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Could Probiotics Be Used to Mitigate Neuroinflammation? Matthew G. Frank,*,†,‡ Laura K. Fonken,§ Linda R. Watkins,†,‡ Steven F. Maier,†,‡ and Christopher A. Lowry‡,∥,⊥,#,∇,○ †
Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado 80309, United States Center for Neuroscience, University of Colorado Boulder, Boulder, Colorado 80309, United States § Division of Pharmacology and Toxicology, University of Texas at Austin, Austin, Texas 78712, United States ∥ Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado 80309, United States ⊥ Department of Physical Medicine & Rehabilitation, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, United States # Center for Neuroscience, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, United States ∇ Veterans Health Administration Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Denver Veterans Affairs Medical Center (VAMC), Denver, Colorado 80220, United States ○ Military and Veteran Microbiome Consortium for Research and Education (MVM-CoRE), Denver, Colorado 80220, United States
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ABSTRACT: Neuroinflammatory processes promote a constellation of neurochemical and hormonal changes resulting in profound effects on motivational states (anhedonia), mood (depression and anxiety disorders), and cognitive function (decrements in learning and memory). The enhancement of immunoregulatory processes, such as increasing anti-inflammatory cytokines in the CNS, is a highly effective strategy for curtailing neuroinflammation. Here, we explore recent evidence that probiotic treatment approaches might be an effective strategy to induce long-lasting immunoregulation in the CNS and thus mitigate the neural and behavioral effects of neuroinflammation. KEYWORDS: Neuroinflammation, immunoregulation, probiotic, M. vaccae
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INTRODUCTION The immune system exerts considerable influence over the development and function of the CNS. Indeed, products of an innate immune response such as interleukin (IL)-1β, a prototypical proinflammatory cytokine, are capable of inducing inflammatory processes in the brain via well-characterized immune-to-brain signaling pathways. In turn, these neuroinflammatory processes promote a constellation of neurochemical, hormonal, and behavioral changes, which resemble endophenotypes observed in a number of neuropsychiatric disorders.1 Indeed, chronic low-grade inflammatory processes are now thought to play an etiological role in the pathogenesis of several neuropsychiatric disorders including post-traumatic stress disorder (PTSD), major depression, and anxiety disorders. In this Viewpoint piece, we explore recent evidence suggesting that probiotics might be efficacious therapeutic interventions to modulate immune-to-brain signaling and thus mitigate behavioral pathologies elicited by chronic immune activation in the brain.
during development. This microbial input produces appropriate and balanced immune responses, which are characterized by immunoregulatory mechanisms (e.g., regulatory T cells) that halt inappropriate immune responses, for example, to self, harmless allergens, or gut contents. Immunoregulatory mechanisms are also essential for switching off excessive inflammatory reactions, in part by increased secretion of antiinflammatory cytokines, including IL-10 and transforming growth factor beta (TGFβ).2 As noted, chronic low-grade inflammatory processes are a characteristic of several neuropsychiatric disorders and decrements in immunoregulation can occur in these disorders. Interestingly, there is a higher prevalence of neuropsychiatric disorders in urban compared to rural environments, suggesting that reduced exposure to microbial diversity in urban environments might play a causal role in this higher prevalence of neuropsychiatric disorders.2 In consideration of the pivotal role that beneficial microbes or “Old Friends” might play in shaping immunoregulatory processes, the emerging field of microbial pharmacology has taken a treatment approach of reintroducing beneficial microbes. In animal models of neuropsychiatric disorders, this psychobiotic approach has attempted to understand the immunological and neural
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THE HYGIENE HYPOTHESIS The hygiene or “Old Friends” hypothesis posits that increases in chronic low-grade inflammation in modern urban societies may stem from decreased exposure to environmental sources of naturally occurring beneficial microbes, or “Old Friends”. Indeed, modern urban societies exhibit reduced microbial diversity compared to rural settings. Exposure to microbial diversity is considered vital for shaping the immune system © XXXX American Chemical Society
Received: July 30, 2018 Accepted: August 1, 2018
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DOI: 10.1021/acschemneuro.8b00386 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience
Figure 1.
