COMMENTARY
Psychobiotics Highlight the Pathways to Happiness Philip W.J. Burnet and Philip J. Cowen
T
here is no doubt that enteric commensal microbiota are important benefactors of mammalian intestinal health. The professed “good” bacterial species, Lactobacilli and Bifidobacteria, lack the external proinflammatory lipopolysaccharide chains that are anchored to the cell walls of pathogenic bacteria such as E. coli and Salmonella. The host gut, therefore, is tolerant to extensive colonization by beneficial bacteria, which compete with the establishment of detrimental microbes and lower the risk of infection. Importantly, Bifidobacteria, Lactobacilli, and other innocuous species are detected and monitored by the intestinal immune system from early-life, but because they do not carry the necessary inflammatory elements, a full immunogenic response is not initiated. Rather, host immunity develops a robust antiinflammatory repertoire that minimizes damage to the gut, whilst any invading harmful bacteria are engulfed by immune cells. (1). Thus, individuals nurturing “good” bacteria maintain a healthy balance between the anti- and pro-inflammatory responses that, via the circulation, impart physiological advantages to all organs, including the brain. On the basis of this parsimonious scenario alone, it is hardly surprising that the last few years have seen a surge of reports demonstrating the influence and potential benefits of gut bacteria on brain health. In this issue of Biological Psychiatry, Dinan et al. (2) provide a comprehensive review of recent compelling research into the microbiome–gut–brain axis and summarize the evidence for the anxiolytic and antidepressant action of Bifidobacteria or Lactobacilli in rodents and humans after their ingestion as live cultures (probiotics). The authors have proposed the term “psychobiotic” for those single bacterial species with psychotropic properties. A brief synopsis of the nature and composition of the gut microbiota by Dinan et al. (2) provides perspective on the scale and heterogeneity of the microbial ecosystem within the gut, and an appraisal of the potential routes through which this, essentially virtual organ, might influence the brain makes a persuasive case to further investigate the clinical applications of this phenomenon. The human adult gut is populated by 10–100 trillion microbes that encapsulate approximately 150 times more genetic material than the human genome itself. The Lactobacilli, of which there are 17 species, and the 30 species of Bifidobacteria only account for a small percentage of the total microbial population [e.g., .01% of Lactobacilli in total fecal bacteria (3)], although this can vary between individuals. In their review, Dinan et al. (2) rightly mention the influence of diet on the balance between beneficial and detrimental microbial colonization, but the possibility that diet itself might catalyze bacterial communication with the brain should be emphasized. Gut bacteria readily metabolize indigestible fibers, such as oligosaccharides, and yield small chain fatty acids (SCFAs), including acetate, butyrate, lactate, and propionate, which then From the Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom. Address correspondence to Phil Burnet, Ph.D., Neurosciences Building, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX3 7JX, UK; E-mail: [email protected]. Received Jul 30, 2013; accepted Aug 1, 2013.
0006-3223/$36.00 http://dx.doi.org/10.1016/j.biopsych.2013.08.002
enter the circulation from the large intestine (4). The relative proportion of blood SCFAs might vary according to diet and specific bacteria. For instance, the intake of malt products by rodents results in a significant elevation of serum butyrate but only in the presence of Lactobacillus rhamnosus (5). Although most of these fermentation metabolites enter the liver and muscle, a small proportion permeate the brain, where their psychotropic actions have been documented (6,7). Thus, further consideration of SCFA signaling within the microbiome–gut–brain axis and working within the concept that “good bacteria are only as good as what one eats” might lead to the development of optimal dietary and bacterial formulae to assist in the maintenance of brain health. One strategy might be to use prebiotics (purified mixtures of oligosaccharides), either alone or with probiotics, because these compounds mediate both the formation of SCFAs and the proliferation of other potentially psychotropic, intrinsic commensal bacteria (8). Dinan et al. (2) highlight the established link between gut bacteria and immunity, which is one pathway through which psychobiotics might initiate their psychotropic effects. Proinflammatory molecules such as tumor necrosis factor-α (TNFα) and interleukin (IL)-6 are increased in depression, although the etiological basis for these changes is not clear; for example, depressive illness is often associated with poor nutrition and/or circadian disturbance, which