennia, gluten is ubiquitous, not just in food, but also vitamins, hair and skin products, even toothpaste. For those with celiac, avoiding gluten imposes a heavy burden, and reading labels becomes a family sport. Indeed, it is common to find whole families suffering from the condition, as those with a parent, child, or sibling with celiac have a risk as high as one in ten of developing the disease. And for 40 percent of adults whose systems are already damaged, even avoiding gluten allows for only a partial recovery.
Scientists have pinpointed two genes associated with celiac, but even if you have both, your likelihood of developing the disease is only 3 percent. Bana Jabri, MD, PhD, and her team at the University of Chicago were convinced there must be some other trigger involved. Because celiac is an autoimmune disease, they thought a microbe might be a likely candidate.
In studies of both mice and humans with “celiac genes,” they found that a reovirus infection, which causes no other symptoms, could break the body’s ability to tolerate gluten and initiate the pathological celiac response. Thus, it likely takes genes coupled with exposure to a particular virus to trigger the autoimmunity—one reason why incidence even within families is lower than might be expected.
Preventing celiac—and perhaps other diseases
This information gives us new potential strategies for gaining control over the disease. Since children lose their maternal antibodies against reovirus around six to nine months of age, introducing gluten to a baby’s diet outside this window might reduce the chances of getting celiac. And vaccinating children at genetic risk against the virus before they first eat gluten might also keep them disease free.
On a scientific level, this study has broader ramifications. It demonstrates that a clinically silent virus—not a usual suspect—can cause a lifelong, pathogenic inflammatory response to an otherwise harmless substance. So environmental factors that seem innocuous can, in combination with genes or other factors, cause some unexpected and serious outcomes. Like a recipe or a team, it’s all in the mix.
As in so many cases, basic science research like Jabri’s provides broad and surprising insights into not just one particular disease or drug, but how our bodies work as a system. It is these kinds of discoveries that can change our whole approach to health and disease.
There is a simple blood screening available for celiac disease. You can schedule an appointment with the University of Chicago Celiac Disease Center at 1-888-824-0200.
Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office
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
Dec 6, 2017 | Microbiome
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
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.
