In-depth study of microbiomes may lead to better UTI care for patients with spina bifida

In this interview, Brendan T. Frainey, MD, highlights a study characterizing the diversity and composition of the urinary and intestinal microbiomes in patients with spina bifida, which was presented at the Society for Pediatric Urology (SPU) and the International Children’s Continence Society (ICCS) Annual Fall Congress in Louisville, Kentucky.¹ Frainey is a pediatric urology fellow at Monroe Carell Jr. Children's Hospital at Vanderbilt University Medical Center in Nashville, Tennessee.

Brendan T. Frainey, MD

Could you describe the background/rationale for this study?

This study is one that our group has been thinking about for a while. [It's] something I'm passionate about, because what we see is that individuals with spina bifida come into the emergency room or the clinic frequently for what is presumed to be a urinary tract infection (UTI). It is challenging to diagnose a “true” or “symptomatic UTI” and distinguish that from what's called asymptomatic bacteriuria. It’s challenging for a variety of reasons, but the primary reason is because individuals with spina bifida don't often present with typical symptoms like dysuria, urgency, or frequency, because they have altered sensation in their lower abdomen and pelvis. So, we often have to go off of limited information and utilize both a positive urine culture and hopefully some clinical symptoms, such as fever, flank pain, nausea, or vomiting, but that doesn't always happen.

My worry as a pediatric urologist who takes care of young adults with spina bifida is that [as] they get older, they present to the hospital with multidrug-resistant bacteria because they either have had many true UTIs over the course of their lifetime or have been overtreated with antibiotics. The goal for this study was to understand, over the lifetime in individuals with spina bifida, what bacteria are present in their urine normally, what bacteria are present when they have a urinary tract infection, and what are some important clinical differences we can tease out to help understand which patients should really be treated.

What were the key findings from this study?

This study had several key findings and a lot of things that we're excited to continue pursuing. The 3 big things that we took away from this thus far are 1, that bacteria are present in the urinary microbiomes of almost all individuals with spina bifida. In the next generation sequencing, or the 16s sequencing we did, 97% of people had some bacterial growth in their urine, and 100% had it in their stool. On the specialized urine cultures that we did—these are patients that weren't having any symptoms at the time—82% of patients had bacteria growing in their urine. The notion that the urine is sterile should be hopefully abolished by now, especially in this group where we know that these individuals do have a lot of bacteria growing in their bladders. We are hoping to understand how that contributes to their overall health.

The second big thing is that in their microbiomes, E coli was a major player. That's a common bug that leads to urinary tract infections. It was the most common organism we found and the most abundant. We looked at all the organisms in their microbiomes or the things that grew on urine culture, and we found that E coli was the dominant organism. In addition to that, we realized that there wasn't a ton of diversity in the microbiomes. These individuals often only had 1 or 2 bacteria that were dominating the whole microbiome, which is very different from a typical individual who has a lot of other what we call commensal bacteria that may be contributing to their health. We don't necessarily know what that means yet, but we know that there's not much diversity in the microbiomes of these individuals, which [may] play a [role] in why they get recurrent UTIs.

Then the final thing, which isn't that surprising, but we proved for the first time, was that patients who catheterize their bladder—a lot of individuals with spina bifida catheterize to empty their bladder—have higher proportions of skin flora growing and living in their bladder. Staphylococcus aureus is one of the common bacteria that lives on our skin and our hands. We took hand swaps and showed that that was more common in individuals that catheterize than those that didn't. It's something that we've presumed, because they're using their hands to catheterize themselves, but we've now shown. Hopefully down the line, we can say, if this bacteria might be growing and they don't have symptoms, that's expected. We shouldn't be treating individuals with spina bifida that have some of these common skin flora in their bladder if they're not having symptoms of a UTI or fevers. I think that'll be helpful to show and to prove down the line.

What gaps do these findings help to address in the current literature?

One of the things that is unique about this study is that we took stool samples, so we looked at the intestinal microbiome as well. There is some suggestion that a lot of the UTIs that patients experience can come from the gut flora. What we showed in our study was that patients that had recurrent UTIs had higher rates of E coli in their gut. While this is just a preliminary piece of information, it's allowing us to drive our hypothesis that the gut may be a reservoir for UTIs for a lot of these patients. Having specimens and doing data analysis on both of these niches within the body will help us understand where these UTIs are coming from and how the gut and bladder are interrelated. That's another unique aspect of our study, which no other study ever has really done before.

[Overall,] there's a lot of gaps in this care, and there's a lot of unknowns. I think our study is hopefully going to be a springboard for future studies, both at our institution and others across the country down the line. I think the interplay of how the microbiome affects our health is something that's gaining a lot of interest, but the urinary microbiome is still very new and understudied. I hope this specific study focusing on a specific group of patients can help give us some information that will lead to future studies within the microbiome, specifically the urobiome, and demonstrate how it can contribute to our health and potentially how some of the interventions that we are asking patients to do can alter their microbiome, such as giving antibiotics or starting someone on a catheter program. We do surgeries like bladder augmentations, where we're taking a piece of intestine and putting it in the bladder. How does that alter someone's microbiome and predispose them to future urinary tract infections down the line? This is an early study helping to characterize some of the key findings, but we have a lot of exciting work that we’re going to continue working on, and hopefully get the field to join in with as well.

What are the implications of these findings for clinical practice?

This is still very preliminary work. We are drawing some associations, but there's no hard conclusions yet. We haven't demonstrated causation. I think some of the things that excite me are understanding that there are bacteria that are living in the bladders of these individuals all the time, and understanding which are the bad players and which are the ones that we can observe and not overtreat our patients with spina bifida. It's a double-edged sword, because this is a common source of morbidity and mortality for these patients, but also something where, in the era of antibiotic stewardship, we need to be doing better for these individuals and not overtreating. I think these data will show us what pathogens are in the bladders of individuals with this condition, but also what bacteria are there that maybe don't need to be treated. We're just getting into how we can decipher that.

I think some of the really interesting things are—once we start getting longitudinal samples in these individuals—understanding how the things that we're doing to these patients change and alter their microbiomes. When they come in with a urinary tract infection, when we get urine, how is that different from when they're healthy? That's the next phase of this, which we're already doing now, but we haven't published data on yet, that I think will start to give us some more conclusive evidence as to which bacteria are the good ones and the bad ones.

Could you expand on some of the ongoing research on this topic?

We have some grant funding and a lot of collaborations ongoing for this project. Like I alluded to, I think the first and most exciting step is getting longitudinal data. The data I presented at SPU and the ICCS was a characterization of 1 point in time of 60 individuals with spina bifida, giving us both urine, stool, and hand samples. But we've been collecting data prospectively over the course of the past year and a half to get repeated samples from these individuals. So, when they come in, either hospitalized for a UTI or back to our clinic for repeated urodynamics, we're getting additional samples. In the interval, what exposures to antibiotics have they had, what interventions have we done to them, what things could alter their microbiome? That's going to give us this evolution of the microbiome that we are really excited about.

I'm [also] working with some talented people in our lab that know how to do some of the bioinformatics and some of the microbiology behind this to look at the next generation sequencing, the 16s, like I talked about. [We’re also looking at] more detailed next generation sequencing—metagenomics, whole genome sequencing—to understand the interplay of these bacteria and how they're surviving within the bladder and coming up with altered mechanisms to thrive and avoid our antibiotics or become resistant. That's the next phase of all this that we're already starting and have some preliminary data. [This will help show] the mechanisms of why this is happening, and not just a point in time characterization, which is where the field is at right now, unfortunately. We want to push this further to understand some causation and to understand at a molecular and microbiology level how this is happening.

It'll be a multi-institutional undertaking, with hopefully additional institutions joining on as we get more grant funding and get more of our data out. We've already expanded to working with Duke University, which has a very large spina bifida cohort and a really successful clinic there. They've been sending us data as well, and they’re going to be very big contributors to our coming data and the findings.

Reference

1. Frainey BT, Reasoner SA, Hadjifrangiskou M, Clayton DB. Characterization of the urinary and intestinal microbiomes in individuals with spina bifida. Presented at: Pediatric Urology Fall Congress. September 12-15, 2024. Louisville, Kentucky. Abstract 67. https://fallcongress.spuonline.org/program/2024/67.cgi