CVD Risk
Conditions
Keywords
stearic acid, bile acid metabolism, post-menopausal women, dietary intervention, saturated fatty acids, gut microbiome
Brief summary
Stearic acid and palmitic acid are two common consumed saturated fatty acids found in foods. Palmitic acid is associated with increases in blood cholesterol, whereas stearic acid is generally considered neutral with respect to blood cholesterol. However, the mechanisms underlying these different effects are not fully understood. The goal of this clinical trial is to determine how replacing dietary palmitic acid with stearic acid affects microorganisms living in the gastrointestinal tract (gut microbiome) and the metabolites they produce, including secondary bile acids, and whether these changes influence heart and metabolic health in postmenopausal women. The main question it aims to answer is whether the cholesterol lowering effect of dietary stearic acid, compared to dietary palmitic acid is due to changes in the composition and function of the gut microbiome and bile acid metabolism. Participants will consume a controlled diet high in palmitic acid for a 10-day run-in period, followed by a controlled diet high in stearic acid for 28 days. During the study, participants will provide biological samples, including blood samples collected in both fasting and non-fasting states, for assessment of cardiometabolic outcomes. Participants will also swallow mini-pills designed to collect samples from different regions of the gastrointestinal tract to assess the gut microbiome and related metabolites. Results will contribute to understanding the relationship between stearic acid mediated microbiota effects on cardiometabolic heath.
Detailed description
Stearic acid (18:0) is unique among saturated fatty acids (SFAs) as it does not increase cardiovascular disease (CVD) risk. Prior work by the study investigators suggests that gut microbiome-mediated alterations in secondary bile acid (BA) metabolism as a potential mechanism for the cholesterol-lowering effects of 18:0. However, to test this hypothesis the investigators were limited to traditional fecal sampling methods, which primarily reflect colonic microbes and do not capture regional heterogeneity in microbial communities or BA transformations which occur mainly in the small intestine. Using a novel ingestible device (mini-pill) which provides real-time sampling of the gastrointestinal environment, this study aims to comprehensively investigate the impact of dietary 18:0 on gut microbial BA transformations in modulating cardiometabolic risk. The study design includes a controlled 38-day dietary intervention trial in post-menopausal females using whole-foods enriched in commercially available sources of 18:0. The objectives are to determine the effect of dietary 18:0 on (i) microbiome composition and BA related functional pathways along the GI tract relative to stool; (ii) BA profiles along the GI tract, in stool and plasma; and (iii) FXR activation (reflected by FGF19 levels) and endogenous cholesterol synthesis in mediating the association between BA metabolizing microbes and BA profiles on CVD risk factors. Fecal whole-genome shotgun sequencing, targeted BA profiling, and bioinformatics will be used to address these objectives. Results will contribute to optimizing dietary/nutrient-labeling guidance to reduce CVD risk by expanding the evidence-base for classifying 18:0 and may offer novel strategies for preventing heart disease by targeting specific gut microbes or BA pathways.
Interventions
The main source of palmitic acid that will be used to prepare the meals will include blends of palm oil and safflower oil, which are commercially available. These blends will be incorporated into foods such as muffins, cookies, sauces, and mixed dishes (e.g., casseroles).
OTHERHigh Stearic Acid Diet
The main source of stearic acid that will be used to prepare the meals will include blends of cocoa butter, fully hydrogenated soybean and safflower oil, all of which are commercially available. These blends will be incorporated into foods such as muffins, cookies, sauces, and mixed dishes (e.g., casseroles).
Sponsors
Tufts University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Pre-post study design. The entire study period will be approximately 38 days, starting with a 10-day controlled run-in phase (high palmitic acid diet) to stabilize baseline variables, and a 28-day controlled feeding phase (high stearic acid diet).
Eligibility
Sex/Gender
FEMALE
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Postmenopausal women (defined as complete natural cessation of menses for \>12 months or a bilateral oophorectomy), who are not currently using hormone replacement therapy (HRT) or gender-affirming hormone treatments 2. Age \>50 years 3. BMI \>20 to \<35 kg/m2, inclusive 4. Non-smoker or former smoker who quit \> 6 months 5. Normotensive with or without medication 6. Normal gastrointestinal function with regular bowel movements at least once every other day 7. Willingness to swallow the mini-pills 8. Willingness to collect and return multiple stool samples 9. Adequate refrigerator and freezer space to store study meals 10. Intent to remain in the greater Boston area during the intervention periods
Exclusion criteria
1. Allergy/intolerance/religious reasons to avoid study meals or food ingredients 2. Regular use of dietary supplements, pre/probiotics, laxatives or fiber supplements (except multivitamins) within the past 3 months 3. Use of steroids (excluding topical) within the past 3 months 4. Regular use of aspirin (except baby aspirin), NSAIDS, or anti diarrheal medication 5. Current smokers or former smokers who quit \< 6 months ago, and use of nicotine replacement products within the last 6 months 6. Chronic constipation 7. Use of oral antibiotics within the past 3 months. 8. Use of dental prophylaxis within the past 3 months 9. Regular use of stomach acid lowering and weight loss medications such as GLP-1 agonists 10. Planned colonoscopy 3 months prior to or during the study period 11. Swallowing disorder or inability or difficulty taking pills 12. Malabsorptive and inflammatory bowel disease, diverticulosis, and history of diverticulitis, gastric esophageal/intestinal surgery, including lap banding or bariatric surgery. 13. History of bowel obstruction, gallstones, gastroparesis, pancreas and liver/gallbaldder disorders. 14. Any form of active substance abuse or dependence (including drug or alcohol abuse). 15. Established major chronic diseases such as CVD, diabetes, active cancer within the last 5 years, or any significant medical condition at the study MD's discretion 16. A clinical condition that, in the judgment of the study MD or PI, could potentially pose a health risk to the subject while involved in the study. 17. Unwillingness to adhere to study protocol 18. Intent to increase or decrease body weight during the study period 19. No Social Security number (for payment and IRS forms). 20. Individuals who directly report to any member of the research team.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Abundance of Gut Microbial Taxa (%) | End of the 10-day palmitic acid run-in period and end of the 28-day stearic acid intervention period. | Gut microbial composition in gastrointestinal luminal and stool samples will be assessed using whole-genome shotgun metagenomic sequencing and reported as relative abundance (%). Alpha and beta diversity will also be evaluated as part of the microbiome analyses. |
| Relative Abundance of Gut Microbial Functional Pathways (%) | End of the 10-day palmitic acid run-in period and end of the 28-day stearic acid intervention period. | Gut microbial functional pathways in gastrointestinal luminal and stool samples will be assessed from whole-genome shotgun metagenomic sequencing data using bioinformatic pathway analysis and reported as relative abundance (%). Analyses will include pathways related to bile acid metabolism as well as other microbial metabolic pathways. |
| Concentrations of Bile Acids in Gastrointestinal Luminal Samples (nmol/mL) | End of the 10-day palmitic acid run-in period and end of the 28-day stearic acid intervention period. | Primary and secondary bile acids, including conjugated and unconjugated bile acids, will be quantified in gastrointestinal luminal samples using targeted mass spectrometry and reported as nmol/mL. |
| Concentrations of Bile Acids in Plasma (nmol/mL) | End of the 10-day palmitic acid run-in period and end of the 28-day stearic acid intervention period. | Primary and secondary bile acids, including conjugated and unconjugated bile acids, will be quantified in fasting and postprandial plasma using targeted mass spectrometry and reported as nmol/mL. |
| Concentrations of Bile Acids in Stool (nmol/mg dry weight) | End of the 10-day palmitic acid run-in period and end of the 28-day stearic acid intervention period. | Primary and secondary bile acids, including conjugated and unconjugated bile acids, will be quantified in stool using targeted mass spectrometry, normalized to fecal dry weight, and reported as nmol/mg dry weight. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Metabolite Concentrations (µmol/L) | End of the 10-day palmitic acid run-in period and end of the 28-day stearic acid intervention period. | Plasma metabolites will be measured using targeted metabolomic profiling and reported as concentrations in µmol/L. |
| Fecal Metabolite Concentrations (nmol/mg dry weight) | End of the 10-day palmitic acid run-in period and end of the 28-day stearic acid intervention period. | Fecal metabolites will be measured using targeted metabolomic profiling, normalized to fecal dry weight, and reported as nmol/mg dry weight. |
| Serum Cholesterol metabolism markers | End of the 10-day palmitic acid run-in period and end of the 28-day stearic acid intervention period. | Cholesterol synthesis markers (squalene, desmosterol, lathosterol) and cholesterol absorption markers (phytosterols) will be measured using gas-liquid chromatography, normalized to total cholesterol, and reported as 10² mmol/mol total cholesterol. |
Countries
United States
Contacts
CONTACTNirupa R Matthan, PhD
Outcome results
None listed