5/17/2019 It's a Gut Feeling: The Microbiome in Inflammatory Disease

morning everyone and welcome to Grand Rounds again thank you for all spending an hour with us of your time and I just want to say that I am very excited this is the second of our chief resident Grand Rounds and there as I said before they're almost always some of our best Grand Rounds so today our Grand Rounds is by dr. Anne - Dhara she is going to be staying on with us thankfully in rheumatology in her Grand Rounds is a gut feeling the microbiome in inflammatory disease now I just have to say you know chief residents they can solve any problem at any time at any time of the day they're on call for everything and it could be something really mundane and something life-threatening and serious so in true style of the chief resident stressful life the whole audio-visual system and the VA went down today so I just want to say that dr. chu Dhara is going to be presenting Grand Rounds kind of she has her own laptop here the system is going to work but nothing stressful like doing a major presentation with no appropriate audio-visual things in Clint thank you for getting everything set up as you happen so dr. chitara I just want to talk a little bit about her her mom is also in the audience here today she did her undergraduate degree here at University of Wisconsin and had a double major in both genetics and Italian she went on to her medical degree here as well which was followed by her internship and residency and was very we were very honored that she was able to stay on and be a chief resident with us here she has had many honors in a very brief time of her early career and I wanted to highlight that she is an Alpha Omega Honor Society member which is absolutely fantastic she's had two publications and posters in her residency which is quite amazing and has been the first author on a paper managing a vascular disease and rheumatoid arthritis clinical updates and three strategic approaches which was in the current rheumatological report I think that's bodes well for us here at University of Wisconsin she's also been involved with service activities here and has been a member of the internal medicine residency wellness committee I know that we're hoping that after a fellowship here in rheumatology next year that she might decide to make University of Wisconsin her forever home for her career and with that [Applause] we have that and we're not a moment and what I'm talking about is the title of my talk the gut microbiome what the microbiome is it's the ecological community of men's little symbiotic and pathogenic organisms that share our body space so as dr. Coburn mentioned I studied genetics in undergrad and I've always loved microbiology and when I was researching this topic I am still amazed by the sheer scale of what goes on inside ourselves how it might relate to disease which I'll tell you about today and just how much we really don't know so I hope they'll take away some of the sense of wonder that I had in exploring this topic and just be aware of kind of what it is because it's going to be something that affects all of our fields in the next few years I can pretty much guarantee that and I hope you have a couple tangible takeaways so we'll start so let's show of hands how much do you think the bacteria in our gut weigh on average who thinks it's a tenth of a kilo anyone how about half of a kilo that's a pound okay how about one kilogram it's like two pounds okay and then how about two they interest you that we 4.4 pounds of bacteria in our gut that's a lot if you think about it now the microbial is a lot of different big numbers because what we're really talking about is populations we're not just talking about individual cultures of single bacteria it's not that 95% of the microbiome is located in the GI tract we think the individual has a unique signature in terms of the gut microbiota and we talk about absolute numbers it's estimated that there's 10 to the 14th organisms that live inside ourselves and it's thought that perhaps ultimately 90% of the disease that we have can actually be linked back to the gut in some way shape or form so a lot of this is you know relatively newer studies right because we've got all this like metagenomic data well it's actually been studied since the 1600s yeah who invented the microscope that's actually his microscope he was actually looking at his own aural and fecal samples under the microscope and noticing that they were different back then he was calling him animal cue balls regardless this is something that's been fascinating people for centuries so I have a few goals for you today I'd like you to be able to name three rolls of the gut microbiome and define what dysbiosis is we'll talk about potential mechanisms of dysbiosis and a few conditions I'm skewed towards Rheumatology but we'll talk about others as well specifically we'll talk about spondyloarthritis rheumatoid arthritis and lupus and then I want to give you some clinical applications of this fairly basic science field with the goal of improving patient care like I said microbiome so much right now so don't do this we'll talk about the gut microbiome we'll spend a portion of time talking there we'll also then move specifically into the examples I mentioned and different diseases and then we'll talk about some lifestyle factors some specific interventions and then the idea of drug response and pharmacokinetics I think that's really compelling so let's start with the government go back now it's thought that when we're born our gut is sterile but by age 2 to 3 years that's when we've got all of our communities and it's established pretty quickly just by how you're delivered and by how you're fed we know it's linked to your adult composition breastfeeding itself has been linked with less incidents of asthma celiac and ankylosing spondylitis and other autoimmune diseases and we've also seen that disruptions at a young age for example antibiotics less than one year of age they actually increase your risk of childhood inflammatory bowel disease later on so we do see that disruptions early on have lasting effects we know there are genetic components there there are some heritable taxa in twin studies using that monozygotic twins are more similar than dies of twins who then are more similar than if you look at mother and offspring pairs and then there are a lot of influences which I will get into but we talk about environment antibiotics medications and a lot of our lifestyle choices that we make so the gut microbiome once established by a couple years in it's not to be generally stable in terms of the populations were thinking of there's an interesting idea that perhaps the resilience of the microbiome when there is an insult whether it's antibiotics a GI illness or something else the ability to take that hit and recompose itself that might be a better indicator of health and just the exact makeup that we're talking about we've seen some gender differences a lot of this is in my studies at the moment but there's really thought to be potentially a hormonal role in terms of what bacteria might be expressed and we also know that women have enhanced reactivity in terms of