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News roundup: March 2020

News roundup: March 2020

Chicago doctor whose blunt speech resonated with millions has another message
In a video PSA, UChicago Associate Professor Emily Landon asks people to stay home and help flatten the curve. (NBC 5 Chicago)

Argonne National Laboratory uses supercomputers to take on coronavirus
Stephen Streiffer, deputy laboratory director for science at Argonne, discusses the use of supercomputers to combat the coronavirus. (CBS Chicago)

Here’s where bacteria live on your tongue cells
UChicago’s Marine Biological Lab scientist Jessica Mark Welch maps how bacteria are grouped together on human tongue cells. (Science News)

A new, shelf-stable film could replace needles and improve global vaccination rates
This film requires no refrigeration and can be given by mouth. (Yahoo News)

How male and female immune responses differ
Sex-specific traits of the immune system, especially in the fat cells of the body, may explain the differences between the genders in their susceptibility to certain diseases. (Futurity)


Mighty mouse (models) to the rescue!

Mighty mouse (models) to the rescue!

by Elise Wachspress

If you are a subscriber to the DFI blog (Easy! Free! See the box to the right!) or a regular reader, you’ve seen and heard a lot about mice. So much of what we have learned thus far about the interplay between the microbiome, immunity, and genetics comes from experiments with these little animals. Why?

Mice have historically been used in a lot of biomedical research. They are small and comparatively less costly to raise and house than other animals, reproduce quickly and often and have a short life span, thus studies can be conducted relatively quickly. Researchers have learned a lot about how to manipulate mice’s genetic inheritance, so the critters can make good models for some human diseases where we know the specific genes at work.

Mice have been especially useful for studying the effects of the gut microbiome, in diseases from obesity to cancer. Their intestinal track is similar to ours, with comparable anatomical features and many of the same kinds of cells—although there are some important differences.

Unlike humans, mice have a fore-stomach that holds food before digestion, creating an entry to the system much less acidic than our stomachs. Our intestines have more folds and a thicker mucus layer—an environment more friendly for bacteria looking to set up homes. The cecum, a part of the large intestine, is relatively larger in mice, offering a better place for microbial fermentation of indigestible fiber. And humans have an appendix, a place for bacteria to hang out when disaster (like diarrhea or other intestinal problems) strikes, the better to repopulate the intestines when the crisis is over.

Despite these caveats, mouse models have proven their value in gut microbiome studies, helping researchers understand some of the complex mechanisms that underlie diabetes, celiac, inflammatory bowel and others diseases. Mice offer huge practical advantages: researchers can readily control their diet, treat them with antibiotics, and transplant them with bacteria—unlike with humans, who are, none-the-less, the ultimate beneficiaries of these experiments.

Of course, transplanting mice with bacteria only works if the mice start out with either no bacteria or very well-characterized bacteria, so researchers can parse out the effects caused by the new microbial additions. After birth, the mice must continue to live their entire lives in an aseptic (no new bacteria) environment—and stay far away from others, as mice have a known habit of eating their cagemates’ poop. Managing this complicated endeavor is where Betty Theriault, DVM, and UChicago’s Gnotobiotic Research Animal Facility (GRAF) come in.

The word gnotobiotic is a mashup of two Greek roots, “known” and “alive.” The premise for the gnotobiotic facility is to understand exactly what microorganisms are alive in each mouse. The GRAF specializes in managing animals free of all organisms (bacteria, viruses, fungi and parasites) and gnotobiotic animals—those who have been intentionally inoculated with a well-defined set of microbes.

Established in 2007, the GRAF is now one of the largest and most successful academic gnotobiotic mouse facilities in the world, with over 90 flexible isolators. Theriault and her crew of 13 dedicated, full-time personnel maintain hermetically sealed, individually ventilated cages on rack systems—think sterile condominium units for mice—which assure each mouse is living with only the microbes it came in with. In 2017, the GRAF was named international laboratory animal team of the year award; you can take a three-minute tour of their approach on YouTube.

Theriault is a veterinarian with three decades of experience working with a broad spectrum of animal species in a variety of settings. After vet school at the University of California, Davis and an internship in Small Animal Medicine and Surgery at Penn, she came to UChicago to advance transplantation immunology research. Although she left for a while to pursue private practice, she returned to UChicago fifteen years ago to develop the GRAF, which is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International, a private nonprofit that promotes the humane treatment of animals in science. (You can watch Theriault present on the challenges involved in setting up a gnotobiotic facility at the National Academies of Sciences, Engineering, and Medicine in 2017).

So what’s the future of gnotobiotic research? Studies have shown that germ-free mice successfully support complex fecal microbiota from humans in their gastrointestinal tracks. Researchers anticipate mouse models will be increasingly useful in predicting patient outcomes to therapeutic interventions or informing personalized approaches to patient care.

While knowledge gained from animal models is not always directly transferable to humans, UChicago’s Gnotobiotic Research Animal Facility is helping us understand many more of the mechanisms at work between our gut microbes and our health, providing insights that may help us live longer, healthier lives.

Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office


The road to the brain: Through the gut?

The road to the brain: Through the gut?

by Elise Wachspress

If you read the news—or this blog—then you know that researchers are identifying more and more interactions between the brain and the gastrointestinal tract. Some of these linkages are directly neurological; many others are chemical interactions caused by digestive byproducts of the bacteria in our guts.

A large group of scientists from the University of Chicago (led by Issam Awad, MD), the University of Pennsylvania, and universities and academic medical centers from New York to San Francisco and Australia to Germany have found another mechanism on the path from the gut to the brain—and with it, perhaps a new way to intervene in diseases that affect the most inaccessible organ of our bodies. Their report was the cover story of Science Translational Medicine this past November.

The story starts with decades of research on a rare condition, cerebral cavernous malformations (CCM). CCM causes enlarged, irregular clusters of capillaries, the tiniest blood vessels. CCM capillaries have abnormally thin walls, without the elastic fibers that make the vessels pliable. These irregularities, which make the vessels prone to lesions and blood leakage, can occur throughout the body. But they are by far most worrisome in the brain and spinal cord, where the leaks can lead to seizures, stroke, hearing or vision loss, even paralysis.

CCM is caused by genetic mutations in one of three different genes, but one of these is not like the others. Patients with mutations in the PDCD10 gene usually suffer much earlier, more severe health events, like brain hemorrhage.

A disorder with such disastrous outcomes linked so closely to single gene mutations encouraged researchers to develop mouse models for each of the three mutations. The models could help them discover the molecular mechanisms involved in each—especially what was different in the PDCD10 mice—and exploit what they learned to develop new treatments and preventive measures for CCM.

But examining the brain slices of the mice under the microscope was expensive and time-consuming. An Australian colleague noted that he had heard of instruments that could do x-ray microcomputed tomography on tiny subjects. Awad discovered only one in the entire Midwest, which happened to be in the basement of ivy-covered Culver Hall, one of the oldest buildings on the UChicago campus. Evolutionary paleobiologist Zhe-Xi Luo, PhD had acquired this microCT (now dubbed a Paleo CT!) to examine tiny, delicate insect fossils. A partnership was born, and, with Luo’s support, Awad’s team had a much faster way to assess precisely the amount of bleeding in each mouse brain and the correlation with various genetic, dietary or pharmacologic manipulations.

The investigators found that mice that developed disease did, in fact, share a characteristic microbiome. These bacteria produced a lipopolysaccharide—often called an endotoxin—on their outer membranes, a likely culprit in fostering disease progression. But the fact that the microbial communities were similar among all three genetic models indicated that it wasn’t the microbes alone that made mutant PCDC10 so much more virulent than the other two mutations.

