Select microbial metabolites in the small intestinal lumen regulates vagal activity via receptor-mediated signaling
Kelly G. Jameson,
Sabeen A. Kazmi,
Takahiro E. Ohara,
Celine Son,
Kristie B. Yu,
Donya Mazdeyasnan,
Emma Leshan,
Helen E. Vuong,
Jorge Paramo,
Arlene Lopez-Romero,
Long Yang,
Felix E. Schweizer,
Elaine Y. Hsiao
Affiliations
Kelly G. Jameson
Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Corresponding author
Sabeen A. Kazmi
Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Takahiro E. Ohara
Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Celine Son
Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Kristie B. Yu
Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Donya Mazdeyasnan
Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Emma Leshan
Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Helen E. Vuong
Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Jorge Paramo
UCLA Goodman-Luskin Microbiome Center, Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, Los Angeles, CA 90095, USA
Arlene Lopez-Romero
UCLA Goodman-Luskin Microbiome Center, Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, Los Angeles, CA 90095, USA
Long Yang
Department of Neurobiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Felix E. Schweizer
Department of Neurobiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Elaine Y. Hsiao
Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Goodman-Luskin Microbiome Center, Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, Los Angeles, CA 90095, USA; Corresponding author
Summary: The vagus nerve is proposed to enable communication between the gut microbiome and the brain, but activity-based evidence is lacking. We find that mice reared germ-free exhibit decreased vagal tone relative to colonized controls, which is reversed via microbiota restoration. Perfusing antibiotics into the small intestines of conventional mice, but not germ-free mice, acutely decreases vagal activity which is restored upon re-perfusion with intestinal filtrates from conventional, but not germ-free, mice. Microbiome-dependent short-chain fatty acids, bile acids, and 3-indoxyl sulfate indirectly stimulate vagal activity in a receptor-dependent manner. Serial perfusion of each metabolite class activates both shared and distinct neuronal subsets with varied response kinetics. Metabolite-induced and receptor-dependent increases in vagal activity correspond with the activation of brainstem neurons. Results from this study reveal that the gut microbiome regulates select metabolites in the intestinal lumen that differentially activate vagal afferent neurons, thereby enabling the microbial modulation of chemosensory signals for gut-brain communication.
