00:00 – Dr. Henry Schreiber: Gut is absolutely a reservoir for infection. We often saw the isolate of the bacteria
00:08 – from their bladder was identical to the strain that was in their gut.
00:25 – Melissa: Dr. Henry Schreiber is an instructor at Washington University School of Medicine in St. Louis. He studies how the bacteria in your gut can influence urinary tract infections with a focus
00:33 – on understanding how we can address UTIs as a whole body problem instead of just a passing infection. Henry trained with Dr. Scott Hultgren, a leader in the field of UTI research, as well as
00:43 – Dr. Sarkis Mazmanian, an expert in the gut microbiome. With this training, Henry continues to explore
00:48 – the gut bladder axis with the goal of developing new therapeutic strategies to prevent UTIs. Thank you so much for joining me to answer our long list of questions.
00:56 – Dr. Schreiber: Oh hey, well thank you so much Melissa for having me. It’s just wonderful to be able to talk with
01:02 – folks about this. Sometimes you get caught in your tower, your ivory tower, and you don’t get a chance
01:08 – to really talk with people much. And so I’m really happy to have the opportunity to talk a little bit
01:14 – about these really important topics. Melissa: I think this is a topic that’s of particular interest to the patient community because we did get a lot of questions, the gut brain axis and the gut
01:22 – bladder axis. And I would love at first if you can share a bit more about your background and your area of research.
01:29 – Dr. Schreiber: Sure, absolutely. So the questions that drive my research and have been
01:39 – developed over the training are really trying to understand the complex relationships that we have
01:44 – with bacteria. So often we have these negative associations with bacteria, especially with
01:51 – people who have recurrent urinary tract infections, people that struggle with these diseases have just
01:57 – this negative association with bacteria. So often we have these important interactions with bacteria
02:04 – that are extremely beneficial to our bodies and our health. And so my research is really trying
02:11 – to understand that dichotomy, like why do some interactions result in beneficial outcomes
02:16 – and why do some result in these toxic negative outcomes. And so trying to navigate that path
02:23 – so that maybe we can push our interactions with our bacterial partners back into a healthy direction.
02:30 – Melissa: It’s all very interesting, as I mentioned, and we got a lot of questions. I think it’s good if we start from a term that people have heard a lot. So that’s the gut brain axis. Can you explain what that is?
02:40 – Dr. Schreiber: Absolutely. So the gut brain axis is a short phrase that describes a really multifaceted,
02:50 – multi-layered type of connection that occurs between our gut and the brain. So the gut microbiome
02:58 – is the collection of organisms that live, inhabit your gut, that are responsible for a
03:06 – huge impact on our health. They are involved in metabolism of the food that we eat. They drive
03:14 – immune education. And then they can also, and through those effects, they influence our immune
03:23 – system responses, as well as the types of molecules that we’re actually being exposed to.
03:31 – It’s the, it is, people often refer to it as this microbial organ. So what that means is that it has
03:38 – a purpose in our bodies in really driving our health through these metabolic and immunological
03:47 – factors. And so that’s the gut microbiome. So when we’re talking about the gut brain axis,
03:53 – we’re really talking about the gut microbiome to the brain interaction. And that can occur in a variety
04:00 – of different connective pathways. One is this immunological response. So the gut bacteria help
04:09 – drive the maturation of your immune system. And as you might expect, the immune system responds not
04:15 – only to invading microbes and pathogens, but it’s also responsible for keeping your body healthy
04:21 – and limiting inflammation. And when there is inflammation, making sure that that inflammation goes away. And so anytime that your gut microbiome is influencing your immune system, it’s also
04:33 – influencing all of the rest of your body that’s affected by your immune system. And then the other
04:38 – part of this that I want to highlight, there’s two more parts. The other part that I want to highlight that’s really important is this metabolic effects of the gut microbiome.
04:48 – A huge proportion of the diet that we eat, the things that we ingest – drugs,
04:58 – things like that are metabolized by the gut microbiome and then are made available based on that metabolism. And so the things that get to your brains, the molecule that gets to your
05:11 – brains first pass through the gut microbiome. And so that’s another area of connection between
05:18 – the gut microbiome and the brain is through this metabolic space. So we have immunology, we have metabolism. And then the last bit is this neuronal connection, especially through the
05:31 – this vagus nerve that connects the brain directly to the gut. So the gut brain axis involves a lot
05:39 – of neuronal communication that can happen through the vagus nerve that reaches the brain. So you
05:45 – can have things that affects direct neuronal activity that could affect the brain. But when
05:51 – people really talk about the influence of the gut microbiome on neuronal communication, a lot of the
05:58 – research is focused on your enteric nervous system. Your enteric nervous system is literally the
06:06 – nervous system that exists in your guts. It’s responsible for regulating hunger. It’s responsible
06:14 – for regulating gut motility. And it’s also involved as a partner in communication with the immune
06:22 – system. And so it’s – each part of this, I presented it as three distinct pathways. It’s much more –
06:31 – it’s much more connected. It’s much less like tree trunks and much more like a shrub where things are getting connected in between them. So it’s not an individual pipelines
06:41 – that are going through. There’s a lot of crosstalk that happens between those. So the gut brain connection is all of those connections leading into these outputs on human health.
06:53 – Melissa: So it’s so connected. And some of the questions that we got are other gut microbiota involved in
06:58 – all bodily sensations like hunger or mood changes. So do those happen in the absence of bacteria as well?
07:05 – Dr. Schreiber: That’s a great question. They can happen in the absence of bacteria. But we know that the
07:14 – gut microbiome through those channels that I was talking about do influence the development of
07:22 – the nervous system. There’s been some – there’s a tool that we use in research where we actually
07:29 – take mice and we remove all of their microbes. We’re able to – we’re able to take the mice and
07:37 – before they’re born into dirty cages, we’re able to actually rear them in sterile cages.
07:44 – And we’re able to keep them so that they don’t have any microbes on them at all. This is obviously
07:50 – not possible with humans but with mice we’re able to do it, also with flies and some some other model
07:55 – organisms. The important bit of this – the reason why this tool is so cool is it allows you to
08:02 – determine what is being driven by the microbes themselves when you compare it to mice that
08:08 – are reared in dirty environments where they have all of those microbes. So this tool that’s called germ free mice. These germ free mice have behavioral differences compared to mice that are – that have
08:20 – bacteria. They have differences in their infection susceptibility. They have differences in their
08:27 – immune system. There’s just around the entire body, just about every organ system or actually every
08:34 – organ system that I know of has an effect from the changes in the gut microbiome because
08:42 – the – you get born, you get exposed to this and evolution loves to take shortcuts. It’s a great
08:48 – shortcut to be born into a bacteria filled world and then use that as a signal to start different
08:55 – developmental processes. And so that’s really the driving factor behind behind this is the exposure
09:01 – to microbes not only in adulthood and throughout adolescence changes what you’re being exposed to
09:07 – but at birth it’s a – this very powerful signal that lets the body know that it’s time to start
09:14 – certain developmental cascades. Melissa: It’s fascinating to think about that and you mentioned the
09:20 – infection states of the germ free mice more susceptible to infection and also that the gut microbiome contributes to the maturation of the immune system but can you talk a little bit more –
09:29 – a bit more about how that happens in humans? Dr. Schreiber: Sure, absolutely. So I should say whether or not
09:37 – an animal is germ free has an impact on whether or not something will be more susceptible or not
09:43 – but there there are instances where a germ free mouse is less susceptible to infection which is
09:50 – really striking. It’s really – it’s all really interesting because you – these mice are generally considered immunocompromised. Their immune system is a fraction of what the – of what a
10:02 – standard immune system is. And so to get to that point, part of the education of your immune
10:10 – system has to deal with the interactions between external sources of information and your immune
10:19 – system in order to tell the immune system that it needs to produce certain types of cells. So you
10:26 – could imagine a scenario where you’re giving a germ free mouse exposure to only stimuli that
10:35 – produce negative results. You could be giving a mouse just those interactions that I was talking
10:42 – about at the beginning of these complex interactions with bacteria that sometimes that lead to healthy outcomes. If you remove those bacteria and give the mouse bacteria that drive it towards a
10:55 – negative outcome then the mouse is more sick. You give a mouse that’s – you make a mouse, that’s more
11:00 – sick that’s immune system is primed for over inflammatory reactions to be more reactive than
11:07 – it should be. But if you take those mice and give them bacteria that drive it towards healthy
11:14 – interactions then their immune system develops more normally. They don’t have over exuberant inflammation. And so to drive that point home, if you take a mouse that is genetically
11:28 – susceptible to inflammatory bowel disease so Crohn’s disease and ulcerative colitis – if you
11:34 – take those mice that are prone to this and remove all of their bacteria, some of these mouse models
11:41 – do not get any inflammatory disease at all. Their colons are just fine. If you give them a microbiome
11:49 – from a human patient that has IBD, suddenly those mice get really robust inflammatory disease. If
11:58 – you give those same mice a microbiome from a healthy person, they might still get disease but
12:04 – it’s much milder. And so there really is something about the interaction that’s happening between
12:09 – the bacteria and there’s a lot of research into understanding the mechanisms that that are undergoing
12:14 – that. But it does appear to be direct interactions between microbial metabolites as well as I mentioned
12:23 – the neuronal signaling plays a role in this as well. It’s of course all interconnected.
12:29 – So it’s really a combination of the metabolites, the bacteria being there in the
12:36 – first place. A lot of things along those lines. Melissa: It’s much more complicated than the way we talk
12:42 – about the gut microbiome in general which is more about good versus bad organisms. And then we have
12:49 – conversations about things like biofilms which are generally considered as a negative thing but are they naturally just part of the gut microbiome anyway?
