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

Primary Purpose

Metabolic Syndrome, Metabolic Endotoxemia

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
MFGM-enriched full-fat dairy milk
Soy phospholipid/lecithin milk
Sponsored by
Ohio State University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Metabolic Syndrome focused on measuring metabolic endotoxemia, milk fat globule membrane, gut health, endotoxin, inflammation, obesity

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Serum Glucose 100-126 mg/dl
  • Waist C >89/102 cm; F/M
  • Serum HDL-C: <50/40 mg/dl; F/M
  • Serum TG: >150 mg/dl
  • BP >130/85 mmHg
  • Serum Endotoxin >25 EU/ml

Exclusion Criteria:

  • 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-mo)
  • Any gastrointestinal disorders
  • Chronic diarrhea
  • Smoker
  • Excess alcohol (>2 drinks/d)
  • Excess aerobic exercise (>5 h/wk)
  • Recent antibiotic or anti-inflammatory agent use
  • BP >140/90 mmHg

Sites / Locations

  • The Ohio State University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

MFGM-enriched full-fat dairy milk

Soy phospholipid/lecithin milk

Arm Description

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.

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

Outcomes

Primary Outcome Measures

Serum Endotoxin (LPS)
Between-treatment change in serum endotoxin (fasting) on day 14 relative to day 0
Serum Endotoxin (LPS)
Between-treatment difference in the area under the curve of serum endotoxin (0-3 hours) on day 14
Plasma Glucose
Between-treatment change in plasma glucose (fasting) on day 14 relative to day 0
Plasma Glucose
Between-treatment difference in the area under the curve of plasma glucose (0-3 hours) on day 14

Secondary Outcome Measures

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

Full Information

First Posted
February 28, 2019
Last Updated
June 18, 2023
Sponsor
Ohio State University
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1. Study Identification

Unique Protocol Identification Number
NCT03860584
Brief Title
Alleviation Of Metabolic Endotoxemia In Adults With Metabolic Syndrome With Milk Fat Globule Membrane
Official Title
Alleviation Of Metabolic Endotoxemia In Adults With Metabolic Syndrome With Milk Fat Globule Membrane
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Completed
Study Start Date
July 1, 2019 (Actual)
Primary Completion Date
December 20, 2020 (Actual)
Study Completion Date
December 20, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Ohio State University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. 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, MEB) or a matched dairy milk that instead contains soy lecithin/phospholipid (control, COMP). 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 whole blood. 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 whole blood 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.
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 whole blood. 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 whole blood 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metabolic Syndrome, Metabolic Endotoxemia
Keywords
metabolic endotoxemia, milk fat globule membrane, gut health, endotoxin, inflammation, obesity

7. Study Design

Primary Purpose
Prevention
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Model Description
2-arm, double-blind, randomized controlled, crossover trial
Masking
ParticipantOutcomes 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).
Allocation
Randomized
Enrollment
24 (Actual)

