Vanderbilt Institute for Infection, Immunology and Inflammation

The composition of the human microbiome, a complex ecosystem of microorganisms, plays a crucial role in lifelong health. Little is known, however, about the detailed molecular mechanisms linking health status to the microbiome of the gut, for example.

To investigate the interaction between diet, the microbiome, and the set of small-molecule chemicals (“metabolome”) produced by these organisms, Jane Ferguson, PhD, and colleagues analyzed the diet, and profiled the microbiome and metabolome of 136 healthy subjects.

Their data suggests that gut microbiome composition influences how diet is metabolized, potentially impacting host health by modulating specific metabolites and their downstream signaling pathways. For example, intake of plant-derived nutrients and artificial sweeteners was associated with differences in circulating metabolites, particularly bile acids, depending on the microbiome composition.

The group’s findings, published in the journal Frontiers in Genetics, suggest that gut microbiome composition modulates how dietary nutrients are metabolized, with potential downstream consequences on metabolic health.

This research was supported by an American Heart Association Scientist Development Grant and an award from the Vanderbilt Digestive Disease Research Center (supported by NIH grant DK058404).

Dr. Jim Cassat is an Assistant Professor of Pediatrics and Pathology, Microbiology, and Immunology and in the Division of Pediatric Infectious Diseases. He is also an Associate Director of VI4.

His lab’s research focuses on host-pathogen interactions during invasive bacterial infection, with a special emphasis on understanding how infection and inflammation perturb musculoskeletal cell biology.

The Cassat Lab has developed a variety of tools to understand how bacteria and inflammation trigger changes in bone biology, including a murine model of Staphylococcus aureus osteomyelitis, high-resolution 3D imaging of bone remodeling, and cell culture models of osteoblast and osteoclast proliferation/function.

They graciously let us take some photos of them, in the lab, and answered our questions, beginning with "What’s going on in your lab that we should get excited about?"

Dr. Cassat responded, "Everything! At the core of our lab, we are interested in understanding how cells in complex tissues sense and respond to bacterial pathogens and the microbiota, and how these responses activate the immune system or alter tissue homeostasis. We have chosen more specifically to study bone infections (osteomyelitis) as a paradigm for understanding how microbes and inflammation alter resident cells. Bone is such an amazing tissue. Resident cells are constantly remodeling our bones to ensure that they remain healthy. In fact, it is estimated that our whole skeleton is replaced on average every 10 years!" Our spotlight interview continued from there.

Cassat Lab, L to R: Chris Peek, Jacob Curry, Laura Fulbright, Jenna Petronglo, Aimee Wilde, Caleb Ford, Jim Cassat

What is something that makes your lab team or your research program really special?

I think our group is special because we are spanning so many scientific fields: immunology, microbial pathogenesis, microbiome sciences, bone cell biology, infectious diseases, epigenetics, etc. The only way this works is to have trainees that are incredibly creative and willing to get out of their comfort zone. I have been extremely fortunate to have such an amazing group in my lab.

What is one topic in your field that you are excited about right now?

With the rise of antibiotic resistance, I am particularly excited in deploying local or targeted therapies to treat invasive infections. Bone infections often require surgery, so our group and many others are thinking about how we can alter the efficacy of antibiotics, improve tissue healing, and activate effective immune responses with local delivery of compounds. In the age of 3D printers, people are getting quite creative with building custom drug delivery systems!

Are there any trends in your field that you think people should be aware of (good or bad)? What topics do you think we will be talking about in 5 years? 10 years?

I am really optimistic about our field in general. It is such an exciting time to be a microbiologist. I think in the next 10 years we are going to have an unprecedented appreciation for the functions of bacteria that live on or in our bodies, rather than just measuring the abundance of these microbes. As an infectious diseases doctor, I am also particularly thrilled that we are beginning to understand the long-standing effects that antibiotics have on our health. I think this data helps us and the public to understand the risk/reward of using antibiotics and encourages stewardship.

What do you think has changed since you've gotten into your field?

When I entered the field of bacteriology, there were only a few published bacterial genomes for clinical isolates of the pathogens I study. Currently, we have more genome data then we know what to do with. I think this is where it becomes critical for us to learn how to use public data repositories to ask questions without completely re-inventing the wheel.

What's your favorite thing about working at VI4/Vanderbilt?

Vanderbilt is my dream job. We are the best-kept secret in microbiology / microbial pathogenesis. With the advent of VI4, we are building an incredible community of researchers across many different disciplines to study infectious disease, immunology, and inflammatory disease. I particularly enjoy that in the same day, I can see patients that have overcome a serious infection, study that same infection in models in my lab, and then hear talks about the next generation of antibiotics that might work even better to treat the infection. I also really enjoy interacting with people outside of my field and using some of the amazing technologies that you can only find at Vanderbilt. A great example of this is our ability to image host-pathogen interactions with unprecedented resolution thanks to resources in the VUIIS and MSRC.

