Fat-fighting microbes? Prove it with a robust study design.

Guest BloggerIPA In The Lab, Uncategorized

By Josh Baisley, B.Sc., Director of Clinical Trials, Nutrasource

Obesity, defined as a body mass index (BMI) ≥30kg/m2, continues to be an important health issue globally, as it is a major risk factor for several diseases, including hypertension, dyslipidemia, diabetes, coronary heart disease, stroke, gall bladder disease, osteoarthritis and some cancers, among others.1,2 Rates of obesity continue to increase across many regions in the world, including both developed and emerging countries.1 The highest rates of obesity are seen in the United States.2 In 2015, obesity rates among adults reached 38.2% in the United States.  Hungary, New Zealand and Mexico boast similar rates at or above 30% of the adult population, followed by Australia, UK, Canada and Chile, rounding at 25% of the population.  While some countries have seen stability in rates, none have seen reductions.  In fact, obesity rates are projected to continue to increase in many countries, and may reach 47% in the United States by 2030.3

From early research in animal obesity models with probiotics to more recent advances in fecal transplant models, there has been increasing interest in both the role of the microbiome as it relates to obesity, and in probiotic supplementation as a strategy for weight management and weight loss.

In recent years, several review articles on probiotics and their effects on obesity have been published; however, the volume and quality of published research is often lacking. 1,4,5 Only a few randomized controlled trials have been published on probiotic strains, including L. gasseri SBT 20556, L. rhamnosus ATCC 531037, L. casei8, and multi-strain formulations containing L. rhamnosus ATCC 53103 with B. lactis9 as well as L. acidophilus with B. ‘bifidus’10.  Within this small data set, it is also important to note that the study populations varied from pregnant women to children and adults.  In some cases, study formulations contained prebiotics in addition to the bacterial strains, and some contained other dietary ingredients, confounding the interpretability of results when evaluating the totality of evidence.  From some of these published clinical trials, it is evident that key aspects of clinical trial design and reporting were lacking.  These confounding variables lead to limitations in interpretability of results when evaluating the totality of evidence.  This is evident in the post available on the NIH Office of Dietary Supplements website regarding probiotic use for weight loss, where NIH concludes from research on this product category that there is “little to no effect on body fat, waist and hip circumference, or body weight”.11

A review of the studies reveals that, in one case, the clinical trial was not a randomized controlled trial and in another, strain designations were not reported, and incorrect references to species (e.g. “B. bifidus”,5,10).  In other cases, study designs and outcomes were not consistent with models for studying weight loss or weight management, including duration of study, relevant study endpoints and appropriate control group(s).

With respect to endpoints, studies in human clinical trials on obesity often measure body weight and BMI. While these biometrics are important and should be measured, the more relevant endpoint in most cases is fat loss, as measured by imaging equipment such as CT, DXA or MRI, which are able to demonstrate when changes in weight are due to fat loss, not water loss or other body composition changes.  It is important to also understand the limitations of BMI.  This index does not reflect changes that occur with age.  As we age, body fat, bone mass and muscle mass change over time, differing between women and men.  Additional factors, including exercise and weight training, may also lead to misclassification based on BMI alone, and may introduce bias in studies.12,13 Therefore, consideration must be given to inclusion criteria based on visceral or intra-abdominal adiposity, either through imaging, or in a more cost-effective, but indirect manner, by measuring waist circumference.

The following summary provides some key aspects (not all-encompassing) that should form the basis of clinical research trial protocols on weight loss and weight management studies using probiotics, in adult subjects:

Elements Recommendations14,15
Study Design Randomized, placebo controlled
Conditions of use should be clear, such as energy-restriction, dietary counselling
Conditions Must specify conditions such as energy-restriction
Duration of Study Minimum 3 months (weight loss, fat loss and waist circumference claims)

Minimum follow-up of 6 months after weight loss (weight maintenance claims)

Endpoints Body fat loss, abdominal/visceral fat loss (measured by CT, DXA, MRI or other valid imaging techniques), weight, BMI
Additional Endpoints of consideration (study dependent) Circumference measurements (e.g. waist, hip, etc.) (supportive), energy expenditure (mechanism), fat oxidation (mechanism), blood markers of comorbid indications and risk factors of related conditions (e.g. blood pressure and pulse, lipoprotein lipids, fasting glucose and insulin and HbA1c (in Type 2 diabetics)
Investigational Product List all ingredients unambiguously (e.g. strain designations) with amount per dosage unit and dosage regimen.