themselves influence immunity (9). Nevertheless, the authors provide a convincing argument for an “infectious etiology” of depression in some patients with an example of Lyme disease, which is associated with an overt inflammatory response and a range of neuropsychological disturbances. Importantly, the full activation of immunity might not be required for mood dysfunction, and the administration of single pro-inflammatory cytokines, such as interferon-α (INFα), also leads to depressive symptoms (2). In animals, pathogen infections in the absence of both sickness behavior and a blatant pro-inflammatory response also manifest anxiety and depressive states. These data support the notion that pro-inflammatory cytokines such as INFα or TNFα alone might elicit symptoms of depression, and because their circulating levels might be reduced by nurturing gut bacteria (10), the therapeutic application of psychobiotics in mood disorders would seem a reasonable proposition. The authors question whether systemic cytokines act directly on the brain, although they acknowledge that their peripheral administration does have detrimental effects on mood. In response, we would emphasize that pro-inflammatory cytokines can access the brain through several means, including active uptake, and ultimately increase the local production of inflammatory mediators such as prostaglandins, cyclooxygenase-2 and nitric oxide, which themselves amplify the production of local cytokine and inflammatory mediators (9). These proinflammatory molecules can reduce central monoamine metabolism and brain-derived neurotrophic factor signaling and thus directly impinge on key pathways fundamental to both resilience to depression and antidepressant action. Thus, the involvement of the immune system in the modulation of mood might be more profound than originally appreciated. Indeed, Dinan et al. (2) suggest that antidepressants might, in part, have their therapeutic BIOL PSYCHIATRY 2013;74:708–709 & 2013 Society of Biological Psychiatry
Commentary effect via an anti-inflammatory mechanism such as the production of IL-10, which is also facilitated by the administration of probiotics (2). Discussions of depression, anxiety, and psychotropic agents are incomplete without consideration of the hypothalamic– pituitary–adrenal (HPA) axis. The authors provide a clear insight into the importance of gut bacteria in the development of the HPA axis, and from studies of germ-free mice, they suggest that the microbiota might also influence central circuitry via the neuroendocrine stress response. Thus, germ-free mice exposed to stress demonstrated an exaggerated release of corticosterone, which was normalized after their inoculation with either pathogen-free bacteria from their control counter-parts or Bifidus infantis alone (2). However, Dinan et al. (2) go on to show that investigations into the HPA axis and psychobiotic action give mixed results. In the rodent maternal separation model of depression, Bifidus infantis normalized behavior but not corticosterone release in adult animals, whereas Lactobacilli attenuated both parameters. In healthy volunteers, a mixture of probiotic strains reduced urinary cortisol, but to date, investigations into HPA axis modulation by psychobiotics in patients have not been undertaken. Nevertheless, the authors highlight, that irrespective of underlying mechanisms (HPA axis and/or immune system), psychobiotics are able to influence key brain targets (e.g., γ-aminobutyric acid receptors) that are known to be implicated in the regulation of mood and anxiety. There are therefore good reasons to test psychobiotics in the treatment of depression and stress-related disorders in humans. Dinan et al. (2) also provide examples where probiotics elicited demonstrable psychological benefits in the clinical setting. For instance, the administration of Bifidus infantis to patients with irritable bowel syndrome alleviated the commonly associated comorbid symptoms of depression and anxiety. In chronic fatigue syndrome, Lactobacillus casei had a significant anxiolytic effect in patients compared with placebo-administered subjects. Finally, in a study of an elderly population, volunteers with the lowest baseline mood reported feeling happier after the repeated intake of probiotic-containing dairy products (although there was no effect on mood on the participant group overall). There is, therefore, intriguing preliminary evidence that probiotic consumption has significant benefits on mood and, importantly, when there are pre-existing deficits. Further studies are required to support current findings and should include an exploration into the individual therapeutic efficacy of psychobiotics, on the basis of findings from relevant animal studies. Reliable and beneficial changes in clinical mood and anxiety symptoms after manipulation of the gut microbiota are likely to be the most pragmatic way to implicate the microbiome in the pathophysiology of mood disorder.
BIOL PSYCHIATRY 2013;74:708–709 709 In their review Dinan et al. (2) deliver a convincing call for both an analysis of the microbiota in mood disorders and the application of psychobiotics in their treatment. Indeed, stratification of patient groups by specific biological phenotypes might help identify which individuals would benefit particularly from psychobiotics. For instance, depressed patients with increased levels of pro-inflammatory markers might be the most likely to respond to these supplements; parenthetically, some depressed patients resistant to conventional antidepressant treatments have high concentrations of circulating TNFα and IL-6 (10). Psychobiotics might also appeal to recovered depressed patients who experience “sub-clinical” residual symptoms but are reluctant to take conventional medication. Overall, the rationale for using psychobiotics in the treatment of mood disorders is sound, and their development and application might well be easier than drug treatments, given that they are unlikely to require the same regulatory procedures as those used for psychotropic drugs. Dr. Burnet receives research funding from Clasado Ltd, UK, as part of a Biotechnology Biological Sciences Research Council Industrial Partners Award. Dr. Cowen is a paid member of an advisory board for Lundbeck. 1. Sansonetti PJ, Medzhitov R (2009): Learning tolerance while fighting ignorance. Cell 138:416–420. 2. Dinan TG, Stanton C, Cryan JF (2013): Psychobiotics: A novel class of psychotropic. Biol Psychiatry 74:720–726. 3. Štšepetova J, Sepp E, Kolk H, Lõivukene K, Songisepp E, Mikelsaar M (2011): Diversity and metabolic impact of intestinal Lactobacillus species in healthy adults and the elderly. Br J Nutr 105:1235–1244. 4. Overduin J, Schoterman MH, Calame W, Schonewille AJ, Ten Bruggencate SJ (2013): Dietary galacto-oligosaccharides and calcium: Effects on energy intake, fat-pad weight and satiety-related, gastrointestinal hormones in rats. Br J Nutr 31:1–11. 5. Bränning CE, Nyman ME (2011): Malt in combination with Lactobacillus rhamnosus increases concentrations of butyric acid in the distal colon and serum in rats compared with other barley products but decreases viable counts of cecal bifidobacteria. J Nutr 141: 101–107. 6. Moretti M, Valvassori SS, Varela RB, Ferreira CL, Rochi N, Benedet J, et al. (2011): Behavioral and neurochemical effects of sodium butyrate in an animal model of mania. Behav Pharmacol 22:766–772. 7. Horn T, Klein J (2013): Neuroprotective effects of lactate in brain ischemia: Dependence on anesthetic drugs. Neurochem Int 62:251–257. 8. Burnet PW (2012): Gut bacteria and brain function: The challenges of a growing field. Proc Natl Acad Sci U S A 109:E175. 9. Felger JC, Lotrich FE (2013): Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications. Neuroscience 246:199–229. 10. Fitzgerald P, O’Brien SM, Scully P, Rijkers K, Scott LV, Dinan TG (2006): Cutaneous glucocorticoid receptor sensitivity and pro-inflammatory cytokine levels in antidepressant-resistant depression. Psychol Med 36: 37–43.
www.sobp.org/journal
Psychobiotics Highlight the Pathways to Happiness Philip W.J. Burnet and Philip J. Cowen
T
here is no doubt that enteric commensal microbiota are important benefactors of mammalian intestinal health. The professed “good” bacterial species, Lactobacilli and Bifidobacteria, lack the external proinflammatory lipopolysaccharide chains that are anchored to the cell walls of pathogenic bacteria such as E. coli and Salmonella. The host gut, therefore, is tolerant to extensive colonization by beneficial bacteria, which compete with the establishment of detrimental microbes and lower the risk of infection. Importantly, Bifidobacteria, Lactobacilli, and other innocuous species are detected and monitored by the intestinal immune system from early-life, but because they do not carry the necessary inflammatory elements, a full immunogenic response is not initiated. Rather, host immunity develops a robust antiinflammatory repertoire that minimizes damage to the gut, whilst any invading harmful bacteria are engulfed by immune cells. (1). Thus, individuals nurturing “good” bacteria maintain a healthy balance between the anti- and pro-inflammatory responses that, via the circulation, impart physiological advantages to all organs, including the brain. On the basis of this parsimonious scenario alone, it is hardly surprising that the last few years have seen a surge of reports demonstrating the influence and potential benefits of gut bacteria on brain health. In this issue of Biological Psychiatry, Dinan et al. (2) provide a comprehensive review of recent compelling research into the microbiome–gut–brain axis and summarize the evidence for the anxiolytic and antidepressant action of Bifidobacteria or Lactobacilli in rodents and humans after their ingestion as live cultures (probiotics). The authors have proposed the term “psychobiotic” for those single bacterial species with psychotropic properties. A brief synopsis of the nature and composition of the gut microbiota by Dinan et al. (2) provides perspective on the scale and heterogeneity of the microbial ecosystem within the gut, and an appraisal of the potential routes through which this, essentially virtual organ, might influence the brain makes a persuasive case to further investigate the clinical applications of this phenomenon. The human adult gut is populated by 10–100 trillion microbes that encapsulate approximately 150 times more genetic material than the human genome itself. The Lactobacilli, of which there are 17 species, and the 30 species of Bifidobacteria only account for a small percentage of the total microbial population [e.g., .01% of Lactobacilli in total fecal bacteria (3)], although this can vary between individuals. In their review, Dinan et al. (2) rightly mention the influence of diet on the balance between beneficial and detrimental microbial colonization, but the possibility that diet itself might catalyze bacterial communication with the brain should be emphasized. Gut bacteria readily metabolize indigestible fibers, such as oligosaccharides, and yield small chain fatty acids (SCFAs), including acetate, butyrate, lactate, and propionate, which then From the Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom. Address correspondence to Phil Burnet, Ph.D., Neurosciences Building, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX3 7JX, UK; E-mail: [email protected]. Received Jul 30, 2013; accepted Aug 1, 2013.