the immune system that has the benefit of having women having lower risk of infection but of course we know that women are at anywhere from two to ten times more risk of autoimmune disease in general and another way to think of this is as a collection of ecosystems so the oral microbiome is different from the stomach which is a pretty inhospitable environment that's different from the duodenum which is different from the colon so it varies along the GI tract but also cross-sectionally I'll talk about the anatomy of a gut barrier in a minute but you'll find different bacteria kind of different levels too so this is an example of a healthy microbiome and this is what a lot of the settings look like so I want to point out the big phyla we're looking at so again we're talking pretty broad categories here we're not down to the species level at all so firmicutes is a group of gram-positive organisms bacteria teas are gram negative organisms and you'll see them together they make up about two-thirds of the whole microbiome again this is a healthy version I'll talk about dysbiosis and a lot of conditions and often times we'll see as the proportions of these two phyla get flipped so we look at relative abundance because we're looking at individual populations so that's an important point and then just to be familiar with these studies a lot of times they'll talk about operational taxonomic units and what that is is a researcher will set a threshold say 97% in which they can actually group similar groups of bacteria so that's the way they're usually referred to now I told you that gut is pretty similar once it's established over the lifespan I like this image because it shows a little bit of the changes that we have as well and early and end-of-life so the red and the white are the two big file that we talked about so you can see that an 8 week old infant who's complete microbiome isn't yet established it looks different than a young healthy adult who's got that kind of ideal proportion there who's different from someone who's a frail elderly person who also start to see a little bit of changes there as well and there's a lot of things that go into that metabolism medications and other things so then we talk about what exactly are these bacteria doing for us now there's a few big roles I want to mention number one is nutrition we've seen that these bacteria are able to synthesize vitamins vitamin K a lot of the water soluble vitamins vitamin C biotin and in part of their commensal role they provide these nutrients to the gut epithelium in which they reside there's a lot to do with metabolism as well those two file I mentioned we know that they have a lot to do with breaking down fats and processing complex carbs and one of the most popular breakdown products to look at it are called short chain fatty acids these are things like butyrate propriété but they're thought to actually have an anti-inflammatory role so that's something looked at and that whole area of study is called metabolomics that's a whole nother area we won't talk a ton about today but these short chain fatty-acids have a role in energy metabolism even glucose and lipid homeostasis they're formed through fiber fermentation and they have a role in influencing satiety so there's some role and body weight there and we've also seen that reduced levels of these short chain fatty acids are actually linked to bowel inflammation and then most importantly I would argue there's this role in the immune system so of course we're trying to balance self tolerance with defense against invaders and if you think about it the most antigenic system or a foreign stimulation we're getting every day is by what we eat so by physical presence and functional presence the normal bacteria are able to out-compete pathogens of course if you have reduced diversity or you know get knocked down by antibiotics that allows pathogens for example c-diff to bloom and cause pathology there there's influences on innate and adaptive immunity and of course we know that got associated lymphoid tissue is makes up about 70% of our immune system that includes peyer's patches lymph nodes so I told you that 95% of them are bacteria in the gut well most of the immune systems there as well and if you start to look into this you will find so many more proposed roles there have been evidence that bite these bacteria are able to produce neurotransmitters so there is potential that it may be involved in mental health in human behavior and I also be briefly mentioned wait so like I said if you keep looking you'll find a lot more ideas so this is the most immune ology we'll talk about today but I wanted to establish what the barrier of the gut actually looks like so this is a layer of epithelial cells here and then there's a mucous layer that is established by the normal good bacteria these are two examples of potential pathogens we've got post radio we got segmented filamentous bacteria and some studies that's pathogenic so they produce these microbial associated molecular patterns these are things like lipopolysaccharide peptidoglycan which are recognized by toll-like receptors located outside of those epithelial cells but also on the antigen presenting cells I think a lot of us are familiar with and South look when they lead to immune system stimulation a lot of the studies will talk about kind of the balance between T regulatory and th17 cells as an influencing autoimmunity and I like this image because it also included the beneficial short chain fatty-acids there so just to remember that we've got kind of the balance of the good and the bad there so then we go into speaking about how do we actually study the microbiome I told you it's a relatively new field in terms of the advanced technology we have and it's really been in the last 13 14 years that we've been able to develop metagenomics and actually study these things so the US had its project you need to describe the microbiome start in 2007 Europe had its sister project in 2008 and the two big techniques I want to talk about our 16s ribosomal RNA and then a genomic shotgun sequencing because that's what mostly all of these studies use 16s rRNA that's produced from the 30s subunit so it's actually specific to bacteria so these studies are able to describe huge populations although they don't get terribly down into they're not able to get down into the genus or species so a little bit limited resolution there conversely metagenomics shotgun sequencing more expensive not surprisingly but it's able to get down into the family genus level so we get a little more taxable resolution and it has the benefit of describing all the other domains that I'm not talking about today so we're talking about bacteria but there are phages there are viruses there are archaea that we're still working on describing and we don't know exactly what there have been doing yet so it's thought that by now we actually have our parts list or kind of the description of what a normal microbiome looks like mostly complete for the prokaryotic domains so the bacteria but not those other ones so that's kind of the next step so why is this all important well you know suppressives are expensive specifically