The team moved on to test whether the PDCD10 mutation might cause some kind of rupture in the mucus membranes coating the gut, and there they found the smoking gun. The mutant gene did, in fact, attack the gut’s mucus layer, allowing the offending microbes access to the deeper tissues of the colon. With the integrity of the gastrointestinal tract compromised, bacterial byproducts could leak into the mice’s blood stream and be carried to the brain.

Awad’s team is currently extending this research in mice to patients with CCM. They hope to see how the microbiome can be used as a biomarker of disease and how targeting therapies to the gut might prevent brain bleeding. In the meantime, they think CCM patients might want to avoid polysorbate 80. They might also try any conditions or foods—or drugs—that foster mucus production, which might be helpful in preventing further degradation not only in the gut, but also the capillaries in the brain.

There are implications for the rest of us. The Awad team has found genetic anomalies in the aging brain similar to those in CCM. So what they learn about the mechanisms of this rare disease might also be used to prevent brain bleeding in the rest of us as we age. By carefully manipulating PDCD10 and the mucus layers of the gut, we may one day learn how to better care for what is arguably the most important and delicate organ in the body—the brain.

Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office


News roundup: January 2020

News roundup: January 2020

Happy New Year! A selection of health news from the University of Chicago and around the globe curated just for you.

Five things you can do to make your microbiome healthier
Fruits and veggies, exercise, and probiotics—yes—but also add resistant starch (like beans and potatoes, especially if refrigerated after cooking) and experiment with different fibers (including whole grains, legumes, and cruciferous veggies like broccoli, kale, cabbage, cauliflower, and bok choy) to maximize your microbiome. (The Conversation)

The difference between celiac, non-celiac gluten sensitivity, and gluten allergy
UChicago pediatric gastroenterologist Ritu Verma, MD, medical director of the University of Chicago’s Celiac Disease Center, explains the characteristics and treatment of each. (The Forefront)

Human health is in the hands of bacteria
Martin Blaser of Rutgers University writes about the dangers of antibiotics overuse and makes the case for a microbiota vault, to preserve ancestral microbes for future generations. (Time)

Installing air filters in classrooms can have large educational benefits
In the face of growing proof of impact of air pollution on cognition, researchers from New York University found that installing $1,000 air filters in a Los Angeles school affected by a massive gas leak raised a class’s test scores as much as cutting class size by a third. (Vox)

Exposure to diesel exhaust particles linked to susceptibility for pneumococcal disease
Streptococcus pneumonia, a common cause of pneumonia and meningitis, usually live harmlessly in the nose and throat of healthy people, but research shows diesel particulates reduce the ability for the immune system to keep these bacteria in check. (Science Daily)


Understanding the role of the microbiome in Alzheimer’s disease

Understanding the role of the microbiome in Alzheimer’s disease

by Helen Robertson

What is your biggest concern about growing old? A decline in physical fitness? A loss of independence? Or perhaps it’s the fear that your mental fitness might start to lose its edge?

For the 50 million people worldwide living with dementia, that last scenario is a reality. A dementia diagnosis comes with big personal, social, and financial consequences: the cost of care for someone living with dementia is reportedly higher than that of both heart disease and cancer combined.

The most common cause of dementia in the US is Alzheimer’s disease. Although its symptoms are well known—cognitive decline, neuroinflammation, and the tell-tale formation of amyloid plaques, the hard aggregation of proteins between nerve cells in the brain—the precise cause remains unknown, and there is no current cure.

As the world population continues to age, dementia is increasing. The need to uncouple its complex biological processes is urgent.

Sangram Sisodia, PhD, has spent the past three decades investigating just that. But in recent years his Alzheimer’s research has taken an exciting and unexpected focus: the gut.

Thanks to recent findings, many of them by research teams at UChicago, we have learned that the bacteria living in our guts can affect many aspects of health. Normally, our gut microbiome contributes to everyday wellbeing and immunity. But just like any other community, the composition of our microbiome can fluctuate on a near-daily basis. And when a shift in balance occurs, things can go awry.

