Alleviation Of Metabolic Endotoxemia In Adults With Metabolic Syndrome With Milk Fat Globule Membrane

Sponsor

Ohio State University (Other)

Overall Status

Completed

CT.gov ID

NCT03860584

Collaborator

(none)

Enrollment

Location

Arms

17.7

Actual Duration (Months)

1.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Metabolic syndrome (MetS) adults (n = 24; 18-65 y) will be enrolled to complete a 2-arm, double-blind, randomized controlled, crossover trial. They will be randomized in 4-unit blocks to receive, for 14 d, a controlled diet with dairy milk (3.5% fat; 3 servings/d) enriched with milk fat globule membrane (MFGM)-derived phospholipid or a matched dairy milk that instead contains soy lecithin/phospholipid (control). All foods during each study period will be provided to ensure weight maintenance and to increase homogeneity of gut and host responses. Anthropometrics and blood pressure will be assessed at days 0, 7, and 14. Prior to (day 0) and after each 2-wk arm (day 14), a fasting blood sample will be collected to assess serum endotoxin and metabolic chemistries (glucose, lipids, insulin), and Toll-like receptor 4 /nuclear factor kappaB (TLR4/NFκB)-dependent genes from isolated peripheral blood mononuclear cells (PBMCs). A breath sample will be collected to assess the correlation analysis of plasma metabolic biomarkers. After the 2-week intervention, from fecal samples collected on day 13, the investigators will assess microbiota composition and function, short chain fatty acids (SCFA), and intestinal inflammatory markers (calprotectin, myeloperoxidase). On d 14, participants in the fasted state will receive a high-fat/high-glucose meal challenge to induce gut-derived endotoxin translocation. At 30-minute intervals for 3-hour, the investigators will evaluate circulating endotoxin, glucose, and insulin; TLR4/NFκB-dependent genes will be assessed from PMBCs at 0 hour and 3-hour. Gut permeability probes will be co-administered with the test meal challenge, and 24-hour urine will be collected to assess gut barrier integrity. Participants will then undergo a 2-week washout prior to receiving the alternative treatment and completing all procedures in an identical manner.

Condition or Disease	Intervention/Treatment	Phase
Metabolic Syndrome Metabolic Endotoxemia	Dietary Supplement: MFGM-enriched full-fat dairy milk Dietary Supplement: Soy phospholipid/lecithin milk	N/A

Detailed Description

Background and hypothesis:

Our preclinical evidence shows that phospholipid-rich milk fat globule membrane (MFGM) attenuates lipopolysaccharide-induced increases in gut permeability and pro-inflammatory cytokines. MFGM also attenuates inflammation in association with a prebiotic and/or antimicrobial activity that modulates microbiota composition. Our central hypothesis is that MFGM-enriched dairy milk compared with a matched milk beverage containing soy lecithin (control) decreases metabolic endotoxemia and improves glucose tolerance in metabolic syndrome (MetS) adults by increasing gut barrier integrity in association with alleviating gut dysbiosis and inflammation.

Study Design:

The investigators will enroll male and female MetS adults (n = 24; 18-65 y) to complete a 2-arm, double-blind, randomized controlled, crossover trial. They will be randomized in 4-unit blocks to receive, for 14 days, a controlled diet with dairy milk (3.5% fat; 3 servings/d) enriched with MFGM-derived phospholipid or a matched dairy milk that instead contains coconut and palm oil (control). The investigators will provide all foods during each study period to ensure weight maintenance and to increase homogeneity of gut and host responses.

Subjects:

Participants will be recruited from Columbus, OH area. Participants having no history of liver or cardiovascular disease or cancer will be enrolled. They will have ≥3 established criteria for MetS: i) glucose (100-126 mg/dL), ii) waist circumference (>89 or >102 cm for F/M), iii) HDL-C (<50 or <40 mg/dL in F/M), iv) TG >150 mg/dL, and iv) blood pressure >130/85 mmHg. Major exclusion criteria include: unstable body mass (±2 kg over prior 3-mo) vegetarian; food allergies or lactose intolerance; user of dietary supplements or probiotics (within past 1-mo); pregnancy, lactation, changes in birth control (within 6-month); any gastrointestinal disorders; chronic diarrhea; smoker; excess alcohol (>2 drinks/day); excess aerobic exercise (>7 h/week); recent antibiotic or anti-inflammatory agent use; blood pressure >140/90 mmHg.

