Oct 16, 2019 | Microbiome
by Elise Wachspress
Relationships. Trust. Engagement. Leadership. A shared culture.
Often, a thriving community hinges on having a critical mass of members who reliably embody and stand up for these values. A core group that creates an environment where everyone—the weak, the hot-tempered, the shy, the energetic, the weirdos, and even the bombastic egotists—can all get along.
Yes, we are talking about your microbiome. And everyone else’s, for that matter.
Scientists who study the many dysfunctions of the human microbiome are entertaining the idea that gut—and systemic—health rely on a core group of bacteria whose “personalities” foster an environment where diversity can thrive long-term. These “universal colonizers” help smooth the inevitable challenges humans face: birth, development, sickness, even a wildly changing diet or variable climate. And that’s a good thing, because the human body has many different needs best served by a working balance of many different bacteria tunable to changing environmental conditions.
So maybe we should turn our attention from the inevitable “bad guys” who grab all the air time (Strep? Salmonella? Anthrax?) and try to figure out what kinds of bacteria can help the whole microbiome community work well together.
Thanks to research support from the Duchossois Family Institute, A. Murat Eren, known as Meren, is on the search for the foundational bacteria that set the stage for a balanced and happy gut flora. For this complex quest, he has pulled together a similarly diverse group of top citizens in microbiome science: Eugene Chang, MD, a specialist in inflammatory bowel disease; Bana Jabri, MD, PhD, expert in celiac; bioengineer and systems biologist Savas Tay, PhD; microbiologist Howard Shuman, PhD; evolutionary geneticist Luis Barriero, PhD; and epidemiologist Thomas Louie, MD, from the University of Calgary, a world expert in fecal microbiota transplant. (Yes, it is just what it sounds like.)
Identifying universal colonizers in an established gut community is challenging. How does one extract all bacteria living in one single gut environment and figure out which ones could thrive—and help others flourish—in any gut environment?
Meren’s first idea was to take a fecal transplant from one healthy donor, implant the microbiota in different recipients, and track how the bacterial populations change in different individuals. Initial analyses showed that while some of the bacteria colonized only one of their new hosts or none at all, some organisms were quite successful in multiple recipients.
These good colonizers also left their traces in individuals studied through the Human Microbiome Project (HMP), a National Institutes of Health initiative that collects microbiome samples from hundreds of healthy volunteers. But rather than zeroing in on all of the individual species in each sample—an all but impossible task with the available technology—the HMP painstakingly analyzes snippets of genetic code from whole communities of bacteria, generating tremendous amounts of data on the microbial mixtures in each of these volunteers.
This kind of communal sequencing, called metagenomics, has its limits. It’s like trying to recreate a recipe by analyzing all the chemical elements in a fully baked cake. It can work…sort of. With a great deal of user analysis and energy.
Following leads generated from metagenome studies, Meren’s team is working with some newer technologies, including a cutting-edge “long-read sequencing” approach which can look at much longer—and thus more uniquely identifiable—stretches of DNA. They also, thanks to Dr. Louie, now have access to a collection of potential colonizers much larger than their original “healthy patient #1.”
Even with the long-read sequencer, the work will depend on a lot of computational expertise. But Meren, whose group continues to hone anvi’o, an advanced, open-source analysis and visualization software that integrates many types of microbial data, has the team for the job. Meren’s leadership in creating anvi’o, a dynamic and unified work environment for data exploration, manipulation, and reporting, is empowering researchers with lesser bioinformatics skills to access and make use of many publicly available datasets, thus accelerating progress by the entire microbiome science community.
Now Meren and his team, especially graduate student Andrea Watson, senior research tech Karen Lolans, and post-doctoral scientist Florian Trigodet, PhD, are using their new long-read sequencing devices to zero in on some of the microbes who seem to have interesting stories to share. The aim is to identify the kind of microbial citizens who fosters a diverse gut community and thus helps their human hosts thrive.
Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office
Jan 25, 2019 | Microbiome
by Kate Dohner
“When you go to the forest, what do you see?” asks A. Murat Eren, whom everyone calls Meren.
While the trees are the most noticeable, it’s important to pay attention to what’s on the forest floor—shrubs, wildflowers, ferns, and mosses. Without them, Meren points out, there would be no forest at all.
Like the forest, the human gut contains a multitude of organisms—bacteria, fungi, and viruses—collectively known as the human microbiome.
‘If you can observe a forest after a fire, you can see how it renews,” Meren said. “It all starts on the forest floor, led by ‘pioneer’ species like grasses and shrubs.”
Similarly, Meren is studying the human microbiome after a period of disturbance to see which bacteria help return it to a healthy state.
For instance, when the balance of bacteria in the gut is disrupted, a bacterium called Clostridium difficile or C. diff can proliferate. While C. diff sometimes responds well to antibiotics, recurrent, resilient infections are not uncommon. In these instances, patients can benefit from fecal microbiota transplantation or FMT, the transfer of “good bacteria” from a donor’s stool to a recipient. Although FMT is successful in many cases, there are risks, including the unintentional transfer of problematic biological material, such as viruses.
“With FMT today, we essentially gather the entire contents of a healthy forest and dump that ecosystem into a disturbed forest,” Meren explained. “Though that may work, we don’t know how.”
Meren and his team are on the hunt for the specific bacteria that can set up a healthy environment in any distressed digestive system, especially for those battling inflammatory bowel diseases.
“The microbes we’re looking for are like the person who can talk to anyone at a party,” Meren said. “She’s happy anywhere and helps put others at ease.”
Collaborating with world-renowned clinical experts (including Thomas Louie and David Rubin), Meren and his team are studying fecal samples from people around the world to identify these versatile microbes. Using the advanced computational tools they develop, Meren’s team can compare and categorize bacteria found in a variety of people—from infants to adults, to those in industrialized countries versus places like Tanzania.
The goal is to not only advance our understanding of the trillions of bacteria that make up the human microbiome, but to track down the special characters that can make any microbial community thrive.
“We scientists often gravitate toward what is most abundant in an environment—a byproduct of our historical relationship with numbers and the methods we have to make sense of them,” Meren said. “As a trained computer scientist, I recognize that bias and always remind myself that function—how something contributes to its environment—is what we’re really after.”
Meren cites the role of police in society; though they make up a small proportion of the population, they are critically important to how communities function. So it may be with certain bacteria.
“Instead of investigating just any bacteria we find in healthy human guts, we are conducting a systematic study to find microbes that can help microbial ecosystems recover from distress,” Meren said.
The team has already identified some “microbial peacekeepers” and are continuing their search for more, building a comprehensive genomic and culture library to see how each microbe behaves in different experimental settings.
Ultimately, Meren hopes this work will lead to a targeted, reliable microbial therapeutic that will not only help those with C. diff infections, but also people with inflammatory bowel disease and other gastrointestinal problems.
“Although basic science is demanding and even frustrating at times, important insights will only emerge from this type of work. My group and I believe we are on the right track to finding the critical members that keep the microbial forest in our guts healthy.”
“There’s so much more to learn,” added Meren, “but here at the University of Chicago, we have the right tools to recognize and investigate fundamental questions and are surrounded by tremendous expertise in immunology, microbiology, and gastroenterology—collectively offering us a rare opportunity to transform medicine.”
Kate Dohner is a senior writer for the University of Chicago Medicine & Biological Sciences Development office.
Nov 2, 2017 | Microbiome
by Maggie Zhang
Graduate student in the Committee on Microbiology
In 1683, a Dutch merchant named Leeuwenhoek built his own microscope and focused it on some residue he found on his teeth. What he saw prompted him to fire off a letter to the Royal Society of London, describing the “animalcules” he realized were living in his mouth.
We now appreciate that these microbial creatures are everywhere on Earth, thriving even in hostile environments the likes of which other animals could never tolerate—underneath Antarctic glaciers, within bubbling asphalt lakes, inside hydrogen sulfide gas caves. Some, like Leeuwenhoek’s “animalcules,” grow just fine in the presence of oxygen; other “anaerobes” can’t tolerate air at all.
Bacteria are important members of every ecological niche. We like to give plants all the glory for producing the oxygen necessary for life, but photosynthetic marine and freshwater inhabitants actually produce half of the oxygen we breathe. Meanwhile, bacteria living in the soil are often model citizens, breaking down nature’s waste to obtain nutrients for themselves and recycling the rest into building blocks for new life. What’s more, the human gastrointestinal tract houses over three pounds of bacteria that break down our food and provide us with essential vitamins.
With the fundamental roles that microbes play in our daily lives, it’s important for us to understand them. But how do you physically and genetically dissect something so small?
Scientists initially solved this problem by growing individual strains of bacteria in rich broths to study their biological properties, including their DNA. Soon enough, they ran into a roadblock: less than 1 percent of the bacteria on Earth could be easily cultivated. Studying the other 99 percent was going to require some new tools.
Thus, the field of metagenomics was born. Metagenomics technologies allow us to directly sequence the entire genetic contents of all microbes living within a habitat.
Unfortunately, sequencing the collective genetic makeup of even a 2,000-member community means several million DNA fragments. Although accurately piecing them back together into coherent genomes provides essential insights to microbiologists, the task is not much different than simultaneously assembling 2,000 jigsaw puzzles with all the pieces mixed into one huge pile.
Yikes.
A. Murat Eren, PhD—known to colleagues as Meren—and his team at the University of Chicago are at the frontier of developing the computational tools necessary for this daunting task. They have created several flexible, open-source software packages that allow users to dig deep into their data while retaining command of their analysis. These tools enable scientists to reconstruct novel microbial genomes from environmental samples, study their evolutionary relationships to other organisms, and investigate their abundance and distribution, as well as their functions. Collectively, the approach can tell us a lot about the biological traits important for a given microbe to survive and promote various environmental conditions, including health and disease.
In 2015 Meren and his team launched anvi’o, an advanced analysis and visualization platform. Using this software, scientists can ask a wide range of questions about the metagenomes they are studying through a highly intuitive, fully customizable interactive interface. The team has produced many highly comprehensive tutorials for users.
Anvi’o has already been cited by more than 50 publications, ranging from studies characterizing the human microbiome to articles debating the origins of humankind. Meren and his team make the software freely available online, for researchers all over the world.
At UChicago and affiliated labs at the Marine Biological Laboratory in Woods Hole, Massachusetts, and at Argonne National Laboratory, Meren’s tools are helping colleagues re-envision the future of microbiome research. Scientists are using the tools to study the use of antibiotics during pregnancy, fight serious infections, understand gut inflammation, and even survey oral “animalcules” much like those Leeuwenhoek saw in his mouth centuries ago.
This research would be impossible without scientists like Meren who also excel in computational technologies. With outstanding tools at the centerpiece of the efforts, these collaborative efforts will help us gain knowledge about the microbiome, which will improve health for millions.
As it has been through eons of human history, scientific discovery and tool development are like the chicken and the egg, totally dependent on each other. But Meren and his team put the scientific chicken first: “Although the inherent link between the tool and thinking will continue to bind them together, we believe it must be mostly the intellectual curiosity that drives the direction of science, and not the comfort of what is available. We intend to maintain our flexibility, and let the incoming questions shape and re-shape our software.”
