OR15-3 Contribution of Hyperandrogenemia to Dysbiosis, Gut Inflammation, and Dysregulation of Short-Chain Fatty Acid Homeostasis in Mouse Model of Polycystic Ovary Syndrome

INTRODUCTION AND PURPOSE: Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Notably, PCOS women with hyperandrogenism have a pronounced increased risk for cardio-metabolic comorbidities. The gut microbiome is responsible for fermentation of indigestible fiber to produce short-chain fatty acids (SCFA), which help maintain metabolic function and reduce gut inflammation. Alteration in the gut microbiome, or dysbiosis, affects overall metabolic homeostasis and contributes to pathogenesis of metabolic diseases. While dysbiosis has been observed in women with PCOS, the molecular mechanisms of hyperandrogenemia-induced dysbiosis and its contribution to SCFA excretion and gut inflammation have not been studied in PCOS. METHODS: Four-week old C57BL/6N female mice were implanted subcutaneously with dihydrotestosterone (DHT, 8.0 mg) or vehicle silastic tubes (n=8/grp). Animals were treated day 90 and the gastrointestinal tract was collected. Expression levels of mRNA were assessed by RT-qPCR. Fecal microbiota was assessed by 16S rRNA gene sequencing and profiled using MicrobiomeAnalyst; SCFA concentrations were assessed by LC-MS. RESULTS: DHT-treated female mice had significantly increased lean mass (21.35 ± 0.84 vs 19.25 ± 0.55 g, p<0.05) and increased fat mass (5.18 ± 1.45 vs 2.73 ± 0.64 g, p<0.05) compared to the vehicle counterparts. DHT-treated female mice showed increased HbA1C (5.18 ± 1.45 vs 2.73 ± 0.64%, p<0.05). Hyperandrogenemic females showed altered gastrointestinal morphology, having decreased small intestine (33.03±2.05 vs 28.69±2.604 cm, p<0.05) and colon length (7.88 ± 0.64 vs 6.60 ± 0.55 cm, p<0.05) as well as increased immune cell infiltration assessed by histology. DHT-treated female mice have an increase in the relative percent abundance of Proteobacteria (2.04 ± 0.62 vs 0.35 ± 0.23%, p<0.05) and in the ratio of Firmicutes/Bacteriodetes (1.92 ± 0.47 vs 1.11 ± 0.17, p<0.05). Fecal concentrations of short-chain fatty acids were higher in DHT-females for butyric acid (92.33 vs 404.8 ng/mg feces, p<0.05), acetic acid (571.8 vs 1592 ng/mg feces, p<0.05), and propionic acid (80.59 vs 167.3 ng/mg feces, p<0.05). However, expression of the SCFA receptor Ffar2 in the colon was upregulated by DHT (1.31 ± 0.15-fold, p<0.05), indicating the possibility of a compensation to ameliorate increased SCFA excretion. The mRNA expression of lipopolysaccharide induced inflammation markers were significantly upregulated by DHT in the proximal colon (Litaf, 1.69 ± 0.29-fold; Tlr4 1.27 ± 0.15-fold, p<0.05) compared with vehicles. CONCLUSIONS: Androgen-mediated gut dysbiosis may contribute to altered glucose handling, adiposity, and metabolic homeostasis in PCOS. Increased elimination of SCFA in DHT-treated female mice may indicate less efficient absorption, which can contribute to colonic inflammation, altered gastrointestinal morphology, and increased gut permeability. Together, our results highlight the potential role of androgen-mediated gut dysbiosis to influence metabolic dysfunction. Presentation: Sunday, June 12, 2022 11:30 a.m. - 11:45 a.m.