BACKGROUND: Hypoactive Sexual Desire Disorder (HSDD) is a highly prevalent, clinically impactful female sexual health condition whose pathogenesis is closely associated with disrupted excitation-inhibition homeostasis in the central nervous system, while the mechanistic role of gut microbiota in this pathological process via the gut-brain axis remains largely unelucidated.
AIM: To explore gut microbiota-neurotransmitter interactions in an HSDD-simulating rat model and verify their causal role via fecal microbiota transplantation (FMT).
METHODS: Female Sprague-Dawley rats were stratified into high copulatory behavior, normal copulatory behavior (NCB), and reduced copulatory behavior (RCB) groups via quantified mating behavioral assays, with the RCB phenotype used to establish a preclinical rat model simulating the core features of human HSDD. FMT was performed in four experimental groups: RCB-FMT-RCB, NCB-FMT-NCB, RCB-FMT-NCB, and NCB-FMT-RCB. Gut microbial composition was characterized by 16S rRNA gene sequencing, and prefrontal cortex (PFC) neurotransmitter levels were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Sexual behavioral parameters were assessed following FMT administration.
OUTCOMES: Determined gut microbial and PFC neurotransmitter differences between RCB and normal rats, and validated FMT's regulatory effects on recipients' copulatory behavior, gut microbiota, and neurotransmitter balance.
RESULTS: Compared with NCB rats, RCB rats exhibited a distinct microbial biomarker profile, characterized by enrichment of Oscillibacter and Bacteroides and depletion of Jeotgalicoccus. In the PFC, RCB rats had elevated levels of inhibitory neurotransmitters (5-HT, GABA) and 5-HIAA, alongside reduced levels of excitatory neurotransmitters (DOPA, Glu). FMT induced phenotypic transfer: NCB-FMT-RCB rats displayed diminished sexual desire and developed RCB-like microbial and neurotransmitter profiles, while RCB-FMT-NCB rats exhibited improved copulatory behavioral endpoints and partial normalization of PFC neurotransmitter levels. Spearman's correlation analysis demonstrated that Oscillibacter and Bacteroides abundances were correlated with neurotransmitter imbalance in the PFC.
CLINICAL IMPLICATIONS: This study provides novel preclinical insights into the role of the gut-brain axis in HSDD, supporting further exploration of gut microbiota as a potential research target for HSDD.
STRENGTHS AND LIMITATIONS: Strengths include a validated RCB rat model, bidirectional FMT for causality; limitations involve the inability to assess subjective distress in rodents, rat-human physiological differences, PFC-only neurotransmitter analysis, unclear molecular pathways, and lack of long-term data.
CONCLUSIONS: Gut microbial dysbiosis contributes to RCB (simulating human HSDD) in female rats via modulating prefrontal cortex neurotransmitter excitation-inhibition homeostasis, with Oscillibacter and Bacteroides as key functional genera. These findings provide preliminary preclinical evidence for the gut-brain axis in sexual behavior regulation and human HSDD pathogenesis.