12:57 – Dr. Schreiber: That’s a cool question. I admit that I saw that question and it made me think for a little while so I did a little bit of reading on it. And so
13:07 – the – and, I’m sorry to be a broken record. So it’s complex. So there’s a little bit of yes and a little
13:14 – bit of no. The biofilms are important in the gut microbiome because bacteria when they attach
13:24 – somewhere they like to stay attached. And so they of course they make these biofilms which are these –
13:30 – this extracellular matrix, the slime that the bacteria produce that helps them stay put and also
13:38 – protects them from their environment. You could imagine a dried up slug doesn’t do as well
13:44 – as a slimy slug. Right so they – so the bacteria like to be slimy. That being said, the gut microbiome
13:53 – can be very patchy. So when we think of biofilms you tend to think of like a large sludge mat.
14:01 – That apparently is not the case for most bacteria. Most bacteria tend to exist in kind of micro
14:09 – colonies. So instead of a large colony of you know tens of thousands of bacteria, they’re
14:15 – in much smaller populations that exist within the gut and that those interactions
14:23 – happen, they’re still in biofilm like communities but not the type of biofilms that you would see on
14:29 – catheters for instance. Urinary catheters – if you pull out a urinary catheter it’s just covered
14:35 – in gunk. It’s not that kind of a biofilm. It’s much more of a micro colonies type of situation instead.
14:45 – Melissa: Does that also mean in the bladder that could be the case, these micro colonies exist in a natural and healthy state but not all biofilms are bad necessarily?
14:54 – Dr. Schreiber: That’s an interesting question. The existence of the bladder microbiome, I fully believe that the bladder is not sterile which is
15:06 – a paradigm shift in how we think about the bladder. The existence of biofilm communities
15:16 – in the bladder is not something that I’ve seen evidence for or the existence of these micro
15:23 – colonies. And I think that has a lot to do with the research in the bladder being generally
15:31 – understudied relative to the gut but then the other aspect of it being the difficulty in identifying
15:40 – these microbes because so many of them are not ones that are commonly studied and so that’s
15:49 – the tools that we would use in order to visualize them actually literally look at them
15:55 – in the bladder, they’re just not as many as there are for the gut where the research has been –
16:00 – is more mature. I’m not going to say that they wouldn’t exist, I’m afraid I just don’t know. I’ve
16:08 – not seen evidence for it one way or the other. Melissa: That’s fair enough. You mentioned inflammation
16:13 – with the chronic inflammatory bowel disease and other inflammation. That I think is a common
16:19 – occurrence in bladder infection. A lot of people – that’s also you spoke about the spectrum of some of these mice reacting well than others because of their state and we see that in the patient
16:27 – community that some people report feelings of inflammation or this inflammation that lasts for a long time. Can you talk about how that might happen in the bladder? And there’s been some research
16:37 – recently about nerve growth factor and how this might cause prolonged inflammation in the bladder.
16:43 – Dr. Schreiber: Yeah so that’s a really interesting question. So, we know that urinary tract infections are really
16:49 – driven by this inflammatory response. And again, I’m not talking about pyelonephritis or kidney
16:55 – infection, I’m not talking about bloodstream infections but it’s the cystitis, the bladder infection itself. In research, that’s been done both in clinical in the clinical realm as well as in
17:06 – preclinical models. We have seen that inflammation is a key driver of UTI outcome and also the
17:14 – severity of symptoms. What’s interesting about that is that again there’s a spectrum of inflammatory
17:23 – response and then there’s a spectrum of responses to a particular amount of inflammation. There’s
17:30 – studies that show that patients that don’t have really robust inflammatory response like so there
17:37 – are markers that you could look at in the urine to examine the amount of immune signaling that’s
17:46 – occurring in the bladder that will drive inflammation and a patient, two patients that
17:52 – have similar levels of that immune signaling may have wildly different symptomatology and so it’s
17:59 – not a one-to-one correlation which has made some of the predictive power of this not so great, not
18:06 – so accurate. So then what is driving that and the question that you asked about this nerve
18:13 – growth factor, what’s really interesting about that is out of this, the Abraham lab is looking at
18:19 – nerve growth factor and what they found was that the expression of nerve growth factor
18:30 – from the immune system can have a long-lasting effect on the neuronal signaling within the bladder
18:38 – so that the neuronal signaling itself is kind of primed to continue to respond to stimuli.
18:47 – So what you would expect is that under normal circumstances the threshold to provoke a symptom
18:53 – response associated with pain or urgency might be here but after a urinary tract infection,
18:59 – after this change in neuronal signaling, after this increased expression of nerve growth factor for instance, that threshold drops and so as a result, the person becomes more susceptible to increased
19:12 – stimuli that would normally not provoke a response. So then it’s somebody who’s unlucky enough to be
19:18 – constantly getting UTIs will definitely know what it feels like but the threshold will be lower
19:24 – and so what’s interesting about that is that if the threshold’s lower, it doesn’t mean that the symptoms are lower. It means that the actual light switch to occur happens more robustly.
19:36 – Melissa: Is this a flaw in our immune system then or is there some kind of benefit to having these prolonged symptoms and inflammation?
19:44 – Dr. Schreiber: That’s an interesting thing to consider. That’s a really interesting thing to consider. Is it a flaw in our immune system?
19:52 – Melissa: Or is there a benefit, is it like a fight or flight thing where our body is just alerting us this is happening again but then
19:59 – does it get worse every time you have a UTI? Dr. Schreiber: That’s a great question. I and it’s – it’s a – I can – let me –
20:07 – I’ll walk you through my thinking without giving you a conclusion. My thinking on that is that
20:14 – there is a – there is a benefit in lots of circumstances for your body to be more wary of an infection
20:25 – if it has recently been infected. For instance, right, if you had a diarrheal disease and your body
20:33 – is able to really quash that disease by a strong immune response, then there is a significant benefit
20:41 – to having that threshold be lower. So as a result your immune system is activated more quickly.
20:47 – That is roughly analogous to adaptive immunity where once your body recognizes a pathogen,
20:55 – the threshold to start the very strong immune reaction is dropped. That’s beneficial but
21:03 – what we’re finding with UTIs is that often what we – the paradigm of a strong immune response being
21:10 – really protective is not always the case. There’s times when the patients have these really strong
21:18 – immune responses and it doesn’t clear the infection. It doesn’t help them. And so in those cases, having
21:25 – an even stronger immune response might not be beneficial at all. And so is it a flaw in the
21:31 – immune system. I don’t know if it’s a flaw so much as it probably be a trade-off where the immune
21:39 – system is willing to accept that some people get UTIs and it sucks for them but in these other
21:46 – instances, the evolutionary pressure to have a robust and quick immune response outweighs that
21:54 – negative. So, that would probably be where I’d lie but that’s an interesting, it’s a really cool question.
22:00 – Melissa: Because we have so many patient experiences that we hear from the community where people just have these symptoms every single day and it’s so debilitating and it’s not helpful
22:09 – to be constantly told by your brain or by your gut or anything that your bladder is in danger. There’s nothing you can do about it but you still have to go through this inflammatory response and the symptoms.
22:20 – Dr. Schreiber: It’s brutal. It’s absolutely brutal and the people that have to deal with this
22:27 – every day, you mentioned debilitating, it is crushing. It’s absolutely crushing to
22:34 – have this response and it is a whole body problem. One of the things that we’ve talked
22:42 – to, that happens with this is the – when you get sick, your behavior changes. Everything becomes
22:50 – worse. The – when you feel bad, everything is worse and that is an adaptive response to give
22:58 – your body time to heal. It’s your body making you feel bad so that you don’t do as much.
23:05 – You know, so that you are incentivized to rest and recuperate. Where it breaks down is with these chronic infections, where these chronic inflammatory
23:17 – diseases, where you feel bad all the time and you can’t rest your way through it. Right. It’s like
23:23 – that’s – that becomes – that’s when it becomes really debilitating. That’s a problem with these chronic infections.
23:29 – Melissa: Yeah and that kind of leads us to the next question which is about the neurological symptoms associated with UTI. We get a lot of people reporting those types of symptoms. Is it
23:38 – possible, the bladder is directly connected to the brain or is it via the gut that you think those
23:43 – mood changes or abnormal skin sensations or hot and colds. There’s so many different things that
23:49 – come up with UTI, that aren’t really documented in the standard lists of symptoms but we hear them every single day from the community.
23:57 – Dr. Schreiber: Oh, absolutely. My mom gets UTIs all the time. She – she’s actually on an antimicrobial treatment and still gets UTIs frequently. And we’ve gotten to the
24:10 – point where she doesn’t have – she has atypical symptoms. She does not have pain, urgency, issues
24:18 – with that. What she has are neurological symptoms. I can – talking to her on the phone, I can tell when
24:25 – she has a UTI because her choice of words gets a little fuzzy. Or she gets – her memory gets a
24:33 – little fuzzy. It’s harder for her to continue with a conversation. She just got some brain fog.
24:41 – So and that symptomatology has been documented epidemiologically that enough of that
24:50 – exists that people will be able to pick it up. This is especially prevalent when people who
24:56 – might have Parkinson’s disease or Alzheimer’s, you know, some sort of dementia.
