Oral Contraceptives Induce Time- and Intestinal Segment-Dependent Shifts in the Gut Microbiota

Oral contraceptives (OCs) containing estrogen and/or progesterone are the second most common form of female contraception in the United States. While endogenously synthesized estrogen is known to provide protective effects against cardiometabolic diseases, exogenous forms such as OCs have been linked to increased susceptibility to cardiometabolic diseases and an elevated risk of myocardial infarction. The gut microbiota is thought to be a critical regulator of cardiometabolic disease risk; however, its interactions with OC use remain understudied. OBJECTIVE: We aimed to evaluate the effects of OC use on the intestinal microbiota and investigate microbial associations with intestinal estradiol levels, energy homeostasis, and hepatic oxidative stress markers. METHODS: Female C57BL/6J mice were fed a high-fat diet with or without OCs from 7 to 8 weeks of age and maintained for either 12 or 20 weeks. Duodenal, jejunal, cecal, and colonic microbiota, cecal short- and branched-chain fatty acids, and intestinal estradiol levels were assessed. RESULTS: Both 12- and 20-week of OC treatments significantly elevated colonic estradiol levels. Twenty weeks of OC treatment significantly altered the composition of both cecal and colonic microbiota and increased cecal isobutyric acid concentrations, whereas 12 weeks of OC treatment resulted in only trending shifts in the cecal microbiota and did not alter colonic microbiota or fatty acid compositions assessed. In 12-week treated mice, cecal Lactococcus was positively associated with non-resting energy expenditure, whereas in 20-week treated mice, cecal Lachnoclostridium was positively associated with resting energy expenditure. CONCLUSIONS: OC use induces time- and intestinal segment-dependent shifts in the gut microbiota and branched-chain fatty acid production. The OC-induced increase in colonic estradiol could further influence the gut microbiota and health when utilized long-term. These findings provide critical insight into how OC use may contribute to increased cardiometabolic risk through gut microbial alterations.