Resistant starch treatment of polycystic ovary syndrome: impact on cardiometabolic dysfunction and the gut microbiome

Hyperandrogenic women with polycystic ovary syndrome (PCOS) have a high prevalence of cardiovascular disease (CVD) risk factors including obesity, insulin resistance, hypertension, and dyslipidemia that result in an increased risk of hypertensive disorders of pregnancy, type 2 diabetes and CVD events. Surveys also show

significant dissatisfaction amongst women with PCOS regarding long-term counselling and management of their cardiometabolic risk. Although lifestyle interventions and oral contraceptive pills (OCPs) are recommended as first-line treatment for PCOS, there are no dietary or pharmacological recommendations for prevention of CVD

risk in PCOS, indicating a considerable knowledge gap. Resistant starch, a type of dietary fiber, may offer a promising solution with significant improvements in CVD risk factors and CVD events in the general population. In addition, resistant starch use has been associated with increased abundance of short chain fatty acids (SCFA)-

producing gut bacteria, such as Bifidobacteria, and SCFAs in the general population. Recent studies also showed that Bifidobacteria and SCFAs are decreased in women with PCOS, and that exposure to a healthy gut microbiome via cohousing or fecal microbiome transplantation improved cardiometabolic parameters in PCOS

rodent models. These studies indicate that modulation of the gut microbiome may be a potential novel treatment target for cardiometabolic dysregulation in PCOS. While increased dietary fiber improves cardiometabolic and gut health in the general population, the impact of resistant starch supplementation on cardiometabolic

parameters or the gut microbiome in women with PCOS treated with OCPs has not been investigated. Use of OCPs especially in women with overweight /obesity is associated with dyslipidemia, hypertension and glucose dysregulation. We will test the hypothesis that treatment with resistant starch in combination with OCPs

results in improvement in cardiometabolic parameters, as well as specific gut microbes and metabolites, such as Bifidobacteria and SCFAs compared to OCPs alone. In Aim 1, we will enroll 100 women with hyperandrogenic PCOS and overweight/obesity in a double-blind placebo-controlled 2-arm RCT for 12 weeks:

Arm A) OCP + resistant starch and Arm B) OCP + maltodextrin (resistant starch placebo). We will investigate how resistant starch treatment in combination with OCPs improves individual cardiometabolic parameters, markers of insulin resistance, glucoregulatory status and inflammation compared to OCPs alone. In Aim 2, we

will use metagenomics and metabolomics to determine how OCPs + resistant starch impact abundances of Bifidobacteria and other gut microbes, microbial genes and SCFAs compared to OCPs alone and if changes in the gut microbiome correlate with changes in specific cardiometabolic parameters. Results from this proposal

will provide support for the implementation of a low-cost, nutritional therapy to counter negative cardiometabolic effects of OCPs and improve long-term CVD risk in the high risk PCOS population and provide key insights into the impact of resistant starch treatment on gut health in women with PCOS.