Obesity and Microbiota
December 1, 2013
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Obesity and Microbiota
By Carrie Decker, ND
Founder and Medical Director, Blessed Thistle, Madison, WI
Dr. Decker reports no financial relationships relevant to this field of study.
Trillions of microbes are known to colonize the human body, with different strains of flora common to locations such as the gastrointestinal tract, skin, vaginal canal, and oral cavity. But variations or overgrowth in specific strains of these microbes is often associated with pathology, such as the well-known conditions that bacterial vaginosis or candidiasis represent. Imbalances in flora populations are now being associated with diseases such as irritable bowel syndrome,1 inflammatory bowel disease,2 autoimmune diabetes,3 atherosclerosis,4 and obesity.5 Much study is devoted to seeking an understanding of how the microbiota is related to these diseases and if it is a result of the disease condition or a possible contributing cause.
Obesity is a compelling problem. In 2008, 11% of the world’s adult population aged ≥ 20 years of age were classified as obese (body mass index [BMI] ≥ 30 kg/m2), while 35% were classified as overweight (BMI ≥ 30 kg/m2).6 Childhood and adolescent obesity is also an increasing statistic. In 2009-2010, 16.9% of children and adolescents between 2-19 years old were also classified as obese.7 Many factors lead to these statistics, and questions of diet, exercise, and genetics are often the most obvious to assess. As knowledge about the microbiota and its effect on the health of the organism continues to become more apparent, the gastrointestinal flora is being investigated to assess for possible relationship or contribution to obesity. Obesity is a disease associated with many other problems such as insulin resistance, chronic low-grade inflammation, and non-alcoholic fatty liver disease, so understanding the role the gut microbiota may play in the confluence of these diseases may lead to larger treatment solutions.
Pathophysiology and Mechanisms
Several studies have promoted interest in the relationship of microbiota to obesity. One study involved the analysis and transplantation of the distal cecal microbiota from lean and obese mice into germ-free mice recipients.8 It was found that after a 2-week period, the germ-free mice colonized with the microbiota from the obese mice exhibited a significantly greater increase in adiposity without an increase in food consumption. Similar results were observed with the transplantation of gut microbiota in another study.9
The mechanisms by which the microbiota may be related to adiposity are a current research interest. It has been shown that obese mice have an increased absorption of monosaccharides and hepatic lipogenesis associated with the signaling proteins carbohydrate response element-binding protein and liver sterol response element-binding protein.9 The obese microbiota was also shown to suppress fasting-induced adipocyte factor, leading to increased lipoprotein lipase activity in adipocytes and increased storage of calories as fat.9 The genes of the microbiota from obese leptin-deficient mice have been shown to code for enzymes that break down otherwise indigestible polysaccharides, leading to increased energy extraction from food.8 An inflammation- and obesity-associated pathway has also been associated with diet. A high-fat diet (HFD) has been shown to increase endotoxemia (measured by plasma lipopolysaccharide [LPS]) and affects which microbiota are present, reducing Bacteroides and Bifidobacterium spp., as well as triggering the expression of inflammatory cytokines.10 A chronic low serum level of LPS has been shown to lead to obesity, hyperglycemia, and hyperinsulinemia via immune system-associated pathways.11 Increased circulating levels of LPS in rodents subject to an HFD also have been shown to be directly related to increased intestinal permeability.12
Short-chain fatty acids, prebiotics, and probiotics are some of the interventions being studied for the modification of the microbiota in obese populations.11 Short-chain fatty acids (SCFAs) including acetate, butyrate, and propionate are a metabolic product of the gut microbiota and have an effect on the several of the aforementioned mechanisms. Prebiotics are fibers that resist absorption in the upper gastrointestinal tract, are fermented by intestinal microflora into products including SCFAs, and stimulate the growth and/or activity of gut microbiota associated with health.13 Inulin, oligofructose (OF), fructo-oligosaccharides (FOS), transgalacto-oligosaccharide, and lactulose are some common prebiotics.13 Probiotics are strains of microbiota that directly affect the intestinal flora population and have many health benefits.
Animal Trials
SCFAs. Butyrate at a level of 5% wt/wt has been shown in mouse studies to reduce weight gain in mice on an HFD, inducing satiety14 and increasing energy expenditure via increased mitochondrial function.15 Treatment of mice with butyrate at a level of 5% wt/wt for 16 weeks prevented the development of obesity and insulin resistance despite HFD feeding.15
Prebiotics and Probiotics. The affect of FOS on minimizing the weight gain of mice fed an HFD was assessed in a study with axenic mice. The mice, inoculated with human fecal microbiota, were subject to feeding for 7 weeks of an HFD, an HFD with 10% FOS, or a control diet.16 Both groups of mice on an HFD feeding gained more weight than the control; however, the FOS fed group gained less weight and had less fat deposition. The fecal microbiota of the FOS fed mice had a significant increase in Bifidobacteria and Clostridium coccoides and decreased C. leptum.
