Alleviation Of Metabolic Endotoxemia In Adults With Metabolic Syndrome With Milk Fat Globule Membrane
Condition: Metabolic Syndrome; Metabolic Endotoxemia
MeSH terms: Endotoxemia; Metabolic Syndrome; Syndrome
Study type: Interventional

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.
    

Intervention name(s): MFGM-enriched full-fat dairy milk; Soy phospholipid/lecithin milk
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): 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.; 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).
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: 2-arm, double-blind, randomized controlled, crossover trial
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Prevention
Keywords: metabolic endotoxemia; milk fat globule membrane; gut health; endotoxin; inflammation; obesity