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

Abstract

Background Milk fat globule membrane (MFGM) is a phospholipid-rich component of dairy fat that may explain the benefits of full-fat dairy products on cardiometabolic risk. Preclinical studies support MFGM to decrease gut permeability, which may attenuate gut-derived endotoxin translocation and consequent inflammatory responses that impair cardiometabolic health. Objective To describe the rationale, study design, and planned outcomes that will evaluate the efficacy of MFGM-enriched milk versus a comparator beverage on health-promoting gut barrier functions in persons with metabolic syndrome (MetS). Methods We plan a double-blind, randomized cross-over trial (ClinicalTrials.gov: NCT03860584) in which MetS persons will receive a rigorously controlled eucaloric diet for 2-wk that contains 3 daily servings of an MFGM-enriched bovine milk beverage or a comparator beverage that is formulated with non-fat dairy powder, coconut and palm oils, and soy phospholipids. Compliance will be monitored by assessing urinary para-aminobenzoic acid that is added to all test beverages. After the intervention, participants will ingest a high-fat/high-carbohydrate meal challenge to assess metabolic excursions at 30 min intervals for 3 h. Non-digestible sugar probes also will be ingested prior to collecting 24-h urine to assess region-specific gut permeability. Intervention efficacy will be determined based on circulating endotoxin (primary outcome) and glycemia (secondary outcome). Tertiary outcomes include: gut and systemic inflammatory responses, microbiota composition and short chain fatty acids, gut permeability, and circulating insulin and incretins. Expected Results MFGM is expected to decrease circulating endotoxin and glycemia without altering body mass. These improvements are anticipated to be accompanied by decreased gut permeability, decreased intestinal and circulating biomarkers of inflammation, increased circulating incretins, and beneficial antimicrobial and prebiotic effects in the gut microbiome. Conclusions Demonstration of improvements in gut barrier functions that limit endotoxemia and glycemia could help to establish direct evidence by which full-fat dairy lowers cardiometabolic risk, especially among MetS persons. The clinical trial associated with this paper has been registered at ClinicalTrials.gov, registry number NCT03860584.

Milk-Fat-Globule-Membrane-Enriched Dairy Milk Compared with a Soy-Lecithin-Enriched Beverage Did Not Adversely Affect Endotoxemia or Biomarkers of Gut Barrier Function and Cardiometabolic Risk in Adults with Metabolic Syndrome: A Randomized Controlled Crossover Trial

“…Lastly, despite compelling evidence from rodent models [ 17 , 48 ], intestinal permeability, intestinal inflammation, and fecal SCFAs were unaffected by the MFGM-enriched milk. Overall, this RCT that was designed for research translation of preclinical evidence [ 21 ] did not demonstrate cardiometabolic benefits of MFGM-enriched dairy milk. However, neutral outcomes of this short-term RCT provide contradictory evidence against a long-standing controversy, based largely on observational evidence, suggesting that full-fat dairy milk adversely affects cardiometabolic health [ 15 ].…”

“…Although our RCT was supported by strong rationale [ 21 ] and rigorously controlled, several aspects may have contributed to the lack of observed cardiometabolic benefit of MEB. We carefully considered milk dose (three servings/d) in agreement with observational evidence supporting benefits of full-fat dairy milk [ 14 ] and specifically enriched it with MFGM at levels ≈10 times that typically found in fluid milk [ 27 ].…”

“…Complete details of this double-blind, randomized controlled trial, including its rationale, methodology, and expected outcomes, have been reported previously [ 21 ]. All procedures were approved by The Ohio State University (OSU) Institutional Review Board (2018H0564), and the study was registered at ClinicalTrials.gov (NCT03860584).…”

A narrative review of the functional components of human breast milk and their potential to modulate the gut microbiome, the consideration of maternal and child characteristics, and confounders of breastfeeding, and their impact on risk of obesity later in life

“…The mechanisms of action explaining any anti-obesity effect of MFGM are unclear, but they may imply the ability to moderate alleviations of metabolic endotoxemia. 39 Metabolic endotoxemia is a condition characterised by elevated plasma lipopolysaccharides (LPS). 40 LPS are endotoxins constituting the outer membrane of gramnegative bacteria.…”