0006-3223/$36.00 http://dx.doi.org/10.1016/j.biopsych.2013.08.002
enter the circulation from the large intestine (4). The relative proportion of blood SCFAs might vary according to diet and specific bacteria. For instance, the intake of malt products by rodents results in a significant elevation of serum butyrate but only in the presence of Lactobacillus rhamnosus (5). Although most of these fermentation metabolites enter the liver and muscle, a small proportion permeate the brain, where their psychotropic actions have been documented (6,7). Thus, further consideration of SCFA signaling within the microbiome–gut–brain axis and working within the concept that “good bacteria are only as good as what one eats” might lead to the development of optimal dietary and bacterial formulae to assist in the maintenance of brain health. One strategy might be to use prebiotics (purified mixtures of oligosaccharides), either alone or with probiotics, because these compounds mediate both the formation of SCFAs and the proliferation of other potentially psychotropic, intrinsic commensal bacteria (8). Dinan et al. (2) highlight the established link between gut bacteria and immunity, which is one pathway through which psychobiotics might initiate their psychotropic effects. Proinflammatory molecules such as tumor necrosis factor-α (TNFα) and interleukin (IL)-6 are increased in depression, although the etiological basis for these changes is not clear; for example, depressive illness is often associated with poor nutrition and/or circadian disturbance, which themselves influence immunity (9). Nevertheless, the authors provide a convincing argument for an “infectious etiology” of depression in some patients with an example of Lyme disease, which is associated with an overt inflammatory response and a range of neuropsychological disturbances. Importantly, the full activation of immunity might not be required for mood dysfunction, and the administration of single pro-inflammatory cytokines, such as interferon-α (INFα), also leads to depressive symptoms (2). In animals, pathogen infections in the absence of both sickness behavior and a blatant pro-inflammatory response also manifest anxiety and depressive states. These data support the notion that pro-inflammatory cytokines such as INFα or TNFα alone might elicit symptoms of depression, and because their circulating levels might be reduced by nurturing gut bacteria (10), the therapeutic application of psychobiotics in mood disorders would seem a reasonable proposition. The authors question whether systemic cytokines act directly on the brain, although they acknowledge that their peripheral administration does have detrimental effects on mood. In response, we would emphasize that pro-inflammatory cytokines can access the brain through several means, including active uptake, and ultimately increase the local production of inflammatory mediators such as prostaglandins, cyclooxygenase-2 and nitric oxide, which themselves amplify the production of local cytokine and inflammatory mediators (9). These proinflammatory molecules can reduce central monoamine metabolism and brain-derived neurotrophic factor signaling and thus directly impinge on key pathways fundamental to both resilience to depression and antidepressant action. Thus, the involvement of the immune system in the modulation of mood might be more profound than originally appreciated. Indeed, Dinan et al. (2) suggest that antidepressants might, in part, have their therapeutic BIOL PSYCHIATRY 2013;74:708–709 & 2013 Society of Biological Psychiatry
Commentary effect via an anti-inflammatory mechanism such as the production of IL-10, which is also facilitated by the administration of probiotics (2). Discussions of depression, anxiety, and psychotropic agents are incomplete without consideration of the hypothalamic– pituitary–adrenal (HPA) axis. The authors provide a clear insight into the importance of gut bacteria in the development of the HPA axis, and from studies of germ-free mice, they suggest that the microbiota might also influence central circuitry via the neuroendocrine stress response. Thus, germ-free mice exposed to stress demonstrated an exaggerated release of corticosterone, which was normalized after their inoculation with either pathogen-free bacteria from their control counter-parts or Bifidus infantis alone (2). However, Dinan et al. (2) go on to show that investigations into the HPA axis and psychobiotic action give mixed results. In the rodent maternal separation model of depression, Bifidus infantis normalized behavior but not corticosterone release in adult animals, whereas Lactobacilli attenuated both parameters. In healthy volunteers, a mixture of probiotic strains reduced urinary cortisol, but to date, investigations into HPA axis modulation by psychobiotics in patients have not been undertaken. Nevertheless, the authors highlight, that irrespective of underlying mechanisms (HPA axis and/or immune system), psychobiotics are able to influence key brain targets (e.g., γ-aminobutyric acid receptors) that are known to be implicated in the regulation of mood and anxiety. There are therefore good reasons to test psychobiotics in the treatment of depression and stress-related disorders in humans. Dinan et al. (2) also provide examples where probiotics elicited demonstrable psychological benefits in the clinical setting. For instance, the administration of Bifidus infantis to patients with irritable bowel syndrome alleviated the commonly associated comorbid symptoms of depression and anxiety. In chronic fatigue syndrome, Lactobacillus casei had a significant anxiolytic effect in patients compared with placebo-administered subjects. Finally, in a study of an elderly population, volunteers with the lowest baseline mood reported feeling happier after the repeated intake of probiotic-containing dairy products (although there was no effect on mood on the participant group overall). There is, therefore, intriguing preliminary evidence that probiotic consumption has significant benefits on mood and, importantly, when there are pre-existing deficits. Further studies are required to support current findings and should include an exploration into the individual therapeutic efficacy of psychobiotics, on the basis of findings from relevant animal studies. Reliable and beneficial changes in clinical mood and anxiety symptoms after manipulation of the gut microbiota are likely to be the most pragmatic way to implicate the microbiome in the pathophysiology of mood disorder.
BIOL PSYCHIATRY 2013;74:708–709 709 In their review Dinan et al. (2) deliver a convincing call for both an analysis of the microbiota in mood disorders and the application of psychobiotics in their treatment. Indeed, stratification of patient groups by specific biological phenotypes might help identify which individuals would benefit particularly from psychobiotics. For instance, depressed patients with increased levels of pro-inflammatory markers might be the most likely to respond to these supplements; parenthetically, some depressed patients resistant to conventional antidepressant treatments have high concentrations of circulating TNFα and IL-6 (10). Psychobiotics might also appeal to recovered depressed patients who experience “sub-clinical” residual symptoms but are reluctant to take conventional medication. Overall, the rationale for using psychobiotics in the treatment of mood disorders is sound, and their development and application might well be easier than drug treatments, given that they are unlikely to require the same regulatory procedures as those used for psychotropic drugs. Dr. Burnet receives research funding from Clasado Ltd, UK, as part of a Biotechnology Biological Sciences Research Council Industrial Partners Award. Dr. Cowen is a paid member of an advisory board for Lundbeck. 1. Sansonetti PJ, Medzhitov R (2009): Learning tolerance while fighting ignorance. Cell 138:416–420. 2. Dinan TG, Stanton C, Cryan JF (2013): Psychobiotics: A novel class of psychotropic. Biol Psychiatry 74:720–726. 3. Štšepetova J, Sepp E, Kolk H, Lõivukene K, Songisepp E, Mikelsaar M (2011): Diversity and metabolic impact of intestinal Lactobacillus species in healthy adults and the elderly. Br J Nutr 105:1235–1244. 4. Overduin J, Schoterman MH, Calame W, Schonewille AJ, Ten Bruggencate SJ (2013): Dietary galacto-oligosaccharides and calcium: Effects on energy intake, fat-pad weight and satiety-related, gastrointestinal hormones in rats. Br J Nutr 31:1–11. 5. Bränning CE, Nyman ME (2011): Malt in combination with Lactobacillus rhamnosus increases concentrations of butyric acid in the distal colon and serum in rats compared with other barley products but decreases viable counts of cecal bifidobacteria. J Nutr 141: 101–107. 6. Moretti M, Valvassori SS, Varela RB, Ferreira CL, Rochi N, Benedet J, et al. (2011): Behavioral and neurochemical effects of sodium butyrate in an animal model of mania. Behav Pharmacol 22:766–772. 7. Horn T, Klein J (2013): Neuroprotective effects of lactate in brain ischemia: Dependence on anesthetic drugs. Neurochem Int 62:251–257. 8. Burnet PW (2012): Gut bacteria and brain function: The challenges of a growing field. Proc Natl Acad Sci U S A 109:E175. 9. Felger JC, Lotrich FE (2013): Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications. Neuroscience 246:199–229. 10. Fitzgerald P, O’Brien SM, Scully P, Rijkers K, Scott LV, Dinan TG (2006): Cutaneous glucocorticoid receptor sensitivity and pro-inflammatory cytokine levels in antidepressant-resistant depression. Psychol Med 36: 37–43.
www.sobp.org/journal