25:03 – When they have a sudden worsening of their symptoms and they go to the ER, one of the first
25:10 – things that they will – they’ll first check if the person is coughing to look for a respiratory infection. The next thing that they’ll do is order a urinalysis because that connection between UTI
25:21 – and neurological impairment is really apparent in these neurologically sensitive vulnerable
25:30 – populations. And then of course as you mentioned that happens a lot in people that are not
25:35 – neurologically vulnerable. You know, they have the brain fog, they have you know something that isn’t as drastic. To answer your specific question, my intuition and this is something
25:50 – that – this is a focus of a research that I’m – that’s ongoing, is that the connection
25:56 – between the bladder and the brain. There is connection between the bladder and the brain. There is – through your spinal cord, there is a connection that for your brain to be able to
26:05 – control your bladder and your bladder to send signals to your brain which is of course the reason why – when you feel like you need to go, you can wait to go. You can make a choice to wait to go
26:15 – to the bathroom. Right. You don’t just go. Like you have the choice of when you go. But what’s
26:22 – interesting about this is that it’s not really well understood. There’s not been a lot
26:28 – of mechanistic understanding, mechanistic interrogation of this connection. What are the
26:36 – molecular mechanisms? What parts of our bodies, what cell types are responsible for this connection,
26:43 – is not understood well. There’s been some research that indicates that the
26:53 – connection between the gut and the brain can happen through these immunological
26:58 – factors as well as through these metabolic factors. My guess is that we’re going to see something similar in the bladder where it’s going to be driven between these immunological
27:09 – factors, metabolic factors and my – the easiest place to start looking is probably
27:18 – in these immunological areas but that’s – whether or not that will tell the whole story I’m not
27:24 – sure. Because this is just a wide open area. But to the people who do feel these symptoms, these
27:31 – neurological symptoms, changes in your behavior, changes in your cognition, that’s real things. Those
27:37 – aren’t – that you’re not making them up. You’re not – it’s a real effect. You just don’t understand it well yet.
27:46 – Melissa: I think patients can tell you that it’s a real effect as well but one of the problems in this space is that they’re often told it’s all in their mind. I don’t know
27:53 – that that really means it’s not real either but there’s a strong association between UTI and
27:59 – anxiety or depression and then we have these mood changes. People often say the first symptom of a UTI
28:04 – is this subtle shift in their mood and they can tell it’s about to happen. And so I think it’s a really important area of research that could help patient outcomes in the future.
28:13 – Dr. Schreiber: Absolutely. So we have this – we have this term called sickness behavior. Right.
28:20 – Sickness behavior – if you give a mouse an injection and you give them a microbial
28:30 – metabolite called lipopolysaccharide which is the outer covering of certain types of bacteria
28:37 – and that outer covering is recognized by the immune system and starts an inflammatory
28:42 – reaction. You can make a mouse have anxiety like symptoms. You can make a mouse not want to move
28:50 – very much. You can make a mouse either aggressive or extremely submissive. You know, by giving these
28:57 – my – giving them – just, you don’t have to give them the bacteria. You just have to give them this outer
29:03 – covering. You can – so, to put a fine point on that, you can give a a mammal a microbial product and
29:14 – change their thinking. And so like the – it’s and not – we’re not talking about like this huge decision
29:20 – making. But we’re talking about subtle effects. We’re talking about making the mice grumpy and tired
29:26 – and feel bad, right. And so it’s – that’s important. That’s – those are important features of of thinking.
29:35 – And so trying to understand that I think is extremely important. Like as you said, the
29:41 – patients know this very well. Clinicians don’t have much to say. They you know they don’t have much they can do. It’s really up to us, as researchers, to try and figure out why this happens and then
29:53 – make it better. Try and figure out how to make it better right. Like that’s the path – that’s the
29:59 – path forward. You know, there’s, of course, patients can take things into their own hands the own hands.
30:08 – Patients are always proactive. They’re always looking for ways to get better and those have beneficial impacts and then researchers can, hopefully we can make it better by doing the
30:18 – research to understand why that occurs. Melissa: That would be very helpful, definitely, yeah.
30:24 – Dr. Schreiber: Yeah. Yeah I agree. Yeah, I think I – that’s – I’m hopeful. I’m hopeful for this type, for this area
30:32 – of research. I think that there’s ways to get at these questions – they’re complex questions. One – this is a tangent. So give me a little grace here but the – one of the
30:48 – complexities of treating UTIs is that there are so often people that have bacteria in their
30:55 – bladders without any symptoms. And so often people have symptoms without bacteria in
31:01 – their bladder. Clinicians rely – have to rely because it’s predictive on patient reported symptoms, right,
31:10 – and to do this. And so that means that what’s happening in your bladder has to travel all the
31:16 – way from your bladder, all the way to certain parts of your brain where that information is decoded
31:22 – and then sent to different parts of your brain where that information is recoded into language that you then tell the doctor. That’s a lot of steps to get at this. So,
31:36 – treating UTIs is oftentimes so personal and subjective that it makes, let it that understanding
31:44 – this research I think will help us better, not only develop therapeutics but maybe diagnostics too. So
31:50 – we can actually see how a person, how a person is responding to an infection.
31:55 – Melissa: Yeah, that would be ideal. I think this – that would help patient outcomes a lot. In the meantime, there’s a lot of talk about
32:02 – what we can change ourselves. You’ve mentioned patients taking things into their own hands so let’s talk a bit more about the gut microbiome and how it relates to urinary tract infection.
32:11 – Is it possible that the gut is a reservoir for UTI causing bacteria or candida and this keeps on
32:17 – seeding into the urinary tract? Dr. Schreiber: Great question. The answer is absolutely. The answer is – this is – I’m
32:24 – happy to be definitive for this one. The gut is absolutely a reservoir for infection. We
32:33 – published a great paper in 2022 just a few years ago and looking at the connection between
32:40 – the gut microbiome and the bladder and one of the things that we did was to track people that
32:47 – have recurrent urinary tract infections before they started – before they got a UTI and then at a time
32:54 – of UTI and afterwards and what we found that was truly striking for us was that we often saw
33:05 – that the bacteria that was causing the urinary tract infection or the the isolate of the
33:11 – bacteria from their bladder was identical to the strain that was in their gut. So that’s – that shows
33:18 – a connection. But then when you look back in time, you can see that the patient oftentimes has that
33:26 – bacteria in their gut before the onset of a UTI. And so what – that indicates some level of directionality.
33:33 – It’s not perfect but it does suggest that there’s a level of directionality between the gut and the
33:39 – bladder. And this what I – will take that a step further. After the time of UTI, the patient goes
33:48 – to their doctor, they get antibiotics. Their UTI is cleared. Looking back in the patient’s urine,
33:55 – there’s no sign of that specific isolate. It’s gone. But then we look back in the gut and
34:03 – that bacteria is still hanging around, that exact same same bug. So to put a point on this,
34:11 – what’s happening is that the antibiotics are clearing the bladder of the bacteria but they’re not clearing the gut. So as a result you have this reservoir that persists through
34:24 – infection and the bacteria is able to survive within the gut and it can seed future infections
34:36 – about as your – as the audience is well aware, somewhere between a quarter and a third of
34:41 – urinary tract infections are followed up by a recurrence. About 50% of those recurrences are
34:47 – caused by the exact same strain that caused the first UTI and so we think that the gut in addition
34:54 – to the bladder and probably the vagina and periurethral area, those types of areas,
35:02 – are associated with this reservoir that enables the same strain to persist and cause multiple
35:10 – recurrences. Now here’s the caveat, we have shown this in a way that I think is a reasonable
35:20 – person would accept for E. coli. We don’t have the level of information on things like
35:29 – like candida, klebsiella, proteus, some of these other pathogens. We just – we don’t have the data
35:39 – on that yet. I would be surprised if that were not the case for most of them that there are these
35:46 – extra bladder reservoirs whether or not it’s the gut or other places I’m not sure. But I would be
35:53 – very surprised if it was- if it didn’t turn out to be the case that there was extra bladder reservoirs
36:00 – for all of these pathogens. Melissa: In general, does the gut microbiome of someone with
36:05 – recurrent UTI look different to that of someone who doesn’t experience recurrent UTI?
36:11 – Dr. Schreiber: Yeah in that 2022, paper we asked that question. We asked that question about whether or not somebody
36:18 – who has these recurrences, if they’re gut community, what does the composition look like? Like who is
36:24 – in your neighborhood? Like it’s really a demographic analysis, like what – who’s in that – who’s in your
36:29 – gut neighborhood? And it turns out that they are distinct. We found that people who have
36:36 – recurrent urinary tract infections, have less diverse bacteria and they oftentimes have a
36:46 – lower numbers of the types of bacteria that we generally consider to be beneficial. So these
36:54 – are things that – these are bacteria that make metabolites that are associated with immune health,
37:01 – you know, liver health, gut health, you know, these types of things are called – they make things
37:09 – called short chain fatty acids or SCFAs. And in our study, we found that one particular type of
37:17 – short chain fatty acid producing bacteria that make butyrate which is a four carbon chain. Those four –
37:25 – this butyrate producers are oftentimes are reduced in people with recurrent urinary tract –
37:32 – women with recurrent urinary tract infection relative to demographic controls. So, not only or
37:39 – is there – are they less diverse? But they also have less of these butyrate producers. What’s
37:45 – interesting about diversity, the diversity about the – the reason why I’m focusing a little bit
37:50 – on diversity is because in general, a more diverse community indicates that your gut is
37:57 – healthier. A less diverse community would be one that doesn’t have jobs that all the bacteria
38:06 – can fill. So like there’s – you don’t have maybe you’re not getting all the types of metabolites
38:14 – that you want or your immune system is getting an over abundance of certain types of signals
38:19 – rather than healthy signals. So diversity is generally considered to be beneficial in the gut microbiome. Yeah. So there’s some interesting connections there.