 

References

  1. Sáez-Lara MJ, Robles-Sanchez C, Ruiz-Ojeda FJ, Plaza-Diaz J, Gil A. Effects of probiotics and synbiotics on obesity, insulin resistance syndrome, type 2 diabetes and non-alcoholic fatty liver disease: A review of human clinical trials. Int. J. Mol. Sci. 2016, 17, 928.
  2. Centers for Disease Control and Prevention. Overweight and Obesity: Adult Obesity Causes and Consequences. www.cdc.gov/obesity/adult/causes.html. Accessed 04 Dec 2017.
  3. OECD. Obesity Update 2017. www.oecd.org/health/obesity-update.htm. Accessed 14 Nov 2017.
  4. Kobyliak N, Conte C, Cammarota G, Haley AP, Styriak I, Gaspar L, Fusek J, Rodrigo L, Kruzliak P.   Probiotics in prevention and treatment of obesity: a critical review. Nutrition & Metabolism. 2016, 13:14.
  5. Mekkes MC, Weenen TC, Brummer RJ, Claasen E. The development of probiotic treatment in obesity: A review. Beneficial Microbes. 2014, 5(1):19-28.
  6. Kadooka Y, Sato M, Imaizumi K, Ogawa A, Ikuyama K, Akai Y, Okano M, Kagoshima M, Tsuchida T. Regulation of abdominal adiposity by probiotics (Lactobacillus gasseri SBT2055) in adults with obese tendencies in a randomized controlled trial. Eur J Clin Nutr. 2010 Jun;64(6):636-43. doi: 10.1038/ejcn.2010.19. Epub 2010 Mar 10.
  7. Luoto R, Kalliomäki M, Laitinen K, Isolauri E. The impact of perinatal probiotic intervention on the development of overweight and obesity: follow-up study from birth to 10 years. Int J Obes (Lond). 2010 Oct;34(10):1531-7
  8. Nagata S, Chiba Y, Wang C, Ymashiro Y. The effects of the Lactobacillus casei strain on obesity in children: a pilot study. Beneficial Microbes. 2017. 8(4): 535.543.
  9. Ilmonen J, Isolauri E, Poussa T, Laitinen K. Impact of dietary counselling and probiotic intervention on maternal anthropometric measurements during and after pregnancy: a randomized placebo-controlled trial. Clin Nutr. 2011 Apr;30(2):156-64.
  10. Mikirova NA, Casciari JJ, Hunninghake RE, Beezley MM. Effect of weight reduction on cardiovascular risk factors and CD34-positive cells in circulation. Int J Med Sci. 2011;8(6):445-52.
  11. National Institutes of Health. Office of Dietary Supplements. Dietary Supplements for Weight Loss Fact Sheet for Health Professionals https://ods.od.nih.gov/factsheets/WeightLoss-HealthProfessional/ Accessed 16 Nov 2017.
  12. Rothman KJ. BMI-related errors in the measurement of obesity. Int J Obesity. 2008, 32, S56-S59.
  13. Banack HR, Wactawski-Wende J, Hovey KM, Stokes A. Is BMI a valid measure of obesity in postmenopausal women? Menopause. 2017, Nov 13. E pub ahead of print.
  14. US Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation Research. Draft Guidance. Guidance for industry: Developing products for weight management. Feb 2007.
  15. European Food Safety Authority. Draft Scientific Opinion. Guidance on the scientific requirements for health claims related to appetite ratings, weight management, and blood glucose concentrations. 2011.