Dietary Control:

The intervention will be performed in the Human Nutrition Metabolic Kitchen under the auspice of a registered dietitian (PI Bruno). In each 2-wk intervention, participants' diet will be rigorously controlled. All foods will be prepared, packaged, and provided every 3-4 days to supply a weight maintenance (i.e. eucaloric) diet. To assess compliance, participants will return MFGM/coconut/palm oil milk bottles for counting and any uneaten food portions for weighed measurement. Milk beverages will also be formulated to contain para-aminobenzoic acid (PABA; 80 mg/milk serving). Spot urine samples will be collected 4 times during each study arm coinciding when participants pick up test foods. Urinary PABA will be measured by spectrophotometry. Separate from this, participants will also keep food logs to document any dietary deviation. Diets will be standardized at 50-60% of energy from carbohydrate with low fiber intakes (~15 g/day) similar to Americans' diets to prevent potential masking of the benefits of MFGM, 15-20% from protein, and 25-30% from fat. Importantly, other than test beverages provided as part of the eucaloric diet, diets will be otherwise devoid of significant amounts of dairy foods, fermented products, and probiotics to prevent confounding effects.

Measurements:

Anthropometrics and blood pressure will be assessed at days 0, 7, and 14. Prior to (day 0), at day 7 and after each 2-wk arm (day 14), a fasting blood sample will be collected to assess serum endotoxin and metabolic chemistries (glucose, insulin, lipids (triglyceride, total and HDL cholesterol), and TLR4/NFκB-dependent genes from isolated peripheral blood mononuclear cells (PBMCs). A breath sample will be collected to assess the correlation analysis of plasma metabolic biomarkers. After the 2-week intervention, from fecal samples collected on day 13, the investigators will assess microbiota composition and function, SCFAs, and intestinal inflammatory markers (calprotectin, myeloperoxidase). During this period, participants will also record daily stool characteristics using a 7-point Bristol Stool scale. On days 14, participants in the fasted state will receive a high-fat/high-glucose meal challenge to induce gut-derived endotoxin translocation. At 30-minute intervals for 3 hours, the investigators will evaluate circulating endotoxin, glucose, and insulin; TLR4/NFκB-dependent genes will be assessed from PMBCs at 0 hour and 3-hour. Gut permeability probes will be co-administered with the test meal challenge, and 24-hour urine will be collected to assess gut barrier integrity. Participants will then undergo a 2-week washout prior to receiving the alternative treatment and completing all procedures in an identical manner.

Study Design

Study Type:

Interventional

Actual Enrollment :

24 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

2-arm, double-blind, randomized controlled, crossover trial2-arm, double-blind, randomized controlled, crossover trial

Masking:

Double (Participant, Outcomes Assessor)

Masking Description:

Both participants and key research personnel will be blinded between MFGM-enriched full-fat dairy milk (treatment) and milk with soy phospholipid/lecithin (control).

Primary Purpose:

Prevention

Official Title:

Alleviation Of Metabolic Endotoxemia In Adults With Metabolic Syndrome With Milk Fat Globule Membrane

Actual Study Start Date :

Jul 1, 2019

Actual Primary Completion Date :

Dec 20, 2020

Actual Study Completion Date :

Dec 20, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MFGM-enriched full-fat dairy milk Participants in this arm will receive MFGM-enriched full-fat dairy milk (3 servings/d) that contains MFGM at 10% phospholipid (relative to total lipid content) delivering MFGM at ~10-times that in full-fat dairy milk.	Dietary Supplement: MFGM-enriched full-fat dairy milk MetS adults with metabolic endotoxemia will be enrolled to complete a 2-arm, double-blind, randomized controlled, crossover trial to test the independent benefits of MFGM. For each 2-wk arm, they will receive MFGM-enriched full-fat dairy milk (3 servings/d) or a matched dairy milk that instead contains soy phospholipid/lecithin (control). Milks have been formulated with soy lecithin or MFGM at 10% phospholipid (relative to total lipid content). This delivers MFGM at ~10-times that in full-fat dairy milk, which reflects that consumers obtain MFGM from dairy foods other than whole milk.
Placebo Comparator: Soy phospholipid/lecithin milk Participants in this arm will receive a matched dairy milk that instead contains soy phospholipid/lecithin.	Dietary Supplement: Soy phospholipid/lecithin milk MetS adults with metabolic endotoxemia will be enrolled to complete a 2-arm, double-blind, randomized controlled, crossover trial to test the independent benefits of MFGM. For each 2-wk arm, they will receive MFGM-enriched full-fat dairy milk (3 servings/d) or a matched dairy milk that instead contains soy phospholipid/lecithin (control). Milks have been formulated with soy lecithin or MFGM at 10% phospholipid (relative to total lipid content).

Arm

Intervention/Treatment

Experimental: MFGM-enriched full-fat dairy milk

Participants in this arm will receive MFGM-enriched full-fat dairy milk (3 servings/d) that contains MFGM at 10% phospholipid (relative to total lipid content) delivering MFGM at ~10-times that in full-fat dairy milk.

Dietary Supplement: MFGM-enriched full-fat dairy milk

MetS adults with metabolic endotoxemia will be enrolled to complete a 2-arm, double-blind, randomized controlled, crossover trial to test the independent benefits of MFGM. For each 2-wk arm, they will receive MFGM-enriched full-fat dairy milk (3 servings/d) or a matched dairy milk that instead contains soy phospholipid/lecithin (control). Milks have been formulated with soy lecithin or MFGM at 10% phospholipid (relative to total lipid content). This delivers MFGM at ~10-times that in full-fat dairy milk, which reflects that consumers obtain MFGM from dairy foods other than whole milk.

Placebo Comparator: Soy phospholipid/lecithin milk

Participants in this arm will receive a matched dairy milk that instead contains soy phospholipid/lecithin.

Dietary Supplement: Soy phospholipid/lecithin milk

Outcome Measures

Primary Outcome Measures

Serum Endotoxin (LPS) [day 14]
Between-treatment change in serum endotoxin (fasting) on day 14 relative to day 0
Serum Endotoxin (LPS) [day 14 (0, 30, 60, 90, 120, 150, 180 minutes post-meal challenge)]
Between-treatment difference in the area under the curve of serum endotoxin (0-3 hours) on day 14
Plasma Glucose [day 14]
Between-treatment change in plasma glucose (fasting) on day 14 relative to day 0
Plasma Glucose [day 14 (0, 30, 60, 90, 120, 150, 180 minutes post-meal challenge)]
Between-treatment difference in the area under the curve of plasma glucose (0-3 hours) on day 14

Secondary Outcome Measures

Plasma Insulin [day 14]
Between-treatment change in plasma (fasting) on day 14 relative to day 0
Plasma Insulin [day 14 (0, 30, 60, 90, 120, 150, 180 minutes post-meal challenge)]
Between-treatment difference in the area under the curve of plasma insulin (0-3 hours) on day 14
Plasma HDL-C [day 14]
Between-treatment change in plasma HDL-C (fasting) on day 14 relative to day 0
Plasma Triglyceride [day 14]
Between-treatment change in plasma triglyceride (fasting) on day 14 relative to day 0
Plasma Total Cholesterol [day 14]
Between-treatment change in plasma total cholesterol (fasting) on day 14 relative to day 0
Plasma glucagon-like peptide-1 [day 14]
Between-treatment change in plasma glucagon-like peptide-1 (fasting) on day 14 relative to day 0
Urine Lactulose [day 14]
Between-treatment difference in 24 hour urinal excretion of lactulose post-meal challenge on day 14
Urine sucralose [day 14]
Between-treatment difference in 24 hour urinal excretion of sucralose post-meal challenge on day 14
Urine erythritol [day 14]
Between-treatment difference in 24 hour urinal excretion of erythritol post-meal challenge on day 14
Urine mannitol [day 14]
Between-treatment difference in 24 hour urinal excretion of mannitol post-meal challenge on day 14
Fecal bacterial abundance and composition [day 13]
Between-treatment difference in fecal bacterial abundance and composition on day 13
Fecal Acetate [day 13]
Between-treatment difference in fecal acetate on day 13
Fecal Butyrate [day 13]
Between-treatment difference in fecal butyrate on day 13
Fecal Propionate [day 13]
Between-treatment difference in fecal propionate on day 13
Plasma gastric inhibitory polypeptide (GIP) [day 14]
Between-treatment change in plasma gastric inhibitory polypeptide (GIP) (fasting) on day 14 relative to day 0
Fecal Calprotectin [day 13]
Between-treatment difference in fecal calprotectin on day 13
Fecal Myeloperoxidase [day 13]
Between-treatment difference in fecal myeloperoxidase on day 13
Circulating Toll-like receptor 4 mRNA [day 14]
Between-treatment change in circulating Toll-like receptor 4 mRNA (fasting) on day 14 relative to day 0
Circulating IL-6 mRNA [day 14]
Between-treatment change in circulating IL-6 mRNA (fasting) on day 14 relative to day 0
Circulating TNFa mRNA [day 14]
Between-treatment change in circulating TNFa mRNA (fasting) on day 14 relative to day 0
Circulating Toll-like receptor 4 mRNA [day 14 (0, 3 hour post-meal challenge)]
Between-treatment change in circulating Toll-like receptor 4 mRNA post meal challenge (0-3 h) on day 14
Circulating IL-6 mRNA [day 14 (0, 3 hour post-meal challenge)]
Between-treatment change in circulating IL-6 mRNA post meal challenge (0-3 h) on day 14
Circulating TNFa mRNA [day 14 (0, 3 hour post-meal challenge)]
Between-treatment change in circulating TNFa mRNA post meal challenge (0-3 h) on day 14