speaking to Rheumatology they have toxic side effects and not talking about that kind of steroids we've all seen the effects of them but we really need to identify effective therapies looking for biomarkers to detect disease early to detect disease progression as well as exploring other methods of disease management and really patients are asking I've been in clinic not just Rheumatology clinic but when patients come in with chronic disease they're looking for any way they can help self manage their disease - and it's empowering to have to be able to speak to a certain diet or something else that might be able to help them feel better and also help their disease so that's what this ultimately is getting down to you in my mind so let's talk about this biases and inflammatory disease it could be a couple examples here now what it actually is is a departure from healthy it's characterized by reduced diversity we could have a byot expansion so expansion of those pathogenic organisms subsequently we lose the commensal phyla this is often taking place in a genetically susceptible host we know a lot of the risk alleles for various diseases and these tend to be the studies we're looking at so the idea is that you get overgrowth of a certain bacteria that ultimately leads to inflammation via immune system stimulation so I'll talk about the mechanisms here but we've seen it in a lot of different diseases again if you start digging into this you will find a ton of information so the three always speaking about today's model arthritis lupus and RA but we've seen it in diabetes obesity fatty liver disease even cancer and smoking and more and more if you continue to look so in rheumatology part of what we look at and trying to detect pre clinical disease is one does that break and self tolerance occur does it take multiple hits what's going on there so there's this idea that maybe the beneficial bacteria in our gut might trigger autoimmunity and someone who's genetically predisposed so we talked about a few different mechanisms to know now molecular mimicry is one idea where bacterial peptides are actually just look like a soft peptide and they lead to kind of fooling the immune system and causing stimulation in that regard central ination I'll talk a little bit more about it later all it is is a one amino acid substitution from arginine to citrulline but that is detected as foreign and causes a whole lot of pathogenic effects particularly in rheumatoid arthritis some of these bacteria produce super antigens so they just go on to stimulate the immune system more than normal there's also this idea of epitope spreading so normally we have an MHC class 2 molecule detecting one particular protein well something happens that that molecule is able to TechEd a ton of proteins which just causes more downstream stimulation get auto activation of these self-reactive tiendas lymphocytes and amplification production of inflammatory cytokines Auto antibodies and disease in that regard and interestingly you know we do see 10 years of preclinical disease in a lot of these conditions where you'll see these Auto antibodies but people Knight and I might not have symptoms so there's some sort of underlying pathology going on and that's what this is trying to get at another fact is that when we compare the patterns of dysbiosis so I showed you the normal just a little while ago when we look at the differences they actually are pretty similar between a lot of these inflammatory diseases so comparing the types of inflammatory bowel disease multiple sclerosis RA they have pretty similar patterns of dysbiosis so I mentioned in terms of diversity that's one potential indicator of health well this was a study looking at about 68 patients who they did 16s rRNA sequencing one of those techniques I mentioned they looked at a population of control control healthy people those with spinal arthritis and rheumatoid arthritis here they just looked at numbers of species and you can see that the two inflammatory conditions were not significantly different from each other however compared to normal healthy people there were a lot less species so we see lower diversity there and then there's the idea that when we get towards proof of concept a lot of this is done in mice to start out but what we see in a lot of these conditions is that germ-free mice actually aren't getting the diseases so a couple examples here this is looking like our a autoimmune arthritis we have lupus diabetes this is supposed to be ankylosing spondylitis in a mouse model when they're raised in a germ-free environment so none not even the good bacteria the impact on their disease a lot of them don't end up getting disease lupus is interesting because there's no change but there seems to be some sort of correlation there so I'm gonna first start by talking about spondyloarthritis and just to refresh that's a group of multiple conditions often times affecting the sacroiliac joints we've got ankylosing spondylitis there psoriatic arthritis and it's often characterized by disease and multiple mucosal sites including the eyes so a systemic disease with arthritis as a prominent party so to speak a little bit about that we know that there is a big link between inflammatory bowel disease and spinal arthritis up to a third of patients with IBD will have some sort of arthritis and it goes back the other way we've seen that reduce diversity in a number of these studies so the microbiome is just there are fewer species around potentially allowing pathogens to take over again those germ-free mice who are genetically susceptible they have that HLA allele if they're grown in a germ-free environment they don't get arthritis but if you go and introduce what we think are normal you know lactobacillus for example to those mice they end up with the usual progression of their disease so they get the earth Rytas they get the sacroiliitis so there's something to be said for introducing that bacteria and what effect it might have I would actually group reactive arthritis in this category as well for the reason that you know we're talking about perhaps the idea of gut permeability here as well so reactive arthritis is the syndrome that can occur after a GI illness for example Salmonella or Shigella you get inflammation there and somehow there is a cross of the barrier because we've actually been able to detect DNA from these infections in the joints themselves and leading to a systemic symptoms their syndrome excuse me this is just an example of the many sites that can be affected in reactive arthritis so there's some way for it to get across the gut barrier and actually cause disease in multiple areas the other entity to bring up is gastric bypass associated arthritis this is a rare entity but what I think it actually shows is that you know this is an example of a roux and why Anatomy here so you've got this whole area of bypass small intestine and I'm telling you about these ecosystems these populations there there's a thought that you get some sort of dysbiosis that occurs here perhaps because it's not being stimulated but regardless what ends up happening is you get immune complex formation and deposition in joints again something