Clinical trial NCT03860584: 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
Overall status: COMPLETED
Phase: NA
Conditions: Metabolic Syndrome
Metabolic Endotoxemia
Keywords: metabolic endotoxemia
milk fat globule membrane
gut health
endotoxin
inflammation
obesity
Lead sponsor: Ohio State University
Sponsor class: OTHER
First posted: 2019-03-04
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: 2-arm, double-blind, randomized controlled, crossover trial
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Serum Endotoxin (LPS)
timeFrame: day 14
measure: Serum Endotoxin (LPS)
timeFrame: day 14 (0, 30, 60, 90, 120, 150, 180 minutes post-meal challenge)
measure: Plasma Glucose
timeFrame: day 14
measure: Plasma Glucose
timeFrame: day 14 (0, 30, 60, 90, 120, 150, 180 minutes post-meal challenge)
Secondary outcomes:
measure: Plasma Insulin
timeFrame: day 14
measure: Plasma Insulin
timeFrame: day 14 (0, 30, 60, 90, 120, 150, 180 minutes post-meal challenge)
measure: Plasma HDL-C
timeFrame: day 14
measure: Plasma Triglyceride
timeFrame: day 14
measure: Plasma Total Cholesterol
timeFrame: day 14
measure: Plasma glucagon-like peptide-1
timeFrame: day 14
measure: Urine Lactulose
timeFrame: day 14
measure: Urine sucralose
timeFrame: day 14
measure: Urine erythritol
timeFrame: day 14
measure: Urine mannitol
timeFrame: day 14
measure: Fecal bacterial abundance and composition
timeFrame: day 13
measure: Fecal Acetate
timeFrame: day 13
measure: Fecal Butyrate
timeFrame: day 13
measure: Fecal Propionate
timeFrame: day 13
measure: Plasma gastric inhibitory polypeptide (GIP)
timeFrame: day 14
measure: Fecal Calprotectin
timeFrame: day 13
measure: Fecal Myeloperoxidase
timeFrame: day 13
measure: Circulating Toll-like receptor 4 mRNA
timeFrame: day 14
measure: Circulating IL-6 mRNA
timeFrame: day 14
measure: Circulating TNFa mRNA
timeFrame: day 14
measure: Circulating Toll-like receptor 4 mRNA
timeFrame: day 14 (0, 3 hour post-meal challenge)
measure: Circulating IL-6 mRNA
timeFrame: day 14 (0, 3 hour post-meal challenge)
measure: Circulating TNFa mRNA
timeFrame: day 14 (0, 3 hour post-meal challenge)
Other outcomes:
Locations:
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
Study officials:
affiliation: Ohio State University
name: Richard Bruno, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.