stress by inducing an anti-inflammatory immunophenotype in the CNS. In a recent study,4 we found that M. vaccae immunization was sufficient to promote an enhanced immunoregulatory phenotype in the hippocampus characterized by increased levels of the anti-inflammatory cytokine IL-4 and the immunoregulatory receptor CD200R1, which inhibits innate immune cells such as microglia from becoming proinflammatory. In addition, M. vaccae treatment increased expression of the mannose receptor, which is indicative of an anti-inflammatory immunophenotype. These anti-inflammatory effects of M. vaccae occurred in parallel with reduced expression of two mediators (i.e., NFKBIA and NLRP3) involved in promoting neuroinflammation. Given that M. vaccae treatment resulted in enhanced immunoregulation in the CNS, we examined whether M. vaccae would mitigate the neuroinflammatory and anxiogenic effects of a severe acute stressor. It should be noted that both acute and chronic stressors induce inflammatory processes (e.g., IL-1β) in the CNS, which are involved in the mediation of many of the behavioral, neurochemical and hormonal sequelae of stress exposure (discussed in ref 4). We found that M. vaccae treatment mitigated the stress-induced: (1) exaggeration of proinflammatory responses in microglia, (2) increases in the alarmin, high mobility group box-1, and (3) anxiety-like behavior. Consistent with the effects observed by Reber and colleagues,3 these recent findings suggest that M. vaccae’s induction of an anti-inflammatory milieu in the CNS may underpin, in part, its capacity to impart a stress resilient phenotype (Figure 1).
mechanisms of action whereby beneficial microbes might exert their anxiolytic, antidepressant, and procognitive effects.
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PROBIOTICS FOR MENTAL HEALTH Indeed, a number of studies have demonstrated that microbial treatments can enhance cognitive function and mitigate the anxiogenic and depressive effects of stress exposure, which is a predisposing factor in the etiology of several neuropsychiatric disorders. We have explored the use of a microbial treatment known as Mycobacterium vaccae NCTC 11659 to mitigate the anxiogenic effects of stress in mice via a regulatory T cell (Treg)-dependent mechanism.3 Of note, Treg’s constrain proinflammatory processes, in part through generation of anti-inflammatory cytokines including IL-10, TGF-β, IL-35, and IL-4. M. vaccae is a saprophytic bacterium found in soil, water, and mud and is considered an “Old Friend” with potent immunoregulatory effects. We found that chronic stress exposure induced anxiety-like behavior in parallel with increased proinflammatory cytokine (IL-6 and interferon-γ) secretion from cells isolated from mesenteric lymph nodes. Interestingly, M. vaccae immunization, given as a heat-killed preparation, reduced both the behavioral and proinflammatory effects of stress. Of note, M. vaccae also increased the secretion of the anti-inflammatory cytokine IL-10 in the periphery, suggesting that M. vaccae enhances immunoregulation, thereby countering the proinflammatory effects of stress. To test this possibility, Treg’s were depleted using an anti-CD25 monoclonal antibody that specifically targets Treg’s. Indeed, Treg depletion abrogated the anxiolytic and immunoregulatory effects of M. vaccae, suggesting that M. vaccae promotes enhanced immunoregulation via Treg’s, which shifted the immune response toward an anti-inflammatory state.
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THE FUTURE OF PROBIOTIC TREATMENT: NEUROINFLAMMATION These most recent findings raise the intriguing possibility that M. vaccae, as well as other beneficial microbes, might be used to treat a spectrum of disorders and disease conditions characterized by neuroinflammation. Indeed, our most recent study on neuroimmune activation in the aging brain5 supports this hypothesis. Aging is associated with decrements in brain immunoregulation including decreases in IL-4 as well as reductions in CD200:CD200R1 signaling, which drives disinhibition of innate immune processes and cells (i.e.,
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PROBIOTIC TREATMENT AND STRESS-INDUCED INFLAMMATORY PROCESSES As noted, the immune system is capable of signaling to the brain through cytokine-dependent immune-to-brain pathways that alter the immunological landscape within the CNS.1 Given the capacity of M. vaccae to induce an anti-inflammatory milieu in the periphery, we explored the possibility that immunization with M. vaccae might also mitigate the behavioral effects of B
DOI: 10.1021/acschemneuro.8b00386 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience
The authors declare no competing financial interest.
microglia) in the aged brain. In other words, aging primes or sensitizes these immune processes to inflammatory challenges (e.g., surgery or infection) that signal to the brain. Thus, in aged organisms, there is an exaggerated neuroinflammatory response upon exposure to an inflammatory challenge, contributing to several behavioral pathologies that are characteristic of aging. One such pathology is postoperative cognitive dysfunction or POCD, which occurs in both aged humans and animal models as a result of surgery or trauma. Indeed, surgery induces sustained increases in proinflammatory cytokines in the aged brain and these increases in neuroimmune activation mediate deficits in learning and memory. Importantly, our recent work demonstrates that M. vaccae treatment enhances immunoregulation in the aged CNS via increases in IL-4. Consistent with this enhanced immunoregulation, prior M. vaccae treatment blocked the neuroinflammatory effects of surgery (increased IL-1β and NFKBIA) and prevented postoperative cognitive impairments. M. vaccae also increased expression of Treg markers in the brain, suggesting that Treg’s might communicate the anti-inflammatory signal from the periphery to the brain, thereby providing immunoregulatory input to local CNS immune cells such as microglia.
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(1) Dantzer, R., O’Connor, J. C., Freund, G. G., Johnson, R. W., and Kelley, K. W. (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9, 46−56. (2) Rook, G. A. (2013) Regulation of the immune system by biodiversity from the natural environment: an ecosystem service essential to health. Proc. Natl. Acad. Sci. U. S. A. 110, 18360−18367. (3) Reber, S. O., Siebler, P. H., Donner, N. C., Morton, J. T., Smith, D. G., Kopelman, J. M., Lowe, K. R., Wheeler, K. J., Fox, J. H., Hassell, J. E., Jr., Greenwood, B. N., Jansch, C., Lechner, A., Schmidt, D., Uschold-Schmidt, N., Fuchsl, A. M., Langgartner, D., Walker, F. R., Hale, M. W., Lopez Perez, G., Van Treuren, W., Gonzalez, A., Halweg-Edwards, A. L., Fleshner, M., Raison, C. L., Rook, G. A., Peddada, S. D., Knight, R., and Lowry, C. A. (2016) Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice. Proc. Natl. Acad. Sci. U. S. A. 113, E3130−3139. (4) Frank, M. G., Fonken, L. K., Dolzani, S. D., Annis, J. L., Siebler, P. H., Schmidt, D., Watkins, L. R., Maier, S. F., and Lowry, C. A. (2018) Immunization with Mycobacterium vaccae induces an antiinflammatory milieu in the CNS: Attenuation of stress-induced microglial priming, alarmins and anxiety-like behavior. Brain, Behav., Immun., DOI: 10.1016/j.bbi.2018.05.020. (5) Fonken, L. K., Frank, M. G., D’Angelo, H. M., Heinze, J. D., Watkins, L. R., Lowry, C. A., and Maier, S. F. (2018) Mycobacterium vaccae immunization protects aged rats from surgery-elicited neuroinflammation and cognitive dysfunction. Neurobiol. Aging, DOI: 10.1016/j.neurobiolaging.2018.07.012.
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CONCLUSION Overall, our recent work provides compelling evidence that treatment with a heat-killed preparation of a probiotic can enhance immunoregulation in the CNS and promote a longlasting shift toward an anti-inflammatory immunophenotype and reductions in behavioral phenotypes that reflect neuroinflammation. These findings should encourage the exploration of microbial-based approaches for treating a broad spectrum of neuroinflammatory conditions.
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REFERENCES
AUTHOR INFORMATION
Corresponding Author
*Mailing address: Department of Psychology and Neuroscience, Center for Neuroscience, 2860 Wilderness Place, Campus Box 603, University of Colorado Boulder, Boulder, CO 80301, USA. Tel: 303-919-8116. Fax: 303-492-2967. Email:
[email protected]. ORCID
Matthew G. Frank: 0000-0001-8613-6897 Funding
This work was supported by grants from the National Institutes of Health to M.G.F. and S.F.M. (R01MH108523), to L.K.F. (F32AG048672), and to C.A.L., M.G.F., S.F.M., and L.K.F. (R21MH116263). C.A.L. is supported by the Department of the Navy, Office of Naval Research Multidisciplinary University Research Initiative (MURI) Award (Grant Number N00014-15-1-2809), Department of Veterans Affairs Office of Research and Development (VA-ORD) RR&D Small Projects in Rehabilitation Research (SPiRE) (I21) (Grant Number 1 I21 RX002232-01), Colorado Clinical & Translational Sciences Institute (CCTSI) Center for Neuroscience (Grant Number CNSTT-15-145), the Colorado Department of Public Health and Environment (CDPHE; Grant Number DCEED3510), and the Alfred P. Sloan Foundation (Grant Number G2016-7077). Notes
C.A.L. serves on the Scientific Advisory Board of Immodulon Therapeutics Ltd. C
DOI: 10.1021/acschemneuro.8b00386 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