8. Arms, Groups, and Interventions

Arm Title
MFGM-enriched full-fat dairy milk
Arm Type
Experimental
Arm Description
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.
Arm Title
Soy phospholipid/lecithin milk
Arm Type
Placebo Comparator
Arm Description
Participants in this arm will receive a matched dairy milk that instead contains soy phospholipid/lecithin.
Intervention Type
Dietary Supplement
Intervention Name(s)
MFGM-enriched full-fat dairy milk
Intervention Description
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.
Intervention Type
Dietary Supplement
Intervention Name(s)
Soy phospholipid/lecithin milk
Intervention Description
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).
Primary Outcome Measure Information:
Title
Serum Endotoxin (LPS)
Description
Between-treatment change in serum endotoxin (fasting) on day 14 relative to day 0
Time Frame
day 14
Title
Serum Endotoxin (LPS)
Description
Between-treatment difference in the area under the curve of serum endotoxin (0-3 hours) on day 14
Time Frame
day 14 (0, 30, 60, 90, 120, 150, 180 minutes post-meal challenge)
Title
Plasma Glucose
Description
Between-treatment change in plasma glucose (fasting) on day 14 relative to day 0
Time Frame
day 14
Title
Plasma Glucose
Description
Between-treatment difference in the area under the curve of plasma glucose (0-3 hours) on day 14
Time Frame
day 14 (0, 30, 60, 90, 120, 150, 180 minutes post-meal challenge)
Secondary Outcome Measure Information:
Title
Plasma Insulin
Description
Between-treatment change in plasma (fasting) on day 14 relative to day 0
Time Frame
day 14
Title
Plasma Insulin
Description
Between-treatment difference in the area under the curve of plasma insulin (0-3 hours) on day 14
Time Frame
day 14 (0, 30, 60, 90, 120, 150, 180 minutes post-meal challenge)
Title
Plasma HDL-C
Description
Between-treatment change in plasma HDL-C (fasting) on day 14 relative to day 0
Time Frame
day 14
Title
Plasma Triglyceride
Description
Between-treatment change in plasma triglyceride (fasting) on day 14 relative to day 0
Time Frame
day 14
Title
Plasma Total Cholesterol
Description
Between-treatment change in plasma total cholesterol (fasting) on day 14 relative to day 0
Time Frame
day 14
Title
Plasma glucagon-like peptide-1
Description
Between-treatment change in plasma glucagon-like peptide-1 (fasting) on day 14 relative to day 0
Time Frame
day 14
Title
Urine Lactulose
Description
Between-treatment difference in 24 hour urinal excretion of lactulose post-meal challenge on day 14
Time Frame
day 14
Title
Urine sucralose
Description
Between-treatment difference in 24 hour urinal excretion of sucralose post-meal challenge on day 14
Time Frame
day 14
Title
Urine erythritol
Description
Between-treatment difference in 24 hour urinal excretion of erythritol post-meal challenge on day 14
Time Frame
day 14
Title
Urine mannitol
Description
Between-treatment difference in 24 hour urinal excretion of mannitol post-meal challenge on day 14
Time Frame
day 14
Title
Fecal bacterial abundance and composition
Description
Between-treatment difference in fecal bacterial abundance and composition on day 13
Time Frame
day 13
Title
Fecal Acetate
Description
Between-treatment difference in fecal acetate on day 13
Time Frame
day 13
Title
Fecal Butyrate
Description
Between-treatment difference in fecal butyrate on day 13
Time Frame
day 13
Title
Fecal Propionate
Description
Between-treatment difference in fecal propionate on day 13
Time Frame
day 13
Title
Plasma gastric inhibitory polypeptide (GIP)
Description
Between-treatment change in plasma gastric inhibitory polypeptide (GIP) (fasting) on day 14 relative to day 0
Time Frame
day 14
Title
Fecal Calprotectin
Description
Between-treatment difference in fecal calprotectin on day 13
Time Frame
day 13
Title
Fecal Myeloperoxidase
Description
Between-treatment difference in fecal myeloperoxidase on day 13
Time Frame
day 13
Title
Circulating Toll-like receptor 4 mRNA
Description
Between-treatment change in circulating Toll-like receptor 4 mRNA (fasting) on day 14 relative to day 0
Time Frame
day 14
Title
Circulating IL-6 mRNA
Description
Between-treatment change in circulating IL-6 mRNA (fasting) on day 14 relative to day 0
Time Frame
day 14
Title
Circulating TNFa mRNA
Description
Between-treatment change in circulating TNFa mRNA (fasting) on day 14 relative to day 0
Time Frame
day 14
Title
Circulating Toll-like receptor 4 mRNA
Description
Between-treatment change in circulating Toll-like receptor 4 mRNA post meal challenge (0-3 h) on day 14
Time Frame
day 14 (0, 3 hour post-meal challenge)
Title
Circulating IL-6 mRNA
Description
Between-treatment change in circulating IL-6 mRNA post meal challenge (0-3 h) on day 14
Time Frame
day 14 (0, 3 hour post-meal challenge)
Title
Circulating TNFa mRNA
Description
Between-treatment change in circulating TNFa mRNA post meal challenge (0-3 h) on day 14
Time Frame
day 14 (0, 3 hour post-meal challenge)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Serum Glucose 100-126 mg/dl Waist C >89/102 cm; F/M Serum HDL-C: <50/40 mg/dl; F/M Serum TG: >150 mg/dl BP >130/85 mmHg Serum Endotoxin >25 EU/ml Exclusion Criteria: 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-mo) Any gastrointestinal disorders Chronic diarrhea Smoker Excess alcohol (>2 drinks/d) Excess aerobic exercise (>5 h/wk) Recent antibiotic or anti-inflammatory agent use BP >140/90 mmHg
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Richard Bruno, PhD
Organizational Affiliation
Ohio State University
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Ohio State University
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43201
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32885133
Citation
Quarles WR, Pokala A, Shaw EL, Ortega-Anaya J, Hillmann L, Jimenez-Flores R, Bruno RS. Alleviation of Metabolic Endotoxemia by Milk Fat Globule Membrane: Rationale, Design, and Methods of a Double-Blind, Randomized, Controlled, Crossover Dietary Intervention in Adults with Metabolic Syndrome. Curr Dev Nutr. 2020 Jul 25;4(9):nzaa130. doi: 10.1093/cdn/nzaa130. eCollection 2020 Sep.
Results Reference
derived

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

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