AGpr35tuned gut-brain metabolic axis regulates depressive-like behavior

Abstract

Gene-environment interactions shape animal behavior and the susceptibility to neurobehavioral symptoms such as depression. However, little is known about the signaling pathway that integrates genetic and environmental inputs with neurobehavioral outcomes, preventing the development of targeted therapies. Here we report that Gpr35 engages a gut microbe-to-brain metabolic pathway to modulate neuronal plasticity and depressive behavior in mice. Chronic stress decreases gut epithelial Gpr35, the genetic deletion of which induces despair and social impairment in a microbiome-dependent manner. We identify a dominant role for the imbalance of indole-3-carboxaldehyde (IAld) and indole-3-lactate (ILA) in conferring the behavioral symptoms. Mechanistically, these bacterial metabolites enter the brain to counteractively modulate dendritic spine density and synaptic transmission in the nucleus accumbens. Supplementation of IAld, which is similarly decreased in depressive patients, produce anti-depressant effects in mice. Together, these findings identify a genetics-shaped gut-brain connection underlying the susceptibility to depression and suggest a potential therapeutic strategy to genetic predisposition.

Supplier-origin gut microbiomes affect host body weight and select autism-related behaviors

“…The GM is the complex community of microorganisms colonizing the gastrointestinal tract, functioning in host metabolism, vitamin and short chain fatty acid production, and the synthesis of neuroactive compounds. Growing evidence supports crucial roles for the GM in modulating many host behaviors, including ASD-related behaviors 5,6 . For example, germ-free mice exhibit the core ASD-related behaviors (i.e., a lack of social preference and increased repetitive behaviors) which are reversed by repopulating the gut with complex microbial communities or even single, psychobiotic microbes (e.g., Lactobacillus reuteri) 7,8 .…”