Gut dysbiosis impacts estrogen levels in APP/PS1 transgenic female mice

Alzheimer's disease (AD) is the most common form of dementia, with a higher prevalence in women than in men. It has been suggested that the decline in estrogen production after menopause may increase the risk of developing dementia. Additionally, patients with AD often display dysbiosis of the gut microbiota (GM), even in the early stages of the disease. The GM plays a crucial role in modulating systemic estrogen levels through a mechanism known as the <i>estrobolome</i>. However, it remains unclear whether gut dysbiosis contributes to estrogen imbalance and subsequent cognitive decline in women. In this study, we aim to investigate whether alterations in the GM impact estrogen availability and cognitive function in 6-month-old female APP/PS1 (TG) mice compared to age-matched wild-type (WT) littermates. We included a group of both WT and TG mice treated with a broad-spectrum antibiotic cocktail (ABX) for one month to modify their GM composition. Our results revealed that TG mice exhibited a dysfunctional <i>estrobolome</i> characterized by a decreased abundance of <i>Limosilactobacillus</i> and <i>Lactobacillus</i>, an increased abundance of <i>Ligilactobacillus</i>, and reduced activity of the β-glucuronidase enzyme in fecal samples. Additionally, TG female mice showed low bioavailability of estradiol, disrupted estrous cycle, and cognitive impairments. Notably, WT-ABX mice displayed gut dysbiosis, marked by a decrease in the relative abundances of <i>Limosilactobacillus</i> and <i>Lactobacillus</i>, as well as reduced β-glucuronidase activity. Moreover, WT-ABX exhibited altered estradiol levels and cognitive impairments compared to WT controls. Therefore, our findings suggest that gut dysbiosis may be a contributing factor to female vulnerability in developing dementia by disrupting hormonal levels and cognitive function.