The effects of prebiotics and probiotics were assessed individually and in combination in rats with diet-induced obesity.17 The diet of the rats was supplemented with 10% OF and/or 1 × 1010 colony-forming units (CFU) per day of Bifidobacterium animalis BB-12, and outcomes were compared to control after 8 weeks of feeding. It was found that the prebiotics but not the probiotics reduced energy intake, weight gain, and fat mass. All interventions improved blood sugar compared to control. There was a significant increase in Bifidobacteria and Lactobacilli spp. with OF supplementation but not with B. animalis alone.
Several animal trials have shown varying levels of success with different strains of probiotics. Probiotic strains of Lactobacillus rhamnosus or L. sakei were supplemented to mice at a level of 1 × 108 CFU/day for 3 weeks with a normal chow feeding.18 Both strains were separately shown to reduce epididymal fat mass and obesity-related biomarkers. Supplementation with L. sakei also led to a significantly lower overall weight gain than the control group. No significant difference in feed consumption was noted.
Mice supplemented with Bacteroides uniformis CECT 7771 at a dosage of 5.0 × 108 CFU were fed either a standard diet or HFD and compared to controls with no supplementation after 7 weeks.19 The supplementation of B. uniformis was found to reduce body weight gain, serum cholesterol, triglyceride, glucose, and insulin levels, as well as dietary fat absorption by enterocytes in mice subject to HFD feeding. The changes in gut microbiota induced by the HFD feeding were also decreased with probiotic supplementation.
The effects of four different Bifidobacteria strains (L66-5, L75-4, M13-4, and FS31-12) on weight gain, lipid metabolism, and glucose metabolism in obese mice fed an HFD were assessed after supplementation at a level of 1 × 108 CFUs with HFD feeding for 6 weeks.20 After the 6-week period, the body weight of the group supplemented with the B. M13-4 strain was significantly higher, and the B. L66-5 group was significantly lower. No significant change in body weight from the control was observed with the B. L75-4 or B. FS31-12 supplementation.
Clinical Studies
SCFAs. Supplementation with SCFAs has not yet been investigated in human clinical trials for the treatment of obesity.
Prebiotics. A systematic review of randomized controlled trials (RCTs) was performed to assess the effects of prebiotic intake on appetite, energy intake, and body weight in children and adults.21 A total of 19 RCTs met the inclusion criteria for this review. In pediatrics, only one of four RCTs showed an effect on body weight or BMI.22 In adults, of the three RCTs that assessed body weight, two RCTs showed a significant reduction.23,24 Eleven of the RCTs found no effect of prebiotic supplementation on energy intake. The studies with significant findings are further detailed here.
Adolescents aged 9-13 years old were supplemented with 8 g of a 50/50 inulin/OF blend a day and BMI measurements were compared to a control group supplemented with maltodextrin after a period of 1 year.22 The individuals supplemented with the prebiotic had a BMI increase of 0.73 kg/m2 while the control group had a BMI increase of 1.24 kg/m2, a difference 0.52 ± 0.16 kg/m2 (P = 0.016); confidence interval (CI) was not reported (NR). Calcium intake was also assessed in this study and found to have a negligible effect. A year after the supplementation was stopped, it was found that the BMI of the prebiotic group remained lower, with a difference in BMI of 0.68 ± 0.36 kg/m2 (P = 0.061; CI NR).
OF supplementation was provided to adults with a BMI > 25 kg/m2 at a level of 21 g/day for a period of 12 weeks.23 It was found that there was a decrease in body weight of 1.03 ± 0.43 kg with OF supplementation, and an increase in weight of 0.45 ± 0.31 kg in the placebo group (P = 0.01; CI NR). A 29% reduction in self-reported calorie intake in the OF group was seen at week 6 (P = 0.002; CI NR) and this was associated with different hormones associated with hunger and satiety (ghrelin and peptide YY).
FOS supplementation at a dosage of 20 g or 10 g/70 kg/day was provided to obese women for a period of 120 days.24 It was found that a dosage of 10 g/70 kg/day led to a significant decrease in body weight from 91.2 ± 8.4 kg to 76.2 ± 6.1 kg (P < 0.05; CI NR). Supplementation at a dosage of 20 g/70 kg/day led to significant gastrointestinal side effects and these subjects were excluded from analysis.
