Investigation of strategies for improving metabolic health in postmenopause: cannabidiol, bacterial metabolism of estrogens, and dietary fatty acids
Creators: name: Sui, Ke
Publisher: name: No Publisher Supplied
Year: 2023

description: Menopause is a normal part of aging and marks the end of reproductive years. Ovarian production of 17β-estradiol (E2) starts to decline in perimenopause and eventually ceases in menopause, although small amounts continue to be produced by adipose and adrenal tissues. Postmenopause is defined as one year after final menstruation. As E2 protects women from many chronic diseases, women in postmenopause are at increased risk of cardiovascular disease, osteoporosis, and weight gain. Decline in E2 also results in increased risk of gastrointestinal disorders, compromised gut barrier, reduced gut microbial diversity, and increased proinflammatory cytokines. The gut microbiota contributes to regulation of circulating estrogen levels. Gut bacterial β-glucuronidases deconjugate estrogens to bioactive forms that are reabsorbed via enterohepatic circulation. Hormone replacement therapy (HRT) is linked with increased risk of cancers and cardiovascular diseases, therefore safer treatment options are needed. The studies described herein were designed to investigate how cannabidiol (CBD) or different dietary fatty acids may modulate the gut microbiota to impact metabolism, cognition, and estrogen metabolism. The study described in Chapter 2 provides preclinical evidence suggesting CBD, a non-psychotropic phytocannabinoid extracted from hemp, has therapeutic value for attenuating disease phenotypes in the ovariectomized (OVX) mouse model for E2 deficiency. Briefly, when CBD was administered perorally to OVX mice for 18 weeks, compared to VEH-treated OVX mice, CBD-treated OVX mice showed improvements in energy, glucose, and bone metabolism. Furthermore, compared to VEH-treated OVX mice, CBD-treated OVX mice had increased relative abundance of fecal Lactobacillus species, which have been associated with metabolic improvements in E2 deficient rodents and postmenopausal women. The study in Chapter 3 tested eight human-derived Lactobacillus strains with and without putative GUS activity for their ability to deconjugate glucuronidated estrone (G-E1) and E2 (G-E2). Strains were anaerobically cultured in Man, Rogosa &amp; Sharpe (MRS) broth in the absence or presence of G-E1G-E2. Aliquots of cultures collected over 24 h time course periods were extracted for LC-MS analysis of free and conjugated estrogens. L. jensenii 269-3 was able to deconjugate G-E1 and G-E2 while L. rhamnosus LMS2-1 efficiently deconjugated only G-E1. The remaining six Lactobacillus strains were unable to deconjugate G-E1 or G-E2. These data indicate that estrogen deconjugation activity is dependent on bacterial strain and estrogen type. Obesity, cardiometabolic disease, cognitive decline, and osteoporosis are symptoms of postmenopause, which can be modeled using 4-vinylcyclohexene diepoxide (VCD)-treated mice to induce ovarian failure and E2 deficiency combined with high fat-diet (HFD) feeding. The trend of replacing saturated fatty acids (SFAs), for example coconut oil, with seed oils that are high in polyunsaturated fatty acids (PUFAs), specifically linoleic acid (LA), may induce inflammation, gut dysbiosis, and worsen symptoms of E2 deficiency. To investigate this hypothesis, vehicle (Veh)- or VCD-treated C57BL/6J mice were fed HFD (45 % kcal fat) with a high LA:SFA ratio (22.5%: 8%) referred to 22.5% LA diet or a HFD with a low LA:SFA ratio (1%: 31%) referred to as 1% LA diet for a period of 23-25 weeks in the study of Chapter 4. Compared with VCD-treated mice fed 22.5% LA diet, VCD-treated mice fed the 1% LA diet showed lower weight gain and improved glucose tolerance. However, VCD-treated mice fed the 1% LA diet had higher blood pressure and showed evidence of spatial cognitive impairment. Mice fed 1% LA or 22.5% LA diets showed gut microbial taxa changes that have been associated with a mix of both beneficial and unfavorable cognitive and metabolic phenotypes. In the Chapter 5, Veh- or E2-treated OVX wild type (WT) C57BL/6J and transgenic fat-1 mice were fed the same HFDs used in the Chapter 4 for a period of 14-15 weeks. The transgenic fat-1 mouse carries the Caenorhabditis elegans fat-1 gene encoding omega-3 FAs desaturase and can produce omega-3 FAs from omega-6 FAs. E2 treatment rescued obesity, glucose intolerance, and bone loss in OVX mice. fat-1 mice fed 1% LA diet mitigated weight gain and fat accumulation in Veh-treated OVX mice. fat-1 mice fed 22.5% LA diet had increased energy expenditure and activity as wheel running in E2-treated OVX mice. E2 treatment, coconut oil SFAs and omega-3 FAs can protect against glucose intolerance. Apparent improvement of insulin sensitivity was achieved by E2 treatment in both WT and fat-1 mice fed 1% LA diet, while fat-1 mice fed 22.5% LA diet was protected against insulin resistance without E2 treatment. Data suggested that increased relative abundance of gut microbial taxa associated with short chain fatty acid (SCFA) production correlated with omega-3 FAs production and improved energy homeostasis. Based on data in chapters 2 and 3 we hypothesize that CBD can alleviate E2 decline-induced glucose intolerance, bone loss and proinflammation, at least partially due to a bloom of Lactobacillus species with GUS activity. Data from chapters 4 and 5 suggest that consuming different types of dietary fat from a variety of sources, without overemphasis on any particular type, is the optimal approach for promoting metabolic health regardless of E2 status.