THE MICROBIOME SUMMIT : The Paradigm Shift

The Old Friends Hypothesis & the M.Vaccae Story

Dr. Chris Lowry, PhD

dr-chris-lowry-phd

Dr. Chris Lowry, PhD

University of Colorado Boulder

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Overview

Dr. Chris Lowry is an Associate Professor in the Department of Integrative Physiology and Center for Neuroscience at the University of Colorado Boulder. Dr. Lowry is doing important work with a species of bacteria called Mycobacterium vaccae – which has the potential to prevent serious mental health issues. In this interview, Dr. Lowry will discuss the “Old Friends Hypothesis” which suggests that our body is old friends with certain microorganisms that have been part of our evolution – and how these microorganisms are beneficial to our health.

Transcript

  • TRACEY:
  • Hi, Chris. Thank you for joining me here today.
  • CHRIS:
  • You’re welcome. It’s nice to be here.
  • TRACEY:
  • Your work over the past more than 15 years has been so fascinating and you’re one of the leaders in helping us to understand who our old friends are. Can you explain what the old friends hypothesis is and who we believe are old friends?
  • CHRIS:
  • Sure. So, the old friends hypothesis was put forward by Graham Rook and his colleagues. Graham is an immunologist in London, at UCL. Essentially, Graham and his colleagues put this forward to kind of modify what is called the “hygiene hypothesis” to take the focus away from, you know, using cleaners and anti-bacterial soaps and that kind of thing to really focus on the idea that “old friends” encompasses a much broader group of organisms than originally envisioned, which was really limited to infectious agents. And so, there’s three categories of old friends. The first is commensal organisms that co-evolved with humans throughout evolution. So, bacteria and other microorganisms have been around a lot longer than humans and all of human evolution occurred in the presence of these bacteria, including commensal bacteria that occupied the human host. These are reflected in what we now know are certain probiotics like Lactobacilli and Bifidobacteria that actually colonize a human host. A second category is something called the old infections and this is a particular type of an infection that was present during the time of the hunter-gatherer period of human evolution and what all these infections have in common are mechanisms to prevent inappropriate inflammation. And it’s this type of infection that would have thrived during the hunter-gatherer period because you’ll remember during that period there were small bands of groups of people that lived together, moved together, and we really didn’t have human existing in the great metropolitan centres that we do today. So, the types of infection that would have thrived then were infections that had mechanisms to prevent killing the host, because that would obviously decimate the entire tribe or prevent sterility because, again, this would result in termination of the host. And so, there are certain mechanisms that these old infections used to suppress inappropriate inflammation and persist for long periods of time in the host. We can get into some examples of those types of organisms later but the third category are what we call saprophytic organisms or organisms that were found in the environment that live off of decaying organic matter and would be abundant in meadow soil, for example.
  • TRACEY:
  • Right. Interesting. Now, you have studied one in particular. The Mycobacterium vaccae. Can you explain to us, you know, where it was discovered and what kind of things it’s being research in?
  • CHRIS:
  • So, Mycobacterium vaccae is one of those organisms in the third category, the saprophytic organisms that’s found in the environment. It’s abundant in peaty soil, or soil that has high organic content, where there’s lots of fermentation going on and the strain that we’ve been working on is a strain that was isolated in the 1970s around Lake Kyoga in Uganda. There’s a bit of a story behind this. John Sanford, who was an immunologist working at the time, and his PhD student, John Grange, and others recognized that the efficacy of a vaccination against leprosy at the time, the efficacy varied dramatically depending on geography. There were certain areas where these vaccines were really successful. One of these areas was the area around Lake Kyoga in Uganda so they flew there with the intention of trying to identify microorganisms that can explain why these vaccinations were so successful. When they got there they saw that the shores of the lake were lined with this orange slime. This orange slime turned out to be Mycobacterium vaccae. It turns out Mycobacterium vaccae and Mycobacterium leprae share a lot of the antigens and therefore the M. vaccae in the environment was acting as an adjuvant to boost the efficacy of the Mycobacterium leprae vaccine. It was only later that the immunologists, including John Stanford and Graham Rook, realized that M. vaccae was one of these old friends in the sense that it could induce immunoregulation and suppress inappropriate inflammation and it does this, and other old friends do this, by the induction of something called the regulatory T cell. Regulatory T cells are anti-inflammatory in the sense that they release anti-inflammatory cytokines like interleukin 10 and TGF beta and this prevents exaggerated inflammation mediated by the effector T cells which fall into three categories, TH1, TH2 and TH17 cells.
  • TRACEY:
  • So interesting. Our rise in chronic diseases can be linked to this inappropriate inflammation. Can you discuss some of the studies that you’ve been working on and what diseases, specifically?
  • CHRIS:
  • The original work with M. vaccae in this context was done with allergic asthmas so there are models in mice that use an antigen of albumen, which is a foreign antigen to the mouse, and that induces an allergic asthma response which is characterized by infiltration of particular immune cells into the airways like Eosinophils and these induce a local inflammation that results in the asthma symptoms. In these models, much of that work was done by Laura Rosa Brunet and her colleagues under the supervision of Graham Rook. They found that M. vaccae, a single injection of M. vaccae weeks in advance could protect against allergic asthma in these mouse models. They went on in a nature medicine article to show that it does this, in fact, by inducing these regulatory T cells and production of anti-inflammatory cytokines like interleukin 10 and TGH beta. So, that was the early work with asthma models. Our interest in our laboratory really is focused on psychiatric disorders. At first that may sounds a little bit obscure. Why would you think of psychiatric disorders in the context of the old friends hypothesis. But it turns out that psychiatric disorders, by and large, are in fact characterized by exaggerated inflammation and so trauma, for example, results in a low-grade inflammation that you can detect by measuring cytokine – pro-inflammatory cytokines like interleukin 1, interleukin 6, and these are driving a low-level chronic inflammation that’s implicated in these chronic inflammatory diseases. Another observation which is relative new is that some psychiatric disorders like post-traumatic stress disorder …. those individuals that have a diagnosis of PTSD and therefore a vulnerability also have a much higher risk for autoimmune disease of any kind and this would suggest, although we can’t really infer causality, this would suggest that there’s a common risk factor for having vulnerability to an autoimmune disease of any kind and risk of PTSD. One way that could happen is if the body’s own immunoregulatory circuits are impaired. In other words, if the body can’t shut off inappropriate inflammation then that’s going to result in an exaggeration of inflammation. We know from a study in US marines, a study that involved nearly 3,000 US marines, when they had blood samples taken in boot camp they measured a marker, a bio-marker information which is called C-reactive protein. After deployment, it was the marines who had elevated CRP concentrations at boot camp went on to develop PTSD with a higher degree of vulnerability.
  • TRACEY:
  • So, the connections then between the M. vaccae and what you’re doing with the mice to make them more stress resilient, what is happening there?
  • CHRIS:
  • The idea behind this is to use the body’s own immunoregulatory mechanisms to prevent inappropriate inflammation. If we can prevent inappropriate inflammation we can reduce that source of risk for development of a PTSD-like syndrome. And so we use a particular model in animals, a mouse model that we knew at the time had outcomes that were dependent on the stress-induced exaggeration of inflammation. The model that we’ve been using is a model that was developed by Stefan Rieber and his colleagues at University of Regensberg in Germany and it involves chronic psycho-social stress. This particular stressor involves co-housing four subordinate mice with a dominant male mouse and this formation of dominant-subordinate hierarchies is very common in mice. But there are consequences to this subordinate strategy. Included among those are exaggerated inflammation and we can tell that there are stress-induced exaggeration of inflammation several ways. One, if we take the immune cells out of lymph nodes and simulate those cells from the lymph nodes, the T cells, those T cells are sensitized in a way that they release more proinflammatory cytokines like interferon-gamma, interleukin 6. That’s an indication that there is, in fact, a stress-induced, chronic, inflammatory state. That leads to a spontaneous colitis and by colitis I mean inflammation of the colon. And the way that we’re scoring that in our studies involves a mixture of physical damage to the lining of the colon as well as infiltration of the immune cells which we can determine at the microscopic level.
  • TRACEY:
  • Right.
  • CHRIS:
  • So, the final end point that we’re interested in is anxiety behaviour and that seems to be sensitive to inflammation as well. So, the idea is we can use one of these old friends, set up this immunoregulatory state that can suppress all of that inappropriate inflammation over long period of time and that should prevent any outcomes that are dependent on this inappropriate information. And that’s, in fact, what we found. If we immunize with M. vaccae weeks in advance we find that the mice no longer have the spontaneous colitis, they no longer have the stress-induced exaggeration of pro-inflammatory cytokines from esoteric lymph node cells and they no longer have this exaggerated sensitivity in the chemically-induced colitis model of inflammatory bowel disease. Likewise, immunizations with M. vaccae prevent the stress-induced increases in anxiety. We know that the mice are stressed because they still show long-term changes in the hypothalamic pituitary adrenal axis, the HP axis, which is our stress hormone axis. Those changes still occur. The mice are definitely stressed. They just don’t have the inappropriate levels of inflammation that you would find under normal circumstances. One of the reasons this strategy is effective, we think, if you think about most of our pharmaceutical efforts to control inflammation we’re really targeting one branch of a very complex and interactive inflammatory response. There’s clinical trials using antibodies using specific cytokines, for example. Some anti-inflammatory drugs interfere with cyclo-oxygenase enzyme activity which produces very specific types of inflammatory agents ….I guess the point is, those are all kind of working way downstream in a very specific, inflammatory pathway. If you’re acting at the level of the body’s own immunoregulatory systems, you have a much better chance of suppressing multiple branches of inflammation because you’re really shutting off the tap at the source, so to speak.
  • TRACEY:
  • What is the role of serotonin in all of this? Because typically a person with depression and anxiety is going to be prescribed an SSRI. So, what do you think the role M. vaccae might be playing with serotonin?
  • CHRIS:
  • We published a paper very early in 2007 which, unbelievably, is 10 years ago, showing that if we immunize with M. vaccae and then challenge mice with M. vaccae this very rapidly has major effects on serotonin systems in the brain. The effects on the serotonin systems in the brain are really quite specific to a subset of serotonin neurons in the brain stem that we associate with anti-depressant-like effects. And we saw that those neurons are activated. In addition to that, we saw increases in serotonin in brain regions that are innervated by those neurons, like the pre-frontal cortex. Elevation of serotonin in the pre-frontal cortex is one of the responses that you find after administration of essentially all anti-depressant drugs. So, neuro-chemically, injecting M. vaccae looked like injecting an anti-depressant drug, we then followed up to look at anti-depressant-like behaviours in a mouse model and found that, in fact, injecting M. vaccae has anti-depressant-like effects on behaviour in what is considered the industry standard for screening anti-depressant drugs for potential anti-depressant effects in humans which is forced swim test.
  • TRACEY:
  • Right. So fascinating. So, M. vaccae is not only raising serotonin, it’s also working on the immunoregulatory system?
  • CHRIS:
  • Yeah, we think that those effects are actually mediated by quite different mechanisms. On the one hand, M. vaccae can activate serotonin neurons in the brain; that happens very quickly. The effects on immunoregulation are over a much longer time course and, in fact, seem to last at least three to four weeks. This makes sense immunologically because when T cells differentiate, including regulatory T cells, at least in mice, the half-life of those newly differentiated T cells is 27 days. So, once you make these immune cells, these T cells that are immunoregulatory, they stick around for about a month and you can benefit from the immunoregulatory effects of these cells over several weeks.
  • TRACEY:
  • Right. So, what are the chances that we are going to have inoculations of M. vaccae in the future, for humans?
  • CHRIS:
  • Sure. We’re very interested in continuing to develop the use of M. vaccae in clinical trials. So, there is an investigation on new drug status for the strain that we’re using in the United States. So, this means that the FDA considers M. vaccae as an injectable to be generally safe and we simply have some regulatory hurdles and hoops that we have to jump through in order to begin testing these injections in participants that have psychiatric conditions like PTSD or depression. At least with this particular strain, Microbacterium vaccae isn’t going to become available over the counter as a “nutro-pseudical”, or a nutritional supplement and that’s related to certain restrictions in how compounds are developed with the FDA. Things that are originally tested as for their clinical use as an injectable can’t be re-purposed for, say, a probiotic. These microbacteria, for whatever reason, are very rapidly taken up from the small intestine into the body. This may be true for multiple types of bacteria, but we know from animal studies that within an hour of administration of microbacteria into animals these microbacteria are contacted by what are called microfold cells in the small intestine. They’re associated with Peyer’s patches, you may have heard of that. It’s an immunological organ in the small intestine. And these microfold cells pull the microbacteria inside the cell. They extrude it at the basal surface of the cell where the microbacteria, the intact microbacteria, are engulfed by macrophages and dendritic cells. And so our body’s are constantly sampling the bacteria that come in to the body from the environment and it may be that our bodies are particularly in tune with the microbacteria that are in the environment because they’re so rapidly taken up.
  • TRACEY:
  • Right. Is there any chance that you can inadvertently get exposed to it by gardening?
  • CHRIS:
  • There certainly is. What we’re finding is Noah Fierer at U. Boulder had a project called The Wildlife of Your Homes. From that study, they took samples inside the homes and samples outside the homes above the doorway, dust samples, and often found that the microbacteria are present in higher concentrations inside your home than outside. This might seem like a paradox because we think of microbacteria as being environmental bacteria abundant in the soil, the dust, et cetera, but it turns out there’s something that many people do not know about our homes that’s really interesting when it comes to microbacteria. That is municipal water supplies and the pipes that provide our municipal water, the tap water, are lined with millions or billions of living microbacteria and the reason is because the water treatment plants that use chlorine and other chemicals to purify the water kill many microorganisms but they don’t kill microbacteria. Consequently, microbacteria out-compete other types of bacteria and form bio-films in these municipal water supplies. We’re involved in something called The Shower Head Microbiome Project with a group of other investigators including Noah Fierer and early analysis of the samples coming back from all over the United States suggest that the relative abundance of microbacteria is extremely high in shower heads, for example. So, you can imagine that every time you take a shower you’re literally spraying millions, or perhaps billions, of microbacteria all over your body. If you shower every day, you’re doing that every day. The point of that is, most gardeners or certainly those that are gardening at home use the municipal water source to water their gardens and often they’re doing that as an aerosol. They have some attachment or nozzle on the end of the hose that aerosolizes, in some cases creates a fine mist of the water and that kind of misting of water is ideal for suspending bacteria in aerosols. Not only is that going to, you know, coat the plants which you might later eat, it’ll infiltrate the soil and if it’s a fine mist you’ll undoubtedly be breathing that in which means you’ll have microbacteria going into your airways. Once the microbacteria is in your airways it is frequently swallowed, mucus in small amounts coming up from the airways. People often don’t find microbacteria in samples of the fecal microbio because the fecal microbio is dominated by other taxonomic units that are much more highly abundant in their commensal. But when investigators swab the teeth, the oral cavity, the nose, the upper airways, they found 50 abundant microbacterials, OTUs or operational taxonomic units, in these upper airways. And so, and these were from healthy humans. So, we have many, many microbacteria in our airways and certainly those microbacteria also come into contact with our gastrointestinal system. So, I think it’s very clear that we are still exposed to very high numbers of microbacteria. You would expect that that would be exaggerated if you take a shower, especially if you have a fine aerosol shower. And if you’re gardening and you go out in the morning and you spray microbacteria-laden water all over your plants and the soil then certainly that’s likely to have an impact on the total consumption, so to speak, of microbacteria. I know we’re focused on microbacteria, but remember microbacteria are not the only old friends.
  • TRACEY:
  • That’s right.
  • CHRIS:
  • There are many. Many that have not been discovered.
  • TRACEY:
  • Thank you, Chris. I feel like you’ve given us a really good overview of our old friends and how they’re affecting us in our day-to-day lives and how we have to watch out for them and think about in the future how we want to protect our old friends. So, thank you.
  • CHRIS:
  • You’re very welcome. It’s been a pleasure.