38:32 – We’re really working – now that we found this in people, we want to understand what are the
38:38 – mechanisms? What’s the actual output of that? And so that’s ongoing research. We’re trying to figure out some of the molecular mechanisms that are associated with this observation. Does it
38:49 – have an impact on UTI outcome and overall bladder health. That’s something that we’re currently working on.
38:55 – Melissa: The obvious question from there is if we know diversity is important, has research shown that we can re-establish a healthy microbiome?
39:03 – Dr. Schreiber: That’s – that is a literally a billion dollar question. Like there are like billions of dollars industry trying to understand this.
39:13 – And to be on – and to be to be blunt in my personal opinion, not the opinion of
39:20 – my institute or any of my collaborators, I have found that the efforts to repair the gut microbiome
39:29 – have been mixed. There’s certainly instances when it’s extremely beneficial for somebody to get
39:35 – the microbiome back. But the connection between the gut microbiome and the gut is more
39:43 – complex than just one side or the other. It’s really the interaction between them. And if you –
39:50 – probiotics have been shown to be effective in a lot of areas. They have been shown to be really
39:56 – effective if they’re constantly taken. But what – where they haven’t been shown to be particularly
40:02 – effective is giving a patient a dose of probiotics and then letting them get off the probiotics.
40:11 – Oftentimes, the gut environment is in such a way that they end up moving back in towards the
40:20 – – away from the gut microbiome space that they wanted to be in and towards a more unhealthy
40:26 – version of their gut microbiome. And so that disconnect between the fact that probiotics
40:33 – have beneficial effects and they don’t appear to be permanent effects is an – I think is an area of
40:40 – of interest to a lot of people in trying to understand that it’s beneficial. In terms of
40:48 – RUTI – in terms of recurrent urinary tract infections, I would love it if we could give somebody a dose
40:57 – of probiotics or you know a month of probiotics and then they’re cured. I would say that we
41:04 – are moving towards understanding the system in such a way that we can make that – we can – we could
41:12 – achieve the goal of a healthy gut. I don’t know if dropping in a whole community of microbes will be
41:19 – the way that we do it but it’s certainly something that’s being explored. Melissa: How is fecal matter transfer being looked at in this respect?
41:29 – Dr. Schreiber: Actually there has been. It is wild. There was one paper with a
41:34 – very small, very small cohort that looked at people who have this recalcitrant RUTI, these people
41:44 – that get RUTI no matter what you try and do with them. They – what that – what happens. Or and there’s
41:52 – another study where they – people got a fecal microbiota transplant for other reasons and
42:01 – then they looked at UTI outcome after the fact and in both of those cases it does appear that the –
42:09 – that their UTIs were lessened in both of those papers which is great news. That’s
42:14 – wonderful. Unclear – it’s unclear why. It’s unclear if the change in the gut microbiome
42:21 – changed the immune response or if it did remove that reservoir or made the reservoir much smaller
42:26 – or reservoir space much smaller, that’s unclear. It’s certainly – I can say it’s certainly not
42:35 – something that’s – that will show up next month. I’d be surprised if it were to show up next month.
42:41 – But it’s something that I think is possible. You know, especially for people who are – potentially,
42:48 – people who are hospitalized and their gut microbiomes have been demolished by antibiotics,
42:53 – something like that where their gut microbiomes have just been
42:59 – decimated. Going back and adding back a healthy microbiome could very well be extremely beneficial
43:06 – for them. We just don’t have the research to support that at this time. Doesn’t mean that it
43:13 – doesn’t exist or that it’s not a biological reality. Just don’t have the data on it yet.
43:18 – Melissa: Yet more research that needs to be done. Dr. Schreiber: Oh yeah. Give us money.
43:23 – Melissa: Yeah I know that’s the problem. So what are you working on right now?
43:29 – Dr. Schreiber: Well good questions. So I have a a few projects and I’ll talk about a couple that I’m really excited about. One is following up on this analysis
43:41 – of the gut microbiome influence on UTI severity. So we have this connect – this connection in a
43:47 – clinical setting. And as I mentioned, we really want to understand the molecular mechanisms.
43:53 – You might ask well why? Why do we care? If we can just do a fecal microbiota transplant, why – why?
44:00 – If we can understand the mechanisms then maybe we can make targeted therapies. We can make things
44:06 – that are really specific, that achieve the results that you want without any off target
44:12 – effects. You know, you don’t have – you’re not replace – if you don’t have to replace an entire – a person’s entire gut microbiome, if you can give them something that’s more targeted that just flips
44:22 – the switch that needs to be flipped in order for them to achieve a healthy state, that’s better
44:27 – because it has a less chance of off target effects. So the research that I’m doing right now has moved into a mouse model. We’re trying to develop more targeted approaches that will
44:39 – influence UTI outcome and understand the connections between the gut microbiome and the
44:45 – bladder. And that involves investigations of the immune system as well as these gut metabolites
44:51 – and you’re not using the tools that have been made available through research in the Hultgren lab, these very powerful mouse models. So it’s a really wonderful model of infection
45:03 – that really recapitulates a lot of this human disease. So that’s been an extremely valuable tool
45:09 – in order to understand UTI outcomes using these mouse models. And then –
45:15 – Melissa: Is there anything that you – I just wanted to ask about the targeted therapeutics that you’re working on. Is there anything that will be aiming for a clinical trial in humans in the future?