Probiotics. The probiotic strain L. gasseri SBT2055 has been shown to have a beneficial effect on abdominal adiposity in human studies.25 L. gasseri SBT2055 was supplemented to individuals with a BMI of 24.2-30.7 kg/m2 via fermented milk (a traditional yogurt preparation) at a dosage of approximately 10 × 1010 CFU in 200 g/day of fermented milk for a period of 12 weeks, and compared to a control supplemented with only fermented milk. Abdominal visceral and subcutaneous fat area significantly decreased (P < 0.01) from baseline by an average of 4.6% (mean, -5.8; CI, -10.0 to -1.7 cm2) and 3.3% (mean, -7.4; CI, -11.6 to -3.1 cm2), respectively. Other measures that decreased significantly (P < 0.001) were: body weight, 1.4% (mean, -1.1; CI, -1.5 to -0.7 kg); BMI, 1.5% (mean, -0.4; CI, -0.5 to -0.2 kg/m2); waist, 1.8% (mean, -1.7; CI -2.1 to -1.4 cm); hip, 1.5% (mean, -1.5; CI, -1.8 to -1.1 cm). None of these parameters were found to decrease significantly in the control group.
A second study regarding the probiotic L. gasseri but with strain BNR17 was performed on an overweight and obese population having a BMI ≥ 23 kg/m2.26 Supplementation of L. gasseri BNR17 at the level of 1010 CFU/day occurred for a period of 12 weeks without any other behavioral or dietary intervention. In this study, only a slight reduction in body weight, waist, and hip circumference was noted in the L. gasseri BNR17 supplemented group, but the differences were not significant.
Supplementation of a probiotics combination with dietary counseling was assessed in the prevention of obesity post-pregnancy and compared with dietary intervention alone or a control with no intervention.27 Supplementation of both L. rhamnosus GC and Bifidobacterium lactis at a dosage of 1010 CFU/day was provided from the first trimester until the end of exclusive breastfeeding (up to 6 months). At 6 months postpartum, it was found that the risk of central adiposity (waist circumference 80 cm or more) was lowered in women in the diet/probiotics group compared with the control/placebo group (odds ratio 0.30; CI, 0.11-0.85; P = 0.023), while the diet/placebo group did not significantly differ from the control. The number needed to treat for the prevention of one woman from developing central adiposity was 4.
The probiotic strain L. salivarius Ls-33 was assessed for its effects on inflammation and metabolic syndrome in adolescents with obesity, and after supplementation of 1010 CFU/day for a period of 12 weeks, there was no significant change in any of the biomarkers related to obesity or metabolic syndrome.28
Dosing
SCFAs. In animal studies, 5% wt/wt dosing of butyrate was shown to have a beneficial effect. Dosing at this level was for a period of 4-16 weeks in mouse studies.14,15
Prebiotics and probiotics. Most common amounts of preboitic supplementation in humans range from 10-20 g/day in a single or divided dose either with or before meals.21 Recommendations for minimal gastrointestinal side effects are to dose at 10 g FOS/70 kg/day or to gradually increase the dosage.24 CFUs are the measurement unit of probiotics and describe the amount of organisms present that are viable and able to colonize under controlled conditions in vitro. The dosing of probiotics (various strains, including possibly L. gasseri SBT2055, L. rhamnosus GC, or Bifidobacterium lactis) at a level between 1 × 1010 and 10 × 1010 CFU/day are what are used in the literature and may be an appropriate dose. Dosing of prebiotics and probiotics at these levels is recommended for a period of at least 12 weeks.
Safety and Adverse Effects
SCFAs. High levels of SCFAs, specifically butyrate, have been shown in vitro to have a paradoxical effect, leading to increased intestinal permeability.29 However, this may be mediated by its beneficial effects on the intestinal mucosa barrier.30 Oral formulations of sodium butyrate often have an unpleasant taste and odor, possibly leading to poor patient compliance.
Prebiotics. Digestion of prebiotics such as inulin, FOS, and OF is a known problem in patients with irritable bowel syndrome, and may lead to fructose malabsorption and exacerbation of gastrointestinal symptoms.31 In some of the studies cited, subjects experienced symptoms of diarrhea, abdominal distention, flatulence, and nausea initially during treatment; however, symptoms improved with time. A gradual increase in dosage with time also was utilized to minimize these symptoms. Supplementation with FOS has also been shown to increase lower esophageal sphincter relaxation, worsening incidence of reflux events in patients with gastroesophageal reflux disease.32
Probiotics. The consumption of probiotics is generally recognized as safe; however, as high doses of specific strains are now being utilized for the treatment of a variety of conditions, this question must further be considered. A systemic review assessed the safety of probiotics in 72 case reports, RCTs, and nonrandomized trials.33 The authors found 20 case reports of adverse events in 32 patients, each involving infections associated with either L. rhamnosus GG or S. boulardii. The risk factors identified in these case reports were antibiotic treatment, intravenous access, immune suppression, and conditions involving increased bacterial translocation. Of the 52 trials assessed, most showed no effect or a positive effect on outcomes, with only three trials showing increased complications. Of these three, two trials were associated with administration of a probiotic via a nasojejunal tube, and the third involved treatment of low birth weight, preterm infants. Theoretically, there also may be long-term effects on the immune system and adverse effects during pregnancy as well; however, there presently is no evidence for this.34
Conclusion
The knowledge is far from complete pertaining to how the gut microbiota is related to obesity. Furthermore, how to specifically alter the microbiota to reduce the risk of obesity is far less known. Animal studies have shown that the dietary addition of SCFAs, prebiotics, and specific strains of probiotics confer benefits of reduced weight gain, particularly under conditions of HFD feeding. The possible effects of SCFA supplementation on obesity has no clinical evidence, as testing has only been performed with animal and in vitro studies. Supplementation with prebiotics shows some benefit on body weight clinically; however, a systemic review of RCTs shows few trials with significant effects.21 Adverse gastrointestinal effects also may be experienced with prebiotic supplementation, but can be minimized by gradually increasing the dosage as tolerated up to 10 g/70 kg/day. The probiotics strains of L. gasseri and L. rhamnosus GC with B. lactis may be beneficial for reducing abdominal adiposity, dosing at a level of 1 × 1010 to 2 × 1010 CFU/day.
