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Background and Aims: Vasoactive intestinal peptide (VIP) is a neuropeptide involved in the regulation of feeding behavior and circadian rhythms, metabolism, and immunity. Previous studies revealed the homeostatic effects of VIP signaling on the gut microbiota. VIP-deficient mice demonstrate a gut microbiota dysbiosis characterized by reduced α -diversity and decreased relative abundance (RA) of Gram-positive Firmicutes . However, the mechanism by which VIP signaling affects changes in the microbiota is unknown., Methods: To investigate the role of the 2 cognate G protein-coupled receptors for VIP (VPAC1 and VPAC2) in VIP-mediated homeostasis of the microbiota, fecal samples from VPAC1- and VPAC2-deficient, heterozygous, and wild-type littermate mice were assessed via targeted amplicon sequencing. Their microbiota profiles were additionally compared with microbiota from VIP-deficient, heterozygous, and wild-type littermates, where genotype-dependent changes in the composition and predicted function of each cohort were compared., Results: While wild-type mice in each line differed in α -diversity and β -diversity, consistent changes in both metrics were observed in VIP-deficient and VPAC1-deficient mice. This includes a dramatic reduction in α -diversity, increased RA of Proteobacteria and Bacteroidetes , and decreased RA of Lachnospiraceae , Ruminococcaceae , Muribaculaceae , and Rikenellaceae . Specific amplicon sequence variants and predicted functions found to differ significantly based on VIP or VPAC1 genotype were concordant in their directions of change. Multiplatform predicted functional profiling suggested a defective VIP-VPAC1 axis was associated with reduced amino acid degradation along with reduced quinol and quinone biosynthesis. Furthermore, alterations in predicted functions include increased sugar degradation, nitrate reduction, and fatty acid biosynthetic pathways, among other changes., Conclusion: We conclude that VIP signaling through VPAC1 is critical for the maintenance of normal function of the gut microbiota., Competing Interests: Conflicts of Interest: The authors disclose no conflicts.