to be said for the gut barrier being compromised in that regard so the joint had got are linked a nice study in the nineties actually looked at ileal biopsies from patients who had spondyloarthritis and they found that half of them actually had microscopic gut inflammation but they didn't have any symptoms and they found that when they tracked them and we biopsy them after treatment as the joint inflammation improved so did their gut this was a nice study as well this was from 2014 by a Belgian group they looked at 68 patients and they biopsied them they all had spondyloarthritis and they had a group of healthy patients as well and when they found was people who had chronic got inflammation that's that category there they had significantly increased this is bone marrow edema they're securely at joints seen on MRI and the y axis here is the sparks core which is a radiologic image of damage seen on MRI so those who had chronic inflammation had worse joint inflammation on imaging and I think that just supports this idea of treat to target which is pretty broad across dermatology but the idea being that you really want to completely abrogate any inflammation that you see because in all likelihood we are having a lot more effects on the gut perhaps then even just on the joints we're following a couple more specific examples and these are two populations that were identified as being increased in these spinal arthritis patients died Alistair is one it's a member of that Firmicutes phyla so it was found in looking at patients who again had spondyloarthritis and they had ileal biopsies those who had chronic information it actually correlated as you had more of this dial astir their disease activity score was higher so they found it was more abundant in disease and as your disease worsened you had a higher proportion of this bacterium similarly room in a caucus novice in a different group this is brevets group they found again it was increased in proportion in people who had a sponsor Rattus and IBD particularly so kind of that double hit there but it also again this is a disease activity index amount of room and caucus they found it increased as well so they proposed that perhaps this might be a sort of microbial disease activity marker it's not quite there yet of course this is a lot of basic science but there's something to be said for these increased populations that we don't see in healthy people so next I want to talk about rheumatoid arthritis that being the systemic condition causing a lot of peripheral joint arthritis erosive disease but can also have multiple systemic effects as well so even back in the 70s we were looking at the potential of bacteria being involved a Swedish study actually looked they were able to isolate this diplo streptococcus they found it in 80% of people who had RA only 20% of healthy it's also found in pasteurized milk so what they did was they actually injected it into rats who subsequently developed arthritis started making rheumatoid factors so they said it caused RA now that's not exactly true but there's been this idea that there's some sort of link for many years we seem reduce diversity in early RA this will be a theme you'll hear and then now I want to talk about citral ination and with a shout-out to dr. Shi laughs whose lab focuses on this and I just wanted to say a couple words about it now I mentioned it it's a one amino acid substitution but we know it's a critical step in rheumatoid arthritis and it often occurs years before we see sort of symptoms in people the CCP antibody central unaided antibody it actually correlates with disease duration as well as damage and we've seen evidence that such eliminated proteins are created in the lungs especially in people who smoke and are also related in periodontal disease so we're going to go a little proximally and talk about the oral microbiome for a minute here because RA does have a strong link with periodontal disease as well this was a paper in 1900 in the British Medical Journal actually proposing that dental disease was the root of all disease including arthritis and multiple other disease now hunter wasn't / - he wasn't completely wrong I'll say that because for pheromones gingivalis is one example of a bacteria that is increased in dental disease we know it's there and it actually produces the enzyme pepcid l-arginine deaminase that citrulline aids so here we have a bacteria that can actually caught create these citrulline ated proteins that we know to be in effect in rheumatoid arthritis and 119 years later also in British Medical Journal there's a nice study that just came out looking at pee gingivalis that actually was able to show that an induced rheumatoid arthritis and produce CCP antibodies in the rat so we're starting to see some proof of concept there which I think it's really fascinating and I like this image with this idea of multiple microbiome hits potentially breaking that self tolerance and triggering something like RA here we've got the P gingivalis I told you it consensual in E and then you get this kind of inflammatory cascade leading to RA we're going to talk about the gut microbiome again and specifically this prep atella copper here too so that's another one that has been proposed to be involved so this is one also in that firmicutes class and what I want you to pay attention here this was a nice study of my shear done in 2013 he looked at about 120 people they did 16s ribosomal RNA sequencing on them and they identified that does present a low species that's the red one was increased in people who had new onset rheumatoid arthritis so people who had not yet been treated and that was looking and then those with healthy it's also actually been described in a couple other diseases as well as being increased so here simply they're looking at the number of total reads and a few different conditions so we've got the new onset RA you can see a lot of the red there there's healthy subjects a lot less chronic rheumatoid arthritis and they also looked at psoriatic arthritis so they saw a difference proposed that there the other point I wanted to make though is that it's very interesting that the chronic RA folks who had mostly been treated in this study and were had their disease control they're pretty similar to the healthy people so then there started to be this idea that maybe our treatment is actually helping to normalize the microbiome there are other bacteria that have been linked to RA I'll just briefly mention them there's a few here we've got common sella that actually induced arthritis caused inflammation and a rat Proteus and UTIs epstein-barr virus mycoplasma and EBV itself has actually been shown to citral innate so potentially causing pathology there but in all likelihood it's a molecular mimicry type mechanism for a lot of these and when we actually look at the joint fluid of people with rheumatoid arthritis it has been able to we have been able to see different cell wall constituents things like lipopolysaccharide peptidoglycan as well as bacterial DNA so I mentioned this idea of the microbiome potentially normalizing with treatment so this was a nice study they actually looked at this is people with inflammatory bowel disease and they looked at who responded who partially responded and who didn't respond to a TNF inhibitor and this was at time zero so these are the non-responders here and this is just looking at the diversity and so here they mention that at time zero the non-responders had much lower diversity and then when we get to time three when they all had been treated with a TNF that difference was no longer there so they proposed that perhaps that was representing improvement of the microbiome or at least a loss of that difference there so in another study this was a really nice one in Nature Medicine from 2013 they looked at people with rheumatoid arthritis who were on methotrexate and etanercept they were also able to show that the microbiome partially normalized and what they ended up doing was then they made these training sets this is from a fecal microbiome set but they actually tried to go backwards and say by analyzing the microbiome itself are we able to say which of these patients actually had rheumatoid arthritis this is the receiver operating curve and you can see that it's actually got a pretty decent sensitivity and specificity for trying to predict who has disease based on just looking at the microbiome so some pretty interesting ideas there so then we'll move into talking about lupus definitely the most complicated of the bunch I would say and with a lot of systemic disease particularly renal disease is something we talk about and a lot of auto antibody production another interesting historical fact in the 1930 is DNA anti DNA antibodies were first reported in patients who had bacterial infections things like strep only in the fifties did we know learn that they're actually related in lupus and actually can cause significant pathology like the renal disease I mentioned we see decreased diversity again just contracted ability of the flora to react there and there's a big link between infections there's a whole list of infections that we know to trigger lupus whether it's triggering onset of disease or causing flare but it all have also been reports from patients that having disease actually leads to improvement of their lupus system symptoms and maybe that's because of redirection of the host immune response we've also actually seen that some infections are even protective so there was a study looking at African American patients and those who were h pylori seronegative that was actually associated with earlier onset of lupus and increased incidence of lupus and areas of the world where Hellmann's are endemic tend to be developing countries there is increased incidence of autoimmune diseases not just lupus in all likelihood that's related to the hygiene hypothesis we've also seen that antibiotics can trigger loop players we know a link between sulfa antibiotics and whether that's an immunomodulatory mechanism or potentially affecting the microbiome we aren't able to say yet but these ideas persist so this was a nice image from a review that was comparing the normal healthy gut so you have kind of your normal flora shapes the B cell repertoire is a different antibiotic antibodies but in lupus having this restricted diversity allows for potential pathogens to bloom or take over so the two I'll be speaking about our might sound familiar room in a caucus I mentioned that back in spinal arthritis and also enter Caucus gala nerim so there's a couple different mechanisms they talked about but the idea is that they've been able to show some translocation and ultimately immune system stimulation there so first we will talk about eagle and Erin this was in science last year they orally gave this bacterium to lupus susceptible mice and then they were able to actually sequence the bacteria from different spots in the body medit Eric fans lymph nodes liver somehow it got across and in these mice it ultimately induced double-stranded DNA antibodies so some sort of lupus pathology there then they did a couple more studies where they either gave them oral vancomycin or they vaccinated them against with a he killed strain of Eagle in Ihram and that actually reversed the auto antibodies and improved their mortality so there was some sort of benefit by trying to treat the specific bacteria so then they went to look at humans and the way they did that was they took lupus patients who also had autoimmune hepatitis so some liver involvement and they looked at their liver biopsy results they compared those to healthy cadavers so a little bit of a different population there but they were able to show that you could only see this Enterococcus DNA in the people with liver bhaiyya in that lupus patients who have the liver biopsies and not in those healthy cadavers so image from a PCR this is the Eagle and arrow and you can see the band there we've got the lupus page and it's only present in lupus patients and this is comparing the proportion of the Eagle in Ihram in the liver biopsy's so we've got the control group autoimmune hepatitis significantly increased and then this is not autoimmune cirrhosis there I've spared you from some of the big broad bacterial pictures but I just wanted to bring up this one looking at relative abundance here so the red is Enterococcus this is an example of the controls so much less red and when you look at it compared to autoimmune hepatitis that's how they're interpreting is so in a somewhat similar fashion just earlier this year a group out of NYU looked at room in a caucus novice which I already mentioned and spondyloarthritis but they found that it actually was increased in abundance in lupus patients they looked at a decently sized cohort of female lupus patients it was about 61 patients they had varying levels of lupus activity and they found like five times more incidents of room in a caucus compared to healthy controls and they found that it correlated with double-stranded DNA so there was actually a direct relationship there they did some mechanistic work and proposed that there might be a part of the cell wall that actually was a tolike receptor agonist so potential mechanism and they also looked at levels of fecal calprotectin in these patients now fecal calprotectin we often think of an inflammatory bowel disease it's an accepted indicator of an impaired gut barrier but in a lot of these lupus patients they found elevated levels there so something was going on this is looking at an operational taxonomic units I mentioned those kind of similar groups what this is trying to show is decreased diversity again in the lupus patients compared to healthy controls when they divide a lupus into activity significantly more people who had worse lupus had lower diversity there and then they looked at the entire room in a caucus antibodies here we've got the IgG and they looked up with his patients divided them into who had renal disease who didn't and those who had renal he's had a significantly higher proportion there - so again we're thinking about this idea of potentially bacterial markers which i think is really fascinating and overall what I want to say about that is that we know there's a valence this is kind of the ideal balance we've got normal healthy gut we've got a good balance of the Pro and anti