Recommendation
Prebiotics may be a beneficial adjunctive treatment for promoting reduced body weight; however, gastrointestinal side effects may be experienced. Leeks, asparagus, chicory, Jerusalem artichokes, garlic, onions, and soybeans are sources of prebiotics, so increasing the consumption of these foods will introduce both prebiotics as well as other nutrients to the diet. To achieve the goal of dosing at 5-6 g of prebiotics twice a day, one would need to consume approximately 2 servings of cooked asparagus or a single serving of Jerusalem artichoke, globe artichoke, cooked onion, or leeks to get a single prebiotics serving.35
Supplementation of the probiotic strains of L. gasseri and L. rhamnosus GC with B. lactis may be considered for the objective of weight loss; however, minimal studies have been done to show their clinical effect. Since supplements with these specific probiotic strains are not as economical and widely available as prebiotics, it should be considered as an adjunctive treatment to promote reduced abdominal adiposity if gastrointestinal side effects of prebiotics are not tolerated. The additional health benefits of probiotics, not fully addressed in this review, may also promote interest in their use. A mixed probiotic that includes these specified strains at a dosage of at least 1 × 1010 CFU/day would be an appropriate initial dosage. The intent of supplementation should be on a long-term basis of at least 12 weeks before anticipating notable changes in weight or other parameters.
References
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- Gibson GR, et al. Dietary modulation of the human colonic microbiota: Updating the concept of prebiotics. Nutr Res Rev 2004;17:259-275.
- Lin HV, et al. Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS One 2012;7:e35240.
- Gao Z, et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 2009;58:1509-1517.
- Respondek F, et al. Short-chain fructo-oligosaccharides modulate intestinal microbiota and metabolic parameters of humanized gnotobiotic diet induced obesity mice. PLoS One 2013;8:e71026.
- Bomhof MR, et al. Individual and combined effects of oligofructose and Bifidobacterium animalis on gut microbiota and glycemia in obese rats. Obesity 2013; [Epub 2013 ahead of print].
- Ji YS, et al. Modulation of the murine microbiome with a concomitant anti-obesity effect by Lactobacillus rhamnosus GG and Lactobacillus sakei NR28. Benef Microbes 2012;3:13-22.
- CanoPG, et al. Bacteroides uniformis CECT 7771 ameliorates metabolic and immunological dysfunction in mice with high-fat-diet induced obesity. PLoS One 2012;7:e41079.
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- Liber A, Szajewska A. Effects of inulin-type fructans on appetite, energy intake, and body weight in children and adults: Systematic review of randomized controlled trials. Ann Nutr Metab 2013;63:42-54.
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- Parnell JA, Reimer RA. Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults. Am J Clin Nutr 2009;89:1751-1759.
- GentaS, et al. Yacon syrup: Beneficial effects on obesity and insulin resistance in humans. Clin Nutr 2009;28:182-187.
- Kadooka Y, et al. Regulation of abdominal adiposity by probiotics (Lactobacillus gasseri SBT2055) in adults with obese tendencies in a randomized controlled trial. Eur J Clin Nutr 2010;64:636-643.
- Jung SP, et al. Effect of Lactobacillus gasseri BNR17 on overweight and obese adults: A randomized, double-blind clinical trial. Korean J Fam Med 2013;34:80-89.
- Ilmonen J, et al. Impact of dietary counseling and probiotic intervention on maternal anthropometric measurements during and after pregnancy: A randomized placebo-controlled trial. Clin Nutr 2011;30:156-164.
- Gøbel RJ, et al. Probiotics to adolescents with obesity: Effects on inflammation and metabolic syndrome. J Pediatr Gastroenterol Nutr 2012;55:673-678.
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