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From the Townsend Letter
January 2016

Innovative Approaches to Obesity and Metabolic Syndrome
by Stephen F. