Bacteria sensory transduction from gut to brain to modulate behavior

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SUMMARY Gut microbes are associated with disorders of behavior, including those related to food intake and appetite. Obesity and hyperphagia can be transferred from donor to germ-free recipient mice, simply by microbial transplants. However, the correlative effects seen in mice have yet to be translated to the clinic. There is a critical need to determine how microbial signals alter host behaviors. Specifically, it is unknown how a microbial stimulus arising in the GI lumen is converted into a neural signal reinforces behavior. This gap in our knowledge is a significant problem because knowing how microbial ligands and GI sensory function interact will allow for rational design of gut-based therapies to treat disorders of food intake and promote emotional well-being. Our laboratory recently discovered a neural circuit linking the gut lumen with the brain stem in one synapse. Formed between neuropod cells and vagal neurons, this neural circuit transduces luminal stimuli to the brain in milliseconds (Kaelberer et al., 2018). Moreover, in the proximal small intestine where nutrients are abundant, this neural circuit is necessary for an animal to distinguish sugar from sweeteners (Buchanan et al., 2020). On this basis, our hypothesis is that colonic neuropod cells synapse with vagal neurons to communicate reward from bacterial stimuli. The objectives for this proposal are to define if colonic neuropod cells sense bacterial ligands, transduce bacterial signals onto vagal neurons, and modulate reward behavior. Our rationale is that by elucidating the mechanisms of bacterial sensory transduction from gut to brain, gut microbial therapeutics could be developed to treat disorders of food intake linked to diet and gut microbes.