Analysis of preclinical anxiety due to dysbiosis of gut bacteria

Sarkis K. Mazmanian, Ph.D.

California Institute of Technology

Funded in October, 2012: $200000 for 3 years
LAY SUMMARY . ABSTRACT .

LAY SUMMARY

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Investigators will use imaging to explore the functional connection between anxiety and microbes in the human gut

 The long vagal nerve transmits signals between the brain and the gut. The evolutionally ancient gut microbial systemis made up of 100 trillion bacterial cellscomprised of more than 1,000 species that live in symbiosis with thehuman and non-human host. Evidence of signaling between gut microbiota and the brain are beginning to challenge fundamental theories of neuroscience, includingtheetiologyofhuman anxiety and depression. The investigators hypothesize that alterationsingutmicrobialcommunities play a causative role in the regulation of human emotion via long-distance signaling from thegut to the brain through the vagal nerve.   They will undertake

a two-phase study to test this hypothesis, with the second phase contingent upon demonstrating feasibility of the research approach.

In the first phase, theywilltransplantgutbacteriaexcreted by people diagnosed with high anxiety into mice, and see whether the micedevelopincreasedanxietybehaviorandalteredgenes that are linked to anxiety behaviors in the mice. If this is demonstrated to be feasible, the investigators will embark on the second stage. They will use brain perfusion radiographic imaging mapping methods in the awake and unrestrained, mice to provide 3-dimensional assessments of functional activation in networks throughout the mouse brain. Investigators will determine whether thesemiceshowexaggeratedactivationofemotional circuits in the brain compared to normal mice and to mice transplanted with gut bacteria fromhealthy (non-anxious) people. Thereafter, they will cut the vagus nerve in the “anxious” miceand determine whether the exaggerated network activation and related anxiety behaviors are abolished. .

Significance: Thefindingscouldleadto advances in developing innovative pro-biotic therapies for anxiety and potentially other psychiatric disorders.

ABSTRACT

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Analysis of preclinical anxiety due to dysbiosis of gut bacteria

The interactions between neural systems in the brain, made up of billions of interconnected cells have been considered sufficient to explain such complex behavioral phenomena as cognition, motivation and emotions. Yet the recent discovery of an equally complex, and evolutionary ancient gut microbial system (made up of 100 trillion bacterial cells comprised of >1,000 species) living in symbiosis with the host, and the initial preclinical evidence of communications of the gut microbiota with the brain are beginning to challenge the most fundamental paradigms of neuroscience. Indeed, recent reports have suggested that certain organisms may prove to be useful therapeutic adjuncts in stress related disorders such as anxiety and depression. This proposal aims to test the innovative hypothesis that alterations in gut microbial communities play a causative role in human emotion regulation via long distance, vagally-mediated gut to brain signaling. As a first step toward determining if the microbiota impacts psychiatric disorders, we propose the following aims: (1) To evaluate if transplantation of gut bacteria from high trait anxiety (HTA) human subjects into mice will transfer increased anxiety behavior and alter gene expression for genes linked to anxiety in mice, including the dopamine 01 and 02 receptors, the GABAA and GABA6 receptors, as well as nerve growth factor-inducible clone A and brain-derived neurotrophic factor. (2) To determine in awake, unrestrained mice, the effects that HTA human microbiota has on functional brain activation in fear/anxiety circuit during an acute fear challenge. Regional cerebral blood flow-related tissue radioactivity is quantified by [' C]-iodoantipyrine autoradiography and analyzed in the three-dimensionally reconstructed brain by statistical parametric mapping and functional connectivity. (3) To evaluate if anxiety­ like behavior and changes in limbic activation elicited by transfer of stool microbiota from anxious human subjects to mice are abolished in the animal by prior vagotomy. If the main hypothesis of the proposal is confirmed, it would have far reaching consequences for our understanding of emotion regulation in health and disease, and would open up completely new strategies, including the use of novel probiotic therapies, for the treatment of anxiety and possible other psychiatric diseases.