Background The gut microbiome is receiving considerable attention as a potentially modifiable risk factor and therapeutic target for numerous mental and neurological diseases. Objective This study aimed to explore and assess the difference in the composition of gut microbes and fecal metabolites between women with hypoactive sexual desire disorder (HSDD) and healthy controls. Methods We employed an online recruitment method to enroll “hard-to-reach” HSDD populations. After a stringent diagnostic and exclusion process based on DSM-IV criteria, fecal samples collected from 24 women with HSDD and 22 age-matched, healthy controls underwent microbiome analysis using 16S ribosomal RNA gene sequencing and metabolome analysis using untargeted liquid chromatography–mass spectrometry. Results We found a decreased abundance of Ruminococcaceae and increased abundance of Bifidobacterium and Lactobacillus among women with HSDD. Fecal samples from women with HSDD showed significantly altered metabolic signatures compared with healthy controls. The abundance of Bifidobacterium, Lactobacillus, and several fecal metabolites correlated negatively with the sexual desire score, while the number of Ruminococcaceae correlated positively with the sexual desire score in all subjects. Conclusions Our analysis of fecal samples from women with HSDD and healthy controls identified significantly different gut microbes and metabolic signatures. These preliminary findings could be useful for developing strategies to adjust the level of human sexual desire by modifying gut microbiota. Trial Registration Chinese Clinical Trial Registry ChiCTR1800020321; http://www.chictr.org.cn/showproj.aspx?proj=34267Test
