Exercise, Milk Thistle, and Lactobacillus to Influence Plasma Bilirubin
Condition: Obesity
MeSH terms: Obesity
Study type: Interventional
Phase: Phase 3

Summary: 
      The proposed clinical trial will test our hypothesis that, during exercise, red blood cell
      (RBC) release of heme and catabolism to bilirubin is an essential process that mediates gene
      responses that reduce body fat. We will evaluate whether Milk Thistle extract or
      Lactobacillus Gasseri extends bilirubin circulating times to decrease body fat further. Thus
      we will perform a 12-week, 6-armed trial with one group performing aerobic exercise 5 times
      per week (EX) one group receiving a Milk Thistle extract (MT), one group receiving a
      lactobacillus gasseri supplement (LAC), a group receiving only a placebo (CON), and groups
      both exercising and receiving the MT (MT + EX) and lactobacillus and exercise (LAC + EX).
    

Detailed description: 
      The investigative team's previous work has shown that BR binds to the PPARalpha protein in
      fat and liver tissues to activate genes that improve fatty acid oxidation via a hormone known
      as fibroblast growth factor-21 (FGF21). The investigators recently showed that in high
      capacity running rats (HCR) compared to low capacity running (LCR), in which the latter are
      obese, BR levels and PPARalpha-FGF21 were significantly raised in the high-capacity runners.
      New investigations have shown that Milk Thistle (MT) herbal supplement contains polyphenols
      that activate pathways that suppress the glucuronyl enzyme UGT1A1 that removes BR from the
      blood, improving liver function and moderately increasing BR blood levels by ~2-fold. Similar
      findings have been demonstrated with Lactobacillus Gasseri supplementation. Hence, there is a
      bilirubin-PPARalpha-FGF21 axis that can be driven by exercise and dietary supplementation. We
      will test whether exercise and milk thistle or exercise and lactobacillus gasseri
      synergistically increase bilirubin-PPARalpha-FGF21, further reducing body fat in patients
      with obesity.

      Participants in the EX, EX + MT, and EX + LAC groups will complete five weekly exercise
      sessions on their own, expending roughly 600 kcal per session. Participants will be provided
      a Polar A-300 heart rate monitor programmed for their individual attributes (height, weight,
      age, training status, gender), which gives a real-time estimate of energy expenditure during
      exercise. Participants will report to the lab once per week to download the exercise sessions
      and verify compliance. If participants are not compliant (defined as completing 85% of their
      assigned exercise sessions per month), they will be disqualified. This intervention has been
      successfully used by the investigators in multiple studies to produce significant weight loss
      without dietary intervention in this population with a retention rate of over 90%
      Participants in the MT and EX + MT groups will be provided 900 mg of standardized milk
      thistle extract daily (300 mg three times per day before meals) over the 12-week regimen. The
      investigators will use the standardized Jarrow Formulas Milk Thistle Veggie Caps containing
      30:1 extract that is standardized to contain 80% total Milk Thistle seed flavonoids
      (polyphenols), including the critical Silymarin fractions isosilybinins A and B, silybinins A
      and B, silychristin and silydianin that is active against suppressing the UGT1A1 enzyme
      increasing plasma bilirubin. The capsules are free of wheat, gluten, soybeans, dairy, egg,
      fish/shellfish, peanuts/tree nuts, and GMOs. Rationale for using this brand: There have been
      inconsistencies with previous studies that did not use a standardized silymarin extract,
      which may have contained low levels of the active polyphenolic flavonoids in the milk thistle
      plant, which varies in the plant's stems, leaves, roots, and flowers.

      Participants in the LAC and LAC + EX groups will receive two doses of 3 billion CFU of
      lactobacillus gasseri per day for a total of 6 billion CFU, the recommended upper level for
      supplementation of probiotic cultures. The Swanson brand Lactobacillus gasseri will be used,
      as these capsules are also free of wheat, gluten, soybeans, dairy, egg, fish/shellfish,
      peanuts/tree nuts, and GMOs. Importantly, this brand uses acid-resistant designed release
      capsules to improve the viability of the lactobacillus in the human stomach.

      Participants in the CON and EX group will receive a placebo (maltodextrin) made to look
      identical to the MT capsules.
    

Intervention name(s): Milk Thistle (MT); Lactobacillus Gasseri (LAC); Exercise (EX); Control (CON)
Intervention type(s): Dietary Supplement; Dietary Supplement; Behavioral; Dietary Supplement
Intervention description(s): Participants in the MT and EX + MT groups will be provided 900 mg of standardized milk thistle extract daily (300 mg three times per day before meals) over the 12-week regimen. We will use the standardized Jarrow Formulas Milk Thistle Veggie Caps containing 30:1 extract that is standardized to contain 80% total Milk Thistle seed flavonoids (polyphenols), including the critical Silymarin fractions isosilybinins A and B, silybinins A and B, silychristin and silydianin that is active against suppressing the UGT1A1 enzyme increasing plasma bilirubin. The capsules are free of wheat, gluten, soybeans, dairy, egg, fish/shellfish, peanuts/tree nuts, and GMOs. Rationale for using this brand: There have been inconsistencies with previous studies that did not use a standardized silymarin extract, which may have contained low levels of the active polyphenolic flavonoids in the milk thistle plant, which varies in the plant's stems, leaves, roots, and flowers.; Participants in the LAC and LAC + EX groups will receive two doses of 3 billion CFU of lactobacillus gasseri per day for a total of 6 billion CFU, the recommended upper level for supplementation of probiotic cultures. We will use Swanson brand Lactobacillus gasseri, whose capsules are also free of wheat, gluten, soybeans, dairy, egg, fish/shellfish, peanuts/tree nuts, and GMOs. Importantly, this brand uses acid-resistant designed release capsules to improve the viability of the lactobacillus in the human stomach.; Participants in the EX, EX + MT, and EX + LAC groups will complete five weekly exercise sessions on their own, expending roughly 600 kcal per session. Participants will be provided a Polar A-300 heart rate monitor programmed for their individual attributes (height, weight, age, training status, gender), which gives a real-time estimate of energy expenditure during exercise. Participants will report to the lab once per week to download the exercise sessions and verify compliance. If participants are not compliant (defined as completing 85% of their assigned exercise sessions per month), they will be disqualified. This intervention has been successfully used by Dr. Flack in multiple studies to produce significant weight loss without dietary intervention in this population with a retention rate of over 90%; Participants in the CON and EX group will receive a placebo (maltodextrin) made to look identical to the MT and LAC capsules.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: 6 armmed, placebo controlled RCT
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Exercise; weight loss; obesity; Lactobacillus; Milk Thistle; Bilirubin