Our intestinal microbes have a particular influence on immunity and neurological function, both important factors in Alzheimer’s. Those with the disease have also been found to experience a change in the character of their gut microbiome.

That’s where Sisodia stepped in.

Over the past few years, his team has been using mouse models of Alzheimer’s to understand how the composition of our gut microbiome might influence neurological inflammation caused by certain immune cells. They thought this inflammation could contribute to both the protein deposition and neurodegeneration in Alzheimer’s.

Sisodia’s research has already generated some interesting findings. His studies, published in Scientific Reports and the Journal of Experimental Medicine, showed that the long-term treatment of mice with broad-spectrum antibiotics reduced neuroinflammation and slowed the growth of amyloid plaques.

After treatment, the mice also showed significant changes in the composition of their gut microbial communities.  Some types of bacteria completely disappeared; others multiplied—suggesting bacterial diversity in the gut plays a role in the immune response during disease progression.

But only for male mice. In females, antibiotics actually increased the inflammatory response, with no change in brain plaques. With Alzheimer’s more prevalent in women than men, this gender difference in immune response clearly warrants more study.

Myles Minter, postdoctoral scholar in Sisodia’s lab who is now a research analyst at William Blair, wondered what might happen if one could prevent Alzheimer’s by treating it early—really early. He gave two-week-old mice pups antibiotics for just one week—which left lifelong effects on both their gut microbiome and amyloid plaque formation.

But this is no simple solution. UChicago neonatologist Erika Claud has shown how changes to the microbiome of premature babies can have a negative impact on neurological development, and Eugene Chang found mouse pups whose mothers were treated with antibiotics were more likely to develop inflammatory bowel disease.

Constantly treating individuals with antibiotics is not a realistic scenario, even for those with genetic predisposition for Alzheimer’s, but Sisodia is keen to investigate further. He has recently been awarded a grant of over $2,000,000 to continue his research into Alzheimer’s disease and immunity. The money comes from the Good Ventures project, involving Massachusetts General Hospital, University of Southern California, Northwestern University and Washington University, with total funding over $10,000,000. The hope is this collaboration can uncover mechanisms at play between our microbiome, our immune system, and Alzheimer’s disease.

This is just another example of how the microbiome offers keys for exploring new preventative and treatment approaches for healthy longevity. As Bette Davis once suggested, “Old age ain’t no place for sissies,” but maybe someday losing our mental fitness may not top our list of concerns about aging.

Helen Robertson is a postdoctoral scholar in Molecular Evolutionary Biology at the University of Chicago, with a keen interest in science communication and science in society.


News roundup: December 2019

News roundup: December 2019

A selection of health news from the University of Chicago and around the globe curated just for you.

Microbes living in the tons of plastics in the oceans
Jessica Mark Welch and colleagues at UChicago’s Marine Biological Laboratory at Woods Hole, MA, aim their new microscopy technique at microplastic samples from the ocean to characterize the extensive biofilms on ocean plastic. (Agro Ecology Innovations)

Staph vaccines likely to work better if administered earlier
Research by former UChicago faculty member Julian Bubeck-Wardenburg, now at Washington University in St. Louis, suggests that vaccinating infants before their first encounter staph, either just after birth or via their mothers during pregnancy, would likely generate a stronger immune response. (Futurity)

Microbial inequity
To the host of ways people experience inequity, add the microbiome: A University of Maine scientist argues that access to fibrous foods, parks, good air quality, other infrastructure affect the development of a healthy microbiome. (The Conversation)

UChicago faculty lauded yet again
Thomas Gajewski, MD, PhD, Abbvie Foundation Professor of Cancer Immunotherapy, is honored with the 2019 Award for Immuno-Oncology from the European Society for Medical Oncology (Healio)

Gut neurons are anti-salmonella warriors
Research from Harvard Medical School have found that nerves in the gut not only regulate the cellular gates that admit microorganisms, but actively boost the number of protective microbes there. (ScienceBlog)