While it is understood that depression is an umbrella term for a spectrum of clinical syndromes describing changes in affect, anxiety, psychomotor speed, and cognition, it is not at all clear why some individuals will develop neuropsychiatric impairment while others will not. To better understand the basis for this selective vulnerability, our lab has been investigating the effects of obesity and high fat diet - known risk factors for depression - on neurobehavior in mice. Based on these data we propose the following hypothesis: Selective vulnerability to neuropsychiatric illness is driven by the gut microbiome. This hypothesis is based on the robust and long-lasting effects of modern high fat diets on gut microbiota, producing a gut dysbiosis typified by reduced bacterial diversity and disrupted pathogen/commensal balance. More importantly, we have shown that gut dysbiosis drives neurobehavioral impairment and brain inflammation even in the absence of dietary fat or obesity. These exciting studies demonstrate the clinical significance of the gut-brain axis, and raise the possibility that gut microbiota could be an effective - and accessible - tool to preserve mental health. This concept has raised considerable hope (and hype) in popular literature, but key data are needed to confirm the legitimacy of the microbiome as a valid therapy. First, to ensure that gut dysbiosis is sufficient to disrupt brain function, neurobehavioral impairment must be tied directly to the microbiome without confounds. Secondly, to ensure that gut dysbiosis is necessary for brain dysfunction, rational microbiome-based therapies need to be designed and tested in physiologically relevant models. To meet these needs, we have devised a unique experimental approach (see Fig. 1) that exploits the synergistic interactions of host- and diet-induced drivers of gut dysbiosis, and an adaptive transplantation paradigm that isolates microbiome effects from cofounds introduced by diet, metabolic dysfunction, genetics, and/or obesity. Using this approach, we will map both the pathophysiologic consequences of gut dysbiosis and the therapeutic potential of microbiome manipulation.
Specific aim 1 will test if gut dysbiosis caused by high fat/calorie Western diet is sufficient to induce neurobehavioral impairment and brain injury in mice.
Aim 2 describes preclinical studies that will test if therapeutic transplantation of gut microbiota can prevent - or reverse - brain injury/dysfunction in the context of Western diet consumption. Completion of these studies will advance understanding of how the microbiome-gut-brain axis participates in mental health. Even more importantly, these studies could identify new approaches that could be quickly translated into safe and effective therapies to preserve mental health.

Public Health Relevance

Unhealthy, high-fat diets increase the risk of depression and can injure the brain. This is a significant challenge to public health in light of the extensive consumption of unhealthy Western- style diets and the increasing costs needed to treat mental health disorders. To address this challenge, research needs to move beyond the confines of conventional therapies and evaluate new ideas. This proposal describes unique and innovative studies that will determine if changes to the gut microbiome mediate brain injury caused by high fat, Western-style diets. Completion of these experiments will increase understanding of how disruption of the gut microbiome contributes to mental illness and could lead to improvements in mental and neurologic health in the context of modern diets and lifestyles.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Desmond, Nancy L
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Lsu Pennington Biomedical Research Center
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Baton Rouge
United States
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Fields, Christopher T; Sampson, Timothy R; Bruce-Keller, Annadora J et al. (2018) Defining Dysbiosis in Disorders of Movement and Motivation. J Neurosci 38:9414-9422
Bruce-Keller, Annadora J; Salbaum, J Michael; Berthoud, Hans-Rudolf (2018) Harnessing Gut Microbes for Mental Health: Getting From Here to There. Biol Psychiatry 83:214-223