inflammatory cytokines when we have dysbiosis which we have observed that's something shifts to support an autoimmune state so we get so I'm sort of overgrowth but the pro-inflammatory cytokines those are really shifted up so the question becomes is this cause or effect is it the gut bacteria themselves that are driving autoimmunity I think that we're starting to see some evidence that they very well could be but the other question is is it just a general inflammatory State that actually in itself is shaping the gut microbiome only time will really tell in terms of what exactly we'll see so then let's move on into some of the practical considerations we'll talk about a few different ideas here but what we're really talking about at its base is modulating the microbiome so we've really been doing this all along even if we don't know it traditional herbal medication even centuries ago actually has an effect and now we're doing things like fecal transplant so we can think of them as targeted approaches probiotics is one example antibiotics as well where we're giving one specific strain and having an effect there or untargeted methods that's where fecal transplant comes in you're trying to shift someone's whole microbiome into someone else diet in all likelihood as well and medications as I'll show you so dyad when we think about prebiotics this term is big all it is is food ingredients that can stimulate growth or activity of gut bacteria this is like all the micronutrients that we have and these are foods that are rich in prebiotics probably not surprising that it's a lot of fruits and vegetables the things we're supposed to eat right but this was a nice study actually looking at the contribution of fiber and I think a fiber is a really big part of this because I mentioned earlier that some of the breakdown products of fiber namely those short chain fatty acids are in all likelihood to inflammatory and have an effect there this study was looking at mice and they were able to show that if you fed these mice a fiber rich diet they had a normal barrier oh as well if you gave these same mice a fiber free diet you just did not have a good barrier those normal microbiota were not able to produce the mucus keep that barrier intact like they were supposed to or if you grew them in a germ-free environment so they really had no bacteria whether you gave him five or not they just you just didn't have evidence of a good barrier so this is really the idea that it's an important part of what our diet should be thinking a little more about specific evidence there specifically in rheumatoid arthritis there's been a lot of small studies oftentimes they'll start with like a seven to ten day subtotal fast and then they'll do their diet intervention there's an idea that maybe even the subtotal fast actually induces a transient immunosuppression and the mechanism for that might just be that you're getting less antigenic stimulus less foreign protein and so that actually calms things down for a bit but regardless we've seen clinical and functional improvements some weight loss some lipid improvement but when they do look at the microbiome they don't see specific changes in flora one study looked at the Nurses Health Study and they found that a healthier diet was associated with reduced risk of RA with a pretty compelling hazard ratio there and the other conditions I've talked about and lupus it's more than looking at specific micronutrients things like vitamin D or E omega-3s maybe those decrease some disease activity measures maybe they alter the flora but it's not great data and again in spondyloarthritis one study looking at high dose omega-3 fatty acids found and improved disease activity index but others have found really no effect so we definitely don't have enough information to say but people will come to you and ask they will ask me what is an anti-inflammatory diet what can I tell them my answer would be it's probably Mediterranean type and I'll tell you why there was a randomized control trial back in 2003 looking all right they put people on the Mediterranean diet for 12 weeks and they actually found improved disease activity measures and no change in the control when they looked at their fatty acid profile they were able to see that that improved so in all likelihood were increasing those levels of short chain fatty acids there just to remind ourselves what the Mediterranean diet looks like the base while the base is being active and sharing meals but you've got fruits you've got vegetables the Greens olive oil legumes then we got kind of the healthier meats right got a little bit of wine in there too but you know the general Mediterranean diet there was a nice study in circulation earlier this year oh is a systematic review and meta-analysis that they I took this actually from that study because I liked what they said the available evidence is large strong and consistent that being able to conform with this diet is associated with better cardiovascular health outcomes for a lot of things coronary heart disease stroke cardiovascular disease so these Rheumatology moto logic conditions I've talked about you're already at hoc way higher risk of cardiovascular disease just from the general inflammation and you know at it being able to add a diet that perhaps reduces that I think is really compelling and then no talk about rheumatoid arthritis or lupus would be complete without mentioning smoking it's a huge part of the environmental risk in rheumatoid arthritis and we've seen evidence of the sit related proteins as I've mentioned earlier we see him in lungs of healthy smokers we see him in early RA if you have these susceptibility genes you're probably just at even higher likelihood we know smokings role of course on cardiovascular disease inflammatory bowel disease pathogenesis particularly in crohn's disease and we've seen that the gut microbiome itself has been linked to elevated cardiovascular risk possibly through an inflammation mechanism there one study looked at diversity again and they looked at the oral microbiome of smokers and they found an increased incidence of this private ala group so again we've seen that in the gut and now in smokers mouths we've also seen it and they also looked at diversity this is a shannon index which is an ecological measure diversity and this is looking actually they looked at control people they looked at people who run east cigarettes as well as tobacco smokers and the tobacco smokers had a significantly reduced diversity compared to everyone else and then I mentioned dental care as well so periodontal disease has a big role in rheumatoid arthritis also in cardiovascular disease and other conditions but dental care is hard to come by not all dental providers except Medicaid or badger care and I wanted to provide a couple resources just to be aware of because this is such an important thing there's a list of free clinics in Wisconsin through the DHS website the Department of Health Services and here at the VA you were eligible based on your level of service connection and also if you're able to to show that someone's dental health is affecting their health conditions that may be an indicator as well to get some care but if someone is really in need there's this cool event called the mission of mercy that actually took place in Madison back in 2012 at the Alliant Energy Center and it's basically like it's a big dental free dental fair that occurs over a day or over a weekend and they try to serve as many people as they can so it's not a substitute for regular good dental care but it is something for people who might not have anything and what it really comes down to though is for these high-risk populations we really need improved coverage so to say a bit more about oral microbiota something going on at our own institution we have something called the cohesion trial which is actually in conjunction with the Marshfield Clinic they're looking at this plaque HD toothpaste it actually is the one that turns your teeth this color we've all probably seen it and they're looking at high sensitivity CRP levels and adults you have mild or severe periodontal disease and as a secondary objective they're actually looking at the microbiome and what it looks like before and after this intervention and I just wanted to mention it because we've got a few of our own involved in this Karen is one of the pis doctors tattersol striker in lemansky also from UW are also involved so I look forward to seeing the results of that and then of course with our own Wisconsin institutes for discovery and UW biotechnology Center we've got our own microbiome hub here and they're looking at a whole bunch of different projects within this realm it's a multi-specialty collaboration dr. Andes is involved in this as well I saw on their website but one of the cool projects they're doing is actually looking at precision editing of the microbiome using bacteria phages and how that might be in effect so that's their website I would encourage you to check it out if you're interested in that but just another example of kind of what we're doing here at UW so a couple more interventions I want to speak about well probiotics are a big one that people really asked about unfortunately one systematic review that looked at healthy people found no effects of different probiotics on microbiome composition they also showed that they did not even engraft so they literally just passed right through in the conditions I've discussed today we found pretty minimal or no evidence of any sort of benefit that we see now I haven't talked much about scleroderma today but it is a disease that has pretty significant GI effects and symptoms there was a pilot study of just 10 patients but they actually found some improvements in a few measures including patient reported measures like reflux or bloating and emotional scales but what I think it really comes down to is we have our established gut microbiome we have it there and it's resistant to colonization by pathogens yes but also by these probiotics that might just be recognized as foreign because they're not similar so I think a way that to perhaps get around this is in the future when we're able to better define what an individual microbiome looks like perhaps then we'd be able to give tailored strains that are more similar to actually have the chance of engrafting within got an actually providing benefit there then of course we'll talk about Pico transplant to remind ourselves what it is it's literally taking stool from a healthy donor putting it in a recipient GI tract usually that's done via capsule form it can also be done via enema and there is an FDA exemption in recurrent c-diff for this treatment and it's been shown that it actually increases microbiome diversity so it has the intended effect if you go to clinical trials.gov you will find over 200 ongoing clinical trials in a lot of different conditions looking at people transplant anything from ankylosing spondylitis which I've talked a little bit about melanoma irritable bowel syndrome even so that's something that remains to be seen now it's talked about a lot in inflammatory bowel disease and I briefly wanted to mention you know of course the pathogenesis of IBD is a lot more complex than c-diff which is an induced defect from antibiotics a big systematic review that came out a couple of years ago looked at in total to 122 patients and they found overall a 45% remission rate after these experimental trials it seems to be more effective and crohn's disease compared to ulcerative colitis but certainly we are nowhere near the point where this can be something we recommend there is also a risk of flare that's been known with this treatment as well so it is something that is out there and I think we'll learn more about all these conditions as we go forward but we can't say much about it there and then there's this idea of super donors so as we learn more about what our microbiome looks like there are certainly people out there who've got the best microbiome the richest the most beauteous one can donate their stool so we will see and then lastly this I think this is where it's going to come in to affecting all of us in terms of drug response so I'll first talk about some findings in rheumatology and then I'll talk a lot of other stuff so there are a lot of chemicals that we already use in rheumatic disease sulfasalazine right fam facin the antimalarials and sulfasalazine that's an image of it there it was actually deliberately created in the 1940s to combine an antibiotic in an anti-inflammatory back when we were still thinking that you know there is an infectious agent in rheumatoid arthritis and even nowadays we know triple therapy which is two of these anti microbials is just as effective as methotrexate and a biologic and rheumatoid arthritis a couple trials actually a couple decades ago now 2006 and 1995 one looked at adding doxycycline to methotrexate and found improved outcomes compared to just methotrexate this was in humans both of these one looked at minocycline and found that that had some improved outcomes compared to placebo now in all likelihood it could be an immunomodulatory effect of the medication itself but knowing what we know now about the microbiome there might be some effects there and then there's this idea of methotrexate so not all patients with RA will respond to oral methotrexate but sama when you inject it then you'll get a response so I've told you that there's dysbiosis in RA right so some of the populations that are increased are these Bacteroides species and it's been shown that some of these Bacteroides are actually have high levels of dihydrofolate reductase so it might actually be competing with a host dihydrofolate reductase to actually cause more rapid metabolization of the methotrexate which is perhaps why when it's given orally it doesn't have as much of an effect so when you bypass that by giving it injected maybe it has an effect there so I like this image because I think the microbiome is going to be something that we really need to think about when we're speaking about pharmacokinetics and drug effect we've got a drug up here we've got the host the genetic factors and we've also got the microbiome has its own entity in metastatic melanoma it's been shown that the microbiome effects who will and won't respond to these pd-1 inhibitors that are baked now also in oncology the floral pyramides microbiome has been found to affect the response metformin is a significant contributor to dysbiosis and type 2 diabetes and in all likelihood has a lot of effects there in cardiology there is a strain called agra tala lenta that actually metabolizes digoxin more frequently it's found in normal gut microbiota so this may perhaps contribute to why it's really hard to get normal digoxin levels and some people also in that realm I mentioned a little bit that the microbiome has a role in lipid metabolism and homeostasis in addition when we give different statins the microbiome actually affects which status people might respond to so overall I would say that meds because people are on a lot of meds generally and we're not knowing all of the effects they're probably the most important Cove area in the composition of what's in our guts right now there was an in vitro screen this was in nature last year they looked at 1200 human marketed drugs FDA approved and they found that half of the non bacterial anti-infective and a quarter of all of the human targeted drugs inhibited at least one gut commensal and this wasn't just things like proton pump inhibitors or h2 blockers they looked at all classes antihypertensives atypical antipsychotics were over-represented so what I'm saying by this is that when we prescribe medications we're probably having even more effects than we can really know at this point so then we get into kind of future directions and you know we're still working on determining what exactly is a healthy microbiome we also need to start looking at these other domains I mentioned the viruses the bacteria phages the archaea the eukaryotes and how did these all interplay we need to establish causality a lot of these studies are observational we're just simply at the point where we're describing what these populations look like we don't actually know the role of a lot of these bacteria I've mentioned today so that's a logical next step as well as showing proof of concept we're starting to see some of that in my studies and more base but of course the next step is getting into humans I think the idea of biomarkers is really compelling there's one act right now looking at looking at the microbiome and Crohn's disease and trying to predict depending on what your microbiome looks like if you stop at TNF inhibitor who's more likely to relapse so there's one example there but also being able to detect preclinical disease as well as follow disease we really need some ideas there I mentioned this idea of the whole mix so a lot of us we've talked about today is metagenomics but we have metabolomic switch is looking at the byproducts we have met a transcriptomics looking at proteins there's all these different fields we have all this big data and really being able to narrow it down and use that in precision medicine is really the next step and I'd love to see bigger better more well-done studies looking at diet looking at probiotics even fecal transplant and these other potential interventions that we can really do to try to help people so in summary I want to say we are really in the infancy of understanding this area of our existence we really need to think of ourselves as hosts and the microbiome in its own right which is definitely a bit of a perspective change we know the microbiome has extensive influence on the immune system I hope I've shown you that there's also a roles in dysbiosis in terms of many diseases and what I think a patient comes and asks the things we can recommend are a good diet probably Mediterranean type keeping up with dental care if at all possible definitely not smoking and controlling inflammatory disease because an all likelihood beyond what we're able to see in the joint what we're able to track clinically we're probably having a lot more beneficial effects and with the reference to one of the best albums of all time I will say that as our technology advances as we learn more we're kind of opening Pandora's box in a sense but I think that in itself is an amazing reason to keep pushing forward and learn more about this because it will affect you in the future Jeremy and Amy for helping me prepare this presentation of nasiha soft are and Karen Hanson for giving me their blessing on this whole microbiome thing Marian dish with evening library my Chiefs I am lucky to get to work with some of my best friends and of course my fiance and my mom dr. Bowman we're doing to our population yeah so dr. Bowman has proton pump inhibitors for example there is research out there it was out of the scope of kind of my talk today but if you actually go and look into this you will find that there are effects and they found thinking to some of what I've read about you know the GI specific mechanisms there are effects on the microbiome in all likelihood it's related to probably restricting some of that diversity they've also seen it with NSAIDs as well having an effect on the gut and whether that's through an inflammatory mechanism or working on the microbiome it's a little bit hard to say but I think there's certainly is research out there and it's being yeah so in that study particularly in terms of the control they were they use the Lupus acceptable mice but they just didn't give them an organism so they were just looking at kind of proof of concept actually giving this bacteria dr. Paris so is their website in the microbiome across mention that I am Not sure that's a great question so she asked you know since there's a much higher incidence of autoimmunity and women and we see some differences in microbiome between men and women is there a fluctuation across the menstrual cycle I would have to look into that that's a wonderful question also just with regard to being postmenopausal and changes there I would I would think there might be since there's an idea that hormones are playing a significant role testosterone and estrogen in terms of what populations were seeing represented so I would think there probably is a role mm-hmm we just might not have defined it yet thank you [Applause]

Channel: UW Department of Medicine

Views: 5,934

Rating: 4.909091 out of 5

Keywords:

Id: Fh6n3oSvMc0

Length: 55min 47sec (3347 seconds)

Published: Fri May 17 2019

Reddit Comments

[u/AutoModerator]

Welcome to r/ankylosingspondylitis! This is a reminder to keep discussions civil and be supportive of one another. Sharing of opinions and experiences is encouraged, but please remember the distinction between opinions and medical facts. This subreddit does not offer medical advice, and information here should not be taken over advice from your doctor.

I am a bot, and this action was performed automatically. Please contact the moderators of this subreddit if you have any questions or concerns.

[u/sleepymoose88]

Took me awhile to watch the whole thing while working, but that’s very impressive. It definitely sheds a lot of light why diet adjustments can have such a large impact on the outcomes of our disease.

Plus it seems like I can stop taking my probiotic. Clearly it’s just going through me and wasting money.

[u/GoldenSeam]

Woah thanks for this!

[u/chasedajuiceman]

this is an awesome share. thanks!