Inflammation and Neurodegeneration Laboratory

FACULTY

  • Annadora Bruce-Keller, Ph.D.

ABOUT THIS LAB

Western diets, obesity, and neurologic health Obesity linked to Western-style diets is the prototypical ailment of the modern era, and remains stubbornly prevalent and refractory to clinical remediation. Indeed, while the components of a healthy lifestyle are generally well known, numerous societal (poverty, food deserts, irregular/sedentary work schedules) and physiological (stress, leptin resistance, metabolic adaptations to caloric restriction) factors combine to prevent successful weight loss. In addition to ties with type 2 diabetes and cardiovascular disease, obesity dramatically increases the risk of anxiety and depression. Indeed, data suggest a reciprocal and synergistic relationship between metabolic dysfunction and depression, with obese individuals having an increased risk for depression, while depressed individuals are significantly more likely to develop metabolic impairments. While these epidemiologic data likely reflect discrete pathways linking metabolic to behavioral dysfunction, such mechanistic links have not yet been identified.

The microbiome-gut-brain axis and neurobehavioral function The human intestinal tract harbors an extensive microbiome of trillions of bacteria from up to 1000 distinct taxa. A surprisingly mutualistic relationship exists between gut microbiota and their human hosts, with microbiota protecting against pathogens, metabolizing otherwise inaccessible complex polysaccharides, neutralizing drugs and carcinogens, and directing the development and homeostasis of the immune system. Modern sequencing and bioinformatics techniques show that modern high fat/calorie diets cause significant disruption to core gut microbiota, inducing a dysbiosis typified by significant reductions in bacterial diversity and widespread imbalance in pathogenic/commensal populations. A growing body of data from our lab and others indicate that such alterations in gut microbiota are directly linked to neurobehavioral impairment.

Multiple endocrine, immune, and neural pathways likely form the microbiome-gut-brain axis. For example, extensive interactions between gut microbiota and intestinal immune elements have been characterized. As elevated inflammation participates in nearly all neurologic disorders, intestinal inflammation and/or endotoxemia could link gut dysbiosis to behavioral dysfunction. Conversely, gut microbiota can act directly on local neural processes, as gut microbial metabolites include neuroactive mediators including catecholamines and monoamines that can directly stimulate enteric and/or vagal fibers. Furthermore, it is possible that the very metabolism of dietary elements could be altered by microbial population shifts, suggesting that the beneficial properties of even “healthy” dietary elements could be undercut by intestinal dysbiosis.

Overall Goals of Bruce-Keller lab: Until recently, the brain was assumed to be fully immunologically privileged and nearly completely shut off from processes occurring in the periphery. In appreciation of the pleiotropic effects of peripheral physiological on the brain, this lab is studying the processes that link complex neurocognitive dysfunction to microbial changes in the bowel, a site about as far as one can get both physically and metaphorically from the brain. More specifically, we are trying to map the gut brain axis and identify the potential mechanisms whereby intestinal dysbiosis influences brain heath and function in mice. Most importantly, we seek to identify lifestyle-related therapies – exercise and/or botanical supplements - that could be used as tools to shape a healthy microbiome that preserves/promotes metabolic resilience in the context of today’s complex dietary landscape. This lab relies heavily on genomic sequencing and metabolomics techniques, as well as comprehensive metabolic and neurobehavioral phenotyping.

Recommended Articles:

  • Bruce-Keller, A.J., J.M. Salbaum, M. Luo, E. Blanchard, C.M. Taylor, D.A. Welsh, and H.R. Berthoud (2014) Gut Microbiota Shaped by High Fat Diet Disrupt Neurocognitive Behavior in Mice. Biol Psychiatry. 77(7):607-15. PMCID:PMC4297748
  • Bruce-Keller, A.J., J.M. Salbaum, M. Luo, E. Blanchard, C.M. Taylor, D.A. Welsh, and H.R. Berthoud (2016) Reply to: High fat Diet-Induced Dysbiosis as a Cause of Neuroinflammation. Biol Psychiatry. 80(1):e5-6. PMID:26774965
  • Bruce-Keller, A.J., S.O. Fernandez-Kim, R.L. Townsend, C. Kruger, R. Carmouche, S. Newman, J.M. Salbaum, and H.R. Berthoud (2017) Maternal Obese-type Gut Microbiota Differentially Impact Cognition, Anxiety and Compulsive Behavior in Male and Female Offspring in Mice. PLoS One. 12(4):e0175577. PMC5404786
  • Bruce-Keller, A.J., J.M. Salbaum, and H.R. Berthoud (2017) Harnessing Gut Microbes for Mental Health: Getting from Here to There. Biol Psychiatry. 83(3):214-223.