02 Jul A chat with research scientist Evann Hilt, LUERECReading Time: 8 minutes
Evann Hilt is a young American scientist who has helped change the course of history. Working with an intelligent, tightknit group at the Loyola Urinary Education and Research Collaborative (LUEREC) in Chicago, USA, her work on the human bladder resulted in the 2014 ground-breaking discovery of the bladder microbiome—dubbed the female urinary microbiota (FUM). This discovery not only dispelled decades of incorrect assumptions that urine is sterile, but it also highlights fundamental flaws in urinary tract infection (UTI) diagnostic tests used throughout the world today. The existence of the FUM is forcing scientists, microbiologist and clinicians to re-think everything previously accepted about urinary tract health and disease, including what causes UTIs and how they are best diagnosed and treated. Evann’s important work now opens up life-changing possibilities for those living with UTIs and other urinary disorders. Although it could still be some time off, she anticipates her work will give clinicians new safe and effective non-antibiotic therapy options that will return the resident FUM to a healthy and harmonious state. You can read more about Evann’s exciting research in our 2018 interview.
(Above image: Dr Alan Wolfe and Evann Hilt analysing culture plates at the LUEREC lab, courtesy of LUEREC.)
Evann Hilt, can you tell us a little about your role with the Loyola Urinary Education and Research Collaborative (LUEREC) and how you came to be part of this progressive research group?
I am currently a PhD graduate student in Dr. Alan Wolfe’s basic science lab that is a part of the LUEREC group. I joined Dr. Wolfe’s lab during my Master’s program in 2012. My Master’s program required me to perform translational research and to have a basic science and clinical mentor. Dr. Wolfe was my basic science mentor while Dr. Paul Schreckenberger was my clinical mentor and both were a part of the LUEREC team.
You have been heavily involved in urinary microbiota research, and in 2015 you received the Loyola Graduate School Thesis of the Year Award in Biomedical Sciences for your work in bladder research. Can you tell us a little about your team’s ground-breaking discovery of the female urinary microbiota (FUM), and why you thought to look for bacteria in the bladder, which had traditionally been considered a sterile environment?
It started off when Dr. Wolfe, Dr. Schreckenberger and I were discussing what I should pursue for my Master’s project. Our group had just published the paper where we showed that we could detect bacterial DNA in the bladder of women with and without lower urinary tract symptoms. A major question at the time was, did the bacterial DNA represent live bacteria? The three of us were looking at the bacterial genera we had detected with DNA sequencing and Dr. Schreckenberger mentioned that it was possible to grow these organisms. It was then that we decided that my project would be to test if the bacterial DNA represented live bacteria by culturing a larger amount of urine under diverse growth conditions.
Can you explain the significance of these bacterial communities living in the urinary tract and what you think this means for on-going and future bladder research?
Bacterial communities living in the urinary tract has completely changed everything we think we know about the bladder because all the previous work was performed under the incorrect assumption that the bladder is sterile. On-going and future bladder research will need to take into consideration bacterial communities and their impact on the host.
It’s common for people to report UTI symptoms to their doctors, but if tests from the local lab comes back negative, they are told they don’t have an infection. Based on your new understanding of the bladder and the FUM, what does this say about our current diagnostic and treatment protocols for urinary tract infections (UTIs), and what are your thoughts on the continued reliance on these tests and how this impacts patients?
I am not a medical doctor but what I can say about the current diagnostic and treatment protocols is that they need to be improved. In my opinion, these diagnostic and treatment protocols work for patients who are truly suffering from a UTI by E. coli and a few other common uropathogens. But evidence from our lab, and others, is mounting that there are other uropathogens to consider, as well as bacterial communities that are in a disturbed or dysbiotic state. Diagnostic and treatment protocols must evolve to handle these types of patients. In addition, many of the organisms we are identifying may not be associated with harm.
Your team has developed a more sensitive culture method—the Expanded Quantitative Urine Culture (EQUC). Using the EQUC, your studies have repeatedly shown that standard urine culture (SUC) (used by clinical labs around the world to diagnose UTIs), have a 90 percent false-negative rate. That’s an alarming failure rate for a commonly used test. How realistic would it be for clinical labs to introduce more sensitive tests like the EQUC, and does it end there, or is the answer to UTI testing more complex?
The 90 percent false-negative rate we have been detecting with EQUC in our studies is simply the presence of bacteria. This is different from the detection of clinical relevant organisms or uropathogens. Our group published a paper in 2015 (Price et. al, J Clin Micro, 2015), where we asked if there was a streamlined version of EQUC that we could recommend to the clinical labs to implement for better detection of uropathogens than the standard culture. We found that the standard culture missed 67 percent of uropathogens in all patients and 50 percent of uropathogens in patients with symptoms. We believe that the streamlined version of EQUC could be easily implemented into clinical labs to aide in their detection of these clinically relevant uropathogens. We currently have a clinical trial where we are randomising women to standard urine cultures versus EQUC. We are testing the hypothesis that using EQUC enhances the clinical care of women.
Earlier last year, Linda Brubaker and Alan Wolfe commented that chronic bladder conditions with unclear aetiology likely have a microbial component despite negative standard cultures. What are your thoughts on people with Lower Urinary Tract Symptoms (LUTS) who have been diagnosed with various chronic urinary syndromes, such as painful bladder syndrome/interstitial cystitis (PBS/IC), over active bladder syndrome (OAB), urgency urinary incontinence (UUI)?
We have seen that people with various LUTS conditions can have different bacterial communities in their bladders compared to individuals who are asymptomatic. At this time, we do not know if these differences cause, contribute to, or are a symptom of LUTS. This an area of active research. One important finding from our group that has not made its way into the practice of most treating clinicians is the use of catheterised urine samples to collect urine. Just as no physician would accept a sputum specimen that was spit into a cup (because of mouth flora), physicians should not be making the diagnosis of UTI unless the specimen has been obtained by urethral catheterisation.
There is growing research from several research centres showing that acute UTIs can develop into recalcitrant infections, causing chronic and recurrent symptoms that last for many years, and sometimes entire lifetimes. These infections involve bacterial colonisations of the cells that line the bladder—either by invading the cells or forming biofilm. How is work from your lab supporting these findings?
Currently, our lab is beginning to look into how the bacteria in the FUM interact with one another and with the bladder epithelial layer known as the urothelium. As stated, we are just beginning to dive into this type of work and I fully expect our results to support findings of other labs.
It’s astounding that chronic and recurrent UTI remains a much-neglected area when it comes to research. There’re only a handful of research teams around the world working on a medical problem so widespread that it impacts 50 percent of all women and is the most common reason worldwide for antibiotic treatment. Can you explain why you think this is and what are the biggest challenges you face?
There are many great research teams doing great work on UTIs and the uropathogens that are responsible for the infection. I think the main reason why it is hard to study chronic and recurrent UTI is because there is no good animal model in place to study this type of infection. A major challenge we will face in the future is similar for all microbiome work—every individual is different from one another. A FUM that is good for me may not be the best FUM for you.
How do you feel your discovery of the FUM, and the significant limitations of standard testing, has been received by colleagues, medical professionals and the public?
Our work has been received well by our colleagues and medical professionals within the clinical microbiology and urogynecology fields. It has brought on a lot more questions than answers at this point, but we are excited for the impact that it has already had on the medical community.
It seems to take such a long time for developments in medical science to be picked up at a clinical level where it can really help patients. Why do you think this is and how can this lag be improved?
It takes a long time to implement developments in medical science into the clinical level because we don’t want to treat patients unnecessarily. For example, our work demonstrates that the FUM exists and because it exists it changes everything we think we know about bladder health. The last thing we want is for doctors to start empirically treating these patients with antibiotics before we understand what the FUM is doing. I don’t know how this lag can be improved.
There is a lot of promise that better understanding the FUM will lead to new therapies for UTIs that will negate the need for antibiotics. What type of treatments do you envisage and, realistically, how far off are these treatments?
The types of treatments I envision are treatments that help shift the FUM back to a healthy state. This includes prebiotic or probiotic treatment and even phage therapy, which is the use of viruses that kill bacteria. I cannot predict how long it will take as it is outside my area of expertise.
There are many people suffering acute and recurrent/chronic UTIs for which antibiotics is presently the only effective treatment. Growing global concern with antibiotic resistance, and improving antibiotic stewardship, is putting increasing pressure on doctors to reduce their prescribing practices. It’s becoming evident that authorities in many countries are trying to change the perception of common infections like UTIs and new diagnostic and treatment guidelines to reduce antibiotic use (i.e. three-day courses and low-dose prophylaxis, as opposed to full therapeutic courses) are being proposed. What are your thoughts on diagnosing and treating today’s UTI patients with these newer protocols, while we await newer therapies that are still some time off?
I strongly support antibiotic stewardship. I am not a clinician so I cannot comment on these recommendations. I look forward to the day when clinicians will have more complete personalised information (such as the composition of a woman’s FUM) and reliable non-antibiotic therapies to add to the traditional antibiotics.
Is there anything else you’d like our readers to know about your work and UTI research in general?
Yes. The biggest problems facing research into all things bladder are: (1) the hesitance to talk about “problems below the belt” and; (2) the lack of funds. There simply is not enough money devoted to the science of UTIs and other lower urinary tract disorders. Performing rigorous science is expensive. In my lab alone, there is so much more that we could explore and thus learn if we only had the funds to do the work.
Evann Hilt, thank you for sharing your thoughts and insights into the important work coming from the LUEREC. Our readers are always looking for new developments in UTI research and we greatly appreciate hearing direct from the scientists at the forefront of this work. On behalf of all our readers, thank you for speaking with us today, and more importantly, thank you for the great work you are doing. Please, keep at it!
Want to know more about Evann’s work?
CLICK HERE if you want to hear more from Evann Hilt in this interview from the 2014 American Society of Microbiology Conference