45:23 – Dr. Schreiber: That is always the goal. Working both
45:28 – with Sarkis and Scott, one of the things that drew me – a shared passion
45:37 – that Scott and Sarkis both have is research to help people. You know there’s you know and
45:45 – a driving force behind that is taking the discoveries that you have and driving towards
45:51 – something that’s deliverable, a deliverable good that can help everybody and so that’s
45:59 – the goal, the motivating factor. I have these questions but the ultimate goal is to
46:06 – find something that can help people. And so those targeted therapeutics are a long way off.
46:14 – I – we don’t – I have not even gotten to the point where I would be comfortable talking about what
46:21 – types of targeted therapeutics I’m actually investigating because I don’t want to – if I –
46:28 – I’m still at a stage where I could be wrong. And I don’t want people to jump in
46:35 – and something that’s where it could be wrong. It’s too – yeah. But the goal – the goal is always
46:42 – to do – and they – and that’s – in Sarkis’s lab, there are goals to treat the gut brain axis. In Scott’s
46:50 – lab, there’s really a lot of focus on understanding how bacteria can colonize and so a lot of the
46:58 – research that I’m happy to say for the Hultgren lab has done some things that are to give hope to people. There are new therapeutic options that are being tested in
47:10 – clinical trials that are – that have shown a lot of efficacy. There’s things that are driving towards
47:18 – preventing bacteria from inhabiting the bladder where they cause disease. So specifically targeted
47:26 – at E. coli, which are caused the vast majority of uncomplicated UTIs, really preventing them
47:35 – from colonizing the bladder. So there are therapeutics that are directed towards that. And then my
47:40 – research is focused a lot on trying to repair the connection between the bacteria and the host
47:47 – in such a way that UTIs don’t develop also. And so those are – those could be combined and
47:53 – we’ll see in the future, you know, at – let me find the big piece of what to knock on. I’m
47:59 – hopeful for the research that we have but, you know, it’s just – it’s not a – I think there’s –
48:06 – there is hope. There’s research being done on these. It’s not – it’s not nearly as
48:12 – neglected as it used to be. It used to be that UTIs were treated as a passing infection.
48:20 – You get your antibiotics and you move on your way. And then in the last 20 years, 25 years, the complexity
48:30 – of UTIs has drawn a lot of interest. And so there’s a lot of work being done towards fixing these things.
48:39 – Melissa: It’s a very encouraging note to end on. It sounds like we should do a follow-up interview at some point to find out more about your next research.
48:47 – Dr. Schreiber: Absolutely. And I think it’s really great. It never stops man. We keep going. It’s – it’s – I’m so lucky. It’s
48:55 – super interesting. It’s super complex. And I really feel like I do strong. I want to – I –
49:03 – we’re working hard. We’re trying. We know that it’s – we know how tough it is for folks.
49:10 – We’re aware of that and we want to help and so we’re doing the best that we
49:16 – can for it. And it’s – I wish it moved faster because you know you get – you – I wish it moved faster. But
49:24 – we have to be careful and we have to be precise. You can’t – you can’t just –
49:33 – I would love to write a book that says I can cure your UTIs tomorrow. And – but i don’t want to be –
49:39 – I don’t think that’s prudent. I don’t think it’s safe and so I –
49:45 – Melissa: Probably not. Dr. Schreiber: No, no, no. And so, anybody – just a last point. There is a lot of stuff out there that talks about things
49:55 – that people can prove your UTIs. Just if it works for you, that’s great. But if it doesn’t work for you,
50:03 – that might just be because biology is weird. Don’t be like – it’s just what’s – just the way it’s –
50:11 – biology is just weird. These things are so complex. So just yeah, just keep up the good fight.
50:17 – We’ll all do the same. Melissa: Yeah. I think it’s a good point to make. Everybody’s journey is different with this. And
50:22 – something that works for one person might not necessarily work for the next. And it’s really important to keep that in mind.
50:28 – Dr. Schreiber: Yeah, absolutely. Melissa: Well, thank you so much again for answering all our questions and I look forward to chatting to you more in the future I hope.
50:36 – Dr. Schreiber: Absolutely, Melissa. This was just an absolute blast. Thank you so much. Like this – you do such a service. So this – thank you so much.
50:45 – Melissa: Thanks so much for watching. I hope you found this expert video helpful. If you’d like to learn more about this or related topics, be sure to check out our other videos or head over
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51:06 – watching and until next time, keep asking questions and pushing for better solutions.