How/When did you know wanted to become a scientist?

I actually wrestled with becoming either a physician or scientist or physician-scientist for many years! It wasn't until I had tried both that I truly appreciated the positives of both jobs. I also didn't realize how much I would enjoy being a PI until I had my own lab. There are parts of this job that you really can't experience/enjoy until you complete all of the training.

What advice you'd give to a new graduate student?

Regarding the question about my own career, I would encourage graduate students to keep an open mind about careers. Even though we can observe other PIs or mentors, you really can't appreciate how incredible being a scientist is until you are through the training process. It is completely okay to have doubts along the way! You may just need to keep pushing to get to the good stuff.

Aimee Wilde,
Graduate Student - Department of Pathology, Microbiology, and Immunology

Christopher Peek,
Microbe-Host Interactions Medical Scientist Graduate Training Program

Engage with Dr. Cassat:  

Dr. Meena Madhur is an Assistant Professor of Medicine and Molecular Physiology and Biophysics. She is also an Associate Director of VI4.

Her research focuses on how T cells and T cell-derived cytokines promote hypertension and renal/vascular dysfunction. Her lab was the first to demonstrate a critical role for the lymphocyte adaptor molecule LNK in hypertension and aortic disease. They also defined mechanisms by which the pro-inflammatory cytokine interleukin 17A (IL-17A) contributes to hypertension and renal sodium retention.

We visited the lab on a dreary February morning. Perched high above the medical center in MRBIV, where you can gaze down at all of campus and downtown Nashville beyond, it's a fantastic setting for the important research being conducted there. We started by greeting everyone and taking a few pictures, then we sat down to talk. We asked, "What’s going on in your lab that we should get excited about?"

She explained "We're using single cell approaches in human blood to perform deep immunophenotyping of human hypertension. We've also uncovered a new critical role for a subset of T cells called T follicular helper cells in hypertension."

Our spotlight interview continued from there.

Madhur Lab: Matthew Alexander, Dr. Meena Madhur, Duncan Smart, Yuhan Chen (visiting MSTP student from China), (not picured: Bethany Dale).

What is something that makes your lab team or your research program really special?

The collaborative nature and the fact that we all work together as a team.

What is one topic in your field that you are excited about right now?

Using immunomodulatory agents as an adjunct treatment for hypertension.

Are there any trends in your field that you think people should be aware of (good or bad)? What topics do you think we will be talking about in 5 years? 10 years?

1. The ability to perform multidimensional flow or mass cytometry, particularly combined with single-cell sequencing and T cell or B cell receptor sequencing, is highlighting the complexity of the immune system and the fact that perhaps no 2 immune cells are the same. Our artificial classification of T cells into 5 major subsets is oversimplified. I think we are starting to understand the true diversity and plasticity of these cells.

2. It is really exciting to me that we uncovering a whole new role of the immune system in homeostatic functions like blood pressure regulation, renal salt and water handling, and vascular function. In addition, aberrant immune activation is a hallmark of metabolic diseases such as obesity, diabetes, and hypertension. Thus, the immune system has this whole other function independent of fighting pathogens or cancer.

What do you think has changed since you've gotten into your field?

A greater appreciation of the role of the immune system in hypertension and hypertensive end-organ damage. Ten years ago, most people didn't realize that hypertension is an inflammatory disease.

What's your favorite thing about working at VI4/Vanderbilt?

The collegiality, willingness to collaborate and form multi-disciplinary teams, and shared research interests.

How/When did you know wanted to become a scientist?

12th grade. I attended the North Carolina School of Science and Mathematics and had the opportunity to spend a few hours a week in a research lab at Duke University. That is when I realized I loved science.

What advice you'd give to a new graduate student?

There will be many setbacks and rejections in your future but don't forget why you started down this path.

Duncan Smart,
Molecular Physiology & Biophysics Graduate Student

Madhur Lab Christmas Party 2016: Bethany Dale, Allison Norlander (graduate student who graduated in 2017), me, Fanny Laroumanie (post-doc fellow who finished in August 2018).

Matthew Alexander, M.D., Ph.D.
4th Year Research Fellow

Engage with Dr. Madhur:  

Dr. Hadjifrangiskou is a microbiologist in the Departments of Urologic Surgery and Pathology, Microbiology, and Immunology; she is also part of our VI4 Leadership Committee as an Associate Director. Her lab studies the ways in which UPEC can sense changes in its surrounding environment and thereby accordingly alter its behavior as it transits through different host and environmental niches. They are also interested in the factors contributing to and the hierarchy of biofilm formation, aiming to define specific stages in the pathway that can be targeted therapeutically. Maria is heavily involved with VI4 outreach activities, specifically MEGAMicrobe, and is working on the very exciting MicroVU initiative.

Hadji Lab Pizza Party with undergrads

VI4: How long have you been at Vanderbilt?

MH: Six years

VI4: Tell us something exciting happening in your lab at the moment.

MH: Two of my science "kids" passed their quals! Yay!! This has been the highlight of this month. It is amazing to see my students go through this right of passage and emerge confident and ready to pursue their scientific goals! On the research side, my lab studies different aspects of bacterial gene regulation. These days, we are particularly excited about how bacteria regulate complex processes like the formation of multicellular communities called biofilms. Biofilms formed during infection are extremely hard to eradicate, because the bacteria within are protected from antibiotic treatment by the presence of a self-secreted coating called the extracellular matrix. In my lab we are beginning to elucidate which members of the biofilm community are responsible for the generation of distinct matrix components and their specific placement within the biofilm. Understanding this division of labor has the potential to open up new avenues for targeting biofilm infections. We performing these studies on uropathogenic E. coli, which is the primary cause of urinary tract infections.

VI4: What is one piece of advice you'd give to a new graduate student?

MH: You have embarked on a journey. Don't loose sight of the shore, but do take the time and learn from each part of your journey. And remember that you are not in it alone!

VI4: What is your favorite lunch spot near campus?
MH: It's got to be Fido

VI4: What is the best thing to do in Nashville during the fall/winter?

MH: Find a new coffee shop and try their hot cocoa. This is something I like to do with my oldest daughter (we love hot cocoa!).

VI4: Peanut Butter: Crunchy or Smooth?

MH: I'm European (from Cyprus originally) so I prefer hazelnut spread!

VI4: Favorite Superhero and why?

MH: Wolverine and Gamora bc they are often misunderstood.

VI4: What/who are you reading right now?

MH: Lois McMaster Bujold - Palladin of souls

Maria's face-painting has been a hit at MEGAMicrobe for two years
Here she is at MM2018

Hadji Lab booth at MEGAMicrobe 2018:
Biofilm Cities

Maria and her daughter Thea at MEGAMicrobe 2017

Engage with Dr. Hadjifrangiskou:  

Dr. Bordenstein is a biologist in the Departments of Biological Sciences and Pathology, Microbiology, and Immunology and we are fortunate to have him on our Leadership Committee as an Associate Director. He is also the founding director of the Vanderbilt Microbiome Initiative and worldwide science education program Discover the Microbes Within: The Wolbachia Project. His laboratory studies the functional, evolutionary and genetic principles that shape symbiotic interactions between animals, microbes, and viruses as well as the major consequences and applications of these symbioses to humans.

VI4: How long have you been at Vanderbilt?

SB: Ten years

VI4: What is one topic in your field that you are excited about right now?

SB: Microbiomes are the totality of microbes in and on an environment, including our bodies and those of other organisms. One of the major questions in the microbiome field is what explains variation in microbiomes….between people, within people across time, or between different types of organisms, such as a wasp versus a fly, or a mouse versus a human? There are surprisingly few bona fide trends to point to as the microbiome field is still quite young and resolving its best practices. What I am excited about are two emerging trends that appear to hold across multiple studies, including our own. 

First, human ethnicity is repeatably linked to microbiome variation across body sites. In the guts of Americans, there appears to be repeatable variation in microbes across different ethnicities, and we think this could be quite important to personalized medicine approaches involving the microbiome. 

Second, microbiomes across animals are not just randomly assembled. They vary extensively and we and others often observe the trend that animal evolutionary history is predictive of microbiome differences between animal species. What this seems to indicate is that components of the animal genome that change rapidly may regulate why one species has a different microbiome than another. Moreover, in some cases, we are finding that the microbiome difference are quite important. They affect the development and survival of these animals. Filtering the right microbiome from the environment may be very important to the function of animals. 

VI4: What’s going on in your lab that we should get excited about?

SB: Oh the tangled web that Nature weaves....Sexual reproduction in animals can be hijacked by bacteriophage genes that reside in intracellular bacteria.

VI4: What’s your favorite day trip from Nashville?
SB: Easy…to boldly go anywhere that has good Hot Chicken.

VI4: Pumpkin Spice Latte, yes or no?

SB: No

VI4: How/When did you know wanted to become a scientist?

SB: Great question. I always like to ask this one to my colleagues. The answers vary quite a bit. We all have our own path to science.  My father was an engineer, and my mother was a lab technician for the hospital, so perhaps their professions had some influence. We also watched Nature shows on the weekends; and I scored a big win with the classic fly eye mutant experiment in high school! So perhaps these experiences were indicators of the decision to come. It was my sophomore year in college. I was en route to major in biology as a pre-med student. But then a course in Evolutionary Biology hit me over the head and changed my trajectory, forever. I never turned back. I fell in love with a course for the first time. Immediately, I wanted to know more..to know what I could do with a major in Evolutionary Biology. I entered a lab as an undergraduate researcher and caught the bug of being a full-time labbie studying animal-Wolbachia interactions. So, immersion research was critical to my future. I’m so enthused that Vanderbilt has placed immersion research as part of the quintessential undergraduate experience. 

Engage with Dr. Bordenstein: