ISNPR: It seems that hardly a week goes by when there isn’t yet another fascinating research article concerning our gut microbiota, or microflora as it was once known, and its connection to human health. What is the more general trend or common thread of this research?
Logan: This is certainly an exciting time, with plenty of experimental and even human studies highlighting the importance of healthy gut microbiota – not just in formally diagnosed gastrointestinal conditions such as Crohn’s disease or irritable bowel syndrome, but in conditions such as type II diabetes, cardiovascular disease, metabolic syndrome, and their common correlate of obesity. There is little in the way of translation to clinical treatment just yet, but there is a forward march toward that goal.
The common thread is the realization of gut microbial influence over systemic metabolism and immune reactivity. Given that many chronic medical conditions – and mental disorders appear to be no exception – involve a viscous cycle of low-grade inflammation and a higher burden of oxidative stress, microbes may have far reaching affects.
ISNPR: Immune reactivity and low-grade inflammation are broad terms, can you be more specific?
Logan: Low-grade inflammation is characterized by elevation of immune regulators, cytokines such as IL-1β, IL-6, and TNF-α. Oxidative stress can enhance inflammatory cytokine production and vice versa. In conditions such as depression, how and why this occurs is multifactorial, and scientists continue to uncover the pathways, including psychological and lifestyle variables, that can contribute to this tandem. Although many questions remain, it is now clear that we cannot dismiss low-grade inflammation and oxidative stress as a mere consequence of chronic disease. If we modestly elevate inflammatory cytokines in otherwise healthy adults, symptoms of depression, anxiety and fatigue often follow. There are also long term consequences – over time, compromised communication between nerve cells.
ISNPR: Back to the microbiota – what can you tell us about their place in this context of low-grade inflammation? How can microbes that are confined to the gut be conducting a systemic orchestra?
Logan: Microbes are continuously interacting with the gut mucosal (intestinal lining) cells, now recognized to be a primary component of the immune system. Scientists are just beginning to scratch the surface of the ways in which such interactions can influence systemic immune functioning. However, a landmark study in 2001 (Reichenberg, et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry. 2001 May;58(5):445-52) was a game-changer. It showed, for the first time, that even very low blood levels of endotoxin, the structural component/coating of select bacteria, could provoke symptoms of depression, anxiety and diminished cognitive functioning. A sort of functional “walking wounded” state, transient so long as the immune reaction to the endotoxin was in place. In the last decade and a half this study has been replicated many times – low dose endotoxin (mostly as lipopolysaccharide endotoxin or LPS) infused into the bloodstream causes these symptoms as well as fatigue and heightened pain sensitivity.
All of this is of relevance because the largest reservoir of LPS, thanks to the trillions of bacteria residing there, is our gut. With the exception of very minimal amounts of endotoxin that can gain access to the bloodstream in healthy adults, without ill affect, LPS is normally kept in gut – at least that is how it is supposed to work. However, we now know that psychological stress, excessive exercise, and/or dietary habits (e.g. high fat, high sugar, Westernized diet) can increase intestinal permeability beyond its normal limits. A more porous gut lining leads to higher LPS in the blood, which in turn causes an appropriate, but ultimately detrimental immune response.
ISNPR: What are some of the conditions in which intestinal permeability has been noted?
Logan: Depression, alcohol dependency, irritable bowel, syndrome, complex regional pain syndrome, fibromyalgia, chronic fatigue, insulin resistance and obesity. The relevance of this to psychiatric research is obvious.
ISNPR: Is there more to it though? Not everyone with mental disorders has intestinal permeability. Are the other ways in which gut microbes can communicate with the nervous system?
Logan: Yes. Experimental studies show that there is more direct microbe-mediated gut-to-brain communication via the vagus nerve. Around the same time that Reichenberg was showing that low-dose endotoxin could provoke human anxiety and depressive symptoms, a separate group discovered that, at least in animals, the administration of tiny doses of the type of bacteria that cause food poisoning (C. jejuni) – but in doses too low to produce an immune response – were causing anxious behavior. It suggested that microorganisms were somehow communicating via more direct neural pathways. Later research would indicate that the pathway is the vagus nerve. Indeed, recent rodent studies involving different models of psychological stress or gut inflammation have shown that the anti-anxiety benefits of probiotics are not realized if the vagus nerve is cut. Still, other animal studies have shown that communication may be ongoing between gut microbes and the brain via other pathways – i.e. non-vagal and non-cytokine mediated reductions in anxious behavior via probiotics.
ISNPR: We have transitioned here to talk of probiotics. It has been over a decade since you and your colleagues in Toronto first postulated the potential use of beneficial microbes in functional disorders and depression. More specifically, you urged that they be the subject of proper research. Of course, the notion that probiotics could improve bowel motility and that, in turn, could improve mental outlook in conditions like IBS was certainly an acceptable concept. But that was not what you were arguing. What provoked you to lay out the scientific framework?
Logan: Prior to August 2002, when we submitted our first paper to Medical Hypotheses, the mere suggestion of a role for beneficial microbes [in disorders where depression is commonly part of the picture] was considered a farce. Viewed superficially, curt and rapid dismissal of the idea was understandable. We understood that in order to make the case for research attention, in order to make a more convincing argument, it would be necessary to tie together various strands of emerging – yet still isolated – research. The provocation, I suppose, was awareness of what would seem to be, at first glance, unrelated lines of research.
As mentioned, there was preliminary research showing that LPS could provoke low-grade inflammation and depressive symptoms; there was reporting that small amounts of potentially pathogenic bacteria could alter animal behavior without an immune response. Psychological stress was also being linked to dysbiosis, and despite what we now consider to be antiquated culture technique, the stool microbiota of those with functional disorders was different than healthy controls. Other groups were linking microbes such as Helicobacter pylori to far-reaching complaints such as migraines and hypertension. There was one more little nugget of relevance, buried in the literature and largely unreferenced since its discovery in 1981 – colonic bacteria are direct contributors to systemic gamma-amino aminobutyric acid (GABA – Schafer, et al. Colonic bacteria: a source of gamma-aminobutyric acid in blood. Proc Soc Exp Biol Med 1981;167:301-3). Then there was a completely different research highway – that which relates more directly to the ISNPR – it was becoming clear that functional disorders and major depression are often characterized by low omega-3 fatty acids or nutritional inadequacies, and that low-grade inflammation and a higher burden of oxidative stress were also common features.
In sum, we had a situation where potentially harmful bacteria and/or their [LPS] products were being linked to behavioral changes. Direct and indirect communication to the brain was possible, but there was no discussion of probiotics in this mix. Furthermore, since microbiota can dictate systemic nutritional status – not just macro and micro nutrients, but also polyphenolics – we felt the nutritional implications of microbiota in general, and probiotics in particular, were being overlooked in mental health.
ISNPR: Okay, so lots of theoretical possibilities. If probiotics could limit systemic LPS, improve intestinal barrier function, and enhance nutritional status, then there may be an influence on neurotransmission. Did anyone or any group show interest in your ideas 12 years ago?
Logan: Yes, scientists from Yakult Honsha in Tokyo showed immediate interest and allowed me to present the case for probiotic-brain research with them in 2003. In our meetings I pushed for clinical research and they as seasoned scientists, perhaps much more appropriately, pushed for experimental research involving animal models. Having just published a paper on brain-derived neurotrophic factor (BDNF), omega-3 fats and major depression at that time (Logan AC: Neurobehavioral aspects of omega-3 fatty acids: possible mechanisms and therapeutic value in major depression. Altern Med Rev 2003, 8:410-25), the topic of this nerve growth factor was on my agenda with them. It would be an easy first step, a simple objective marker to determine if probiotics could make a difference. Of course, I was proposing a human study in those with depression or functional disorders where BDNF and red blood cell omega-3 levels would be measured! The following year, in a Yakult-funded study, it was reported that probiotics could increase BDNF in a germ-free animal model. In any case, Yakult did go on to support human research, including two studies suggesting mental health value – general well-being in otherwise healthy adults, and decreased anxiety in a small study of patients with chronic fatigue (a condition where high levels of anxiety are commonplace).
To be clear, this is not a commercial endorsement of Yakult’s probiotic as some sort of mental health panacea. There is no evidence to suggest that this is even remotely true. The large-scale human study of probiotics in those with depression, inclusive of markers such as BDNF and omega-3 levels that I was dreaming of in 2003 – it still awaits. That said, I would like to think that in order to get to where we need to be in translational medicine, those Tokyo meetings in 2003 were a catalyst of sorts. A catalyst to what end is the question!
ISNPR: We are a decade removed from Sudo’s landmark study showing that probiotics influence BDNF production in rodents. What has changed in the last decade? Are you more or less confident that probiotics really represent an adjuvant intervention in very complex conditions such as major depression?
Logan: Over the last decade there have been major advances in animal research related to the gut-brain axis mediated by probiotics and the ways in which microbiota can influence nutritional status (or vice versa, the ways in which dietary quality influences microbiota and the intestinal barrier). Rodent studies show that probiotics can indeed influence neurotransmission directly and indirectly – they have confirmed that probiotics can influence systemic tryptophan levels and brain omega-3 levels. As mentioned, there have been a sprinkling of human studies, including the French researcher Michaël Messaoudi, who showed that orally administered probiotic (one month vs. placebo) improved subjective depression, anger, anxiety, and lower levels of the stress hormone cortisol. This human study involved a combination of Lactobacillus helveticus and Bifidobacterium longum strains, the same combination that has just been shown to maintain normal nerve growth in the hippocampus and synaptic plasticity under experimental psychological stress. This in itself is interesting, however, there were two remarkable associated findings – 1) the probiotic combination maintained normal intestinal barrier function during the stress (indicating the relevance of preventing intestinal permeability) and 2) the control was actually another Lactobacillus strain – clearly indicting that not all microbes of the same genus (or even species) can be painted with the same brush.
Now, to answer the question about complex disorders such as depression and the potential of probiotics; it would certainly be a tall order to expect that a single strain (or a few strains) of probiotic could influence depression or anxiety in the way that SSRIs or benzodiazepines do. The difference is that probiotics meet up with the correlates of dietary factors and lifestyle factors in the gut lumen. Those with depression and anxiety disorders are more likely to adhere to specific dietary patterns – Westernized patterns, fast food etc. Could we really expect a probiotic to have a meaningful, clinically-relevant impact if it was supplemented in the context of the lifestyle patterns that are conducive to intestinal permeability and dysbiosis? I don’t think the expectations could be high.
Clinical studies involving probiotic administration in adults with depression are finally being considered, so we shall see. Beyond probiotics, biotechnology companies are hard at work developing so-called ‘poo-pills’, a new class of drugs formally known as ecobiotics – a more simple and efficient alternative to fecal transplants. Undoubtedly, these will be the subject of research in mental health at some point in the future. In fact, it is likely that such agents will eclipse probiotics in the mental health realm. Personally, I am disappointed that it has taken so long to get to the point of clinical investigation of probiotics in mental health. It seems to me that there has been a hesitancy to subject internationally best-selling probiotics to human research in this area. Rodent studies are a safe bet, and it’s easy to justify a never-ending stream of studies under the comfortable guise of ‘we need to learn more’. Yes, we need to learn more, but almost all of the probiotics in question, the ones studied over the last decade in this gut-brain category, are not novel agents à la newly synthesized drugs or medical devices. They are already sitting on shelves. Clinical studies, even negative trials, can teach us much about the interaction of commercially-available probiotics, nutritional status and mood. In the meantime, the advantage of focusing on non-patentable or non-commercialized dietary patterns – traditional diets that promote healthy intestinal microbiota in a profile away from that associated with obesity and type II diabetes – is that it is an “upstream” or more relevant conversation, at least for now.
ISNPR: It would be easy to state that in many ways that microbiota are the tail wagging the dog. But your point seems to be that diet should be the center piece in research discussions of mental health and microbiota.
Logan: Yes, that is the idea, and we have tried to underscore this in our writing. Recent investigations have shown us that diet, even over the short term, can have profound influences on gut microbiota. As mentioned, rodent studies have indicated that not all Lactobacilli may be alike in regard to benefits in stress models and so on. Be that as it may, it is also worth noting that about 35% of all lactic acid bacteria isolated from raw fruits and vegetables can survive gastric conditions, and fermented foods (with great diversity of potentially beneficial microbes) still make up a significant part of the traditional diets considered to be healthy. One need only visit a Korean restaurant to bear witness to this – all those little appetizer-size bowls they place around you, many of those dishes are fermented! And wouldn’t you know it, a Lactobacillus pentosus strain derived from fermented cabbage (the Korean dish kimchi) has been recently shown to improve mental functioning and hippocampal BDNF production in animals. The point is that while we await the results of clinical probiotic trials that may or not be forthcoming, adherence to evidence-based traditional dietary patterns is likely to be increasing the odds that we promote gut microbial diversity – and with that, it increases the odds of potentially taking advantage of collateral health benefits associated with healthy microbial diversity.
ISNPR: Finally, on the note of diversity, you have argued that this discussion is part of the more broad context of microbes in the environment. In 2012, you and colleague Eva Selhub M.D. suggested that lack of exposure to environmental microbes might be a form of ‘modern nature deprivation’ of relevance to the brain. The hygiene hypothesis, recently updated by the World Allergy Organization as the “Biodiversity Hypothesis”, is of course a well-trodden path as it relates to risk of allergies, asthma and autoimmune conditions. Can you elaborate on the mental health implications?
Logan: In our 2002 submission to Medical Hypotheses we specifically used the term ‘lactic acid bacteria’ related to their potential benefit in emotional symptoms. Inevitably, lactic acid bacteria, probiotics and fermented dairy products get lumped together in various discussions. However, lactic acid bacteria are not just in kefir and commercial yogurts – they are ubiquitous, commonly found on trees and their leaves, in soil, and they are transported by air. We already mentioned their presence on uncooked fruits and vegetables in indigenous diets. Bifidobacteria too are found very broadly in the environment, including soil samples from some of the harshest climates on the planet. Despite all of the limitations, the available research linking lactic acid bacteria and bifidobacteria with mental health should be forcing us to ask how lack of exposure to natural environments and incidental contact with non-pathogenic microbes might be related to mental health.
There are two recent studies that suggest we take a closer look – 1) 2013 animal study showed that Mycobacterium vaccae added to animal chow improves cognitive performance and decreases behavioral signs of anxiety. M. vaccae is a non pathogenic microbe commonly found in soils and water. It could easily find its way on to edible plants. 2) 2012 human study that showed biodiversity of vegetation close to an individual’s residence is related to greater biodiversity of microbes on the skin. This seems reasonable and perhaps unsurprising. The key finding, however, was that greater biodiversity of green vegetation and skin microbes were both associated with a decreased risk of inflammatory skin conditions.
Greater biodiversity in environments has been linked to the mental health and general well-being among inhabitants, now we need to understand why. To what extent do nutrition and microbes interact in the context of an over-sanitized world where undue antimicrobial administration remains commonplace? The World Allergy Organization is asking such questions – in their Biodiversity Hypothesis position statement they state the following: “Altered indigenous microbiota and the general microbial deprivation characterizing the lifestyle of urban people in affluent countries appear to be risk factors for immune dysregulation and impaired tolerance. The risk is further enhanced by physical inactivity and a western diet poor in fresh fruit and vegetables, which may act in synergy with dysbiosis of the gut flora“. Given all of our discussions above, investigation of the biodiversity hypothesis should be on the radar of mental health researchers as well.
ISNPR: Which only serves to further underscore the Charter of the ISNPR, one which encourages broad collaboration.
Logan: Agreed.
References
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