Research

We study microbiome neuroimmune interactions in host development, physiology, and behavior, with a focus on how the gut microbiome influences the brain throughout all stages of life. This communication occurs through multiple pathways, including the peripheral nervous system, immune signaling, hormones, small molecules, and microbial metabolites. Using laboratory animal models, we have identified a variety of mechanisms by which the gut microbiome modulates behavior. For example, male mice lacking a microbiome exhibit reduced social behavior and heightened stress responses, as evidenced by increased hypothalamic pituitary adrenal (HPA) axis activation. In a separate study, male mice exposed to a microbial metabolite identified in a mouse model of atypical neurodevelopment exhibited altered brain activity, reduced myelination and oligodendrocyte maturation, and behaviors associated with anxiety. These findings highlight the profound influence of microbial compounds on host brain function. Given the vast diversity of microbial species and animal behaviors, it is likely that additional gut-brain associations will continue to emerge. Small molecule metabolites, in particular, represent a key mode of communication within the gut microbiota-brain axis, with the ability to influence host physiology at distant sites such as the brain. To further uncover these mechanisms, we are using mice colonized with microbiota from either wild-caught or laboratory animals, integrating untargeted metabolomics and metagenomics to (a) determine how microbial complexity shapes neurometabolism, (b) discover microbiome-derived compounds that regulate behavior, and (c) identify the underlying microbial taxa and genetic pathways involved. This work aims to advance our mechanistic understanding of gut-brain communication and inform the development of precision microbiome based therapeutics.

The enteric nervous system (ENS) is an extensive network of intrinsic neurons in the gastrointestinal tract often dubbed the "second brain." The ENS coordinates critical digestive functions such as gastrointestinal motility and nutrient absorption, but also influences immune system development and activity. The gut microbiome mediates both the nervous system and immune system, combining to result in innumerable potential effects on the host. We have utilized engineered neurobiological tools and methods developed to investigate the brain in order to manipulate neurons in the gut and observe outcomes on the host and microbiome in mice. Activating separate subpopulations of gut-associated neurons has profound impacts on gut microbiome diversity and composition, gut physiology, host gene expression, and profiles of proteins and metabolites. Continuing research on the ENS and the interconnected biological systems of the gut is an important step in understanding fundamental biology to eventually benefit human gut health. 

The intestinal microbiota influences neurodevelopment, modulates behavior, and contributes to various neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction, as exemplified by Parkinson's disease (PD). Using mice that overexpress αSyn, we report herein that the microbiota is required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial colonization promotes, pathophysiology in adult animals, suggesting disease arises from postnatal signaling between the gut and the brain. Indeed, oral administration of the microbial metabolites, short-chain fatty acids, to germ-free mice promotes neuroinflammation and motor symptoms. Remarkably, colonization of αSyn-overexpressing mice with microbiota from PD patients enhances physical impairments compared to microbiota transplants from healthy human donors. These findings reveal that gut bacteria potentiate numerous Parkinsonian-like features in a mouse model, and suggest that alterations in the human microbiome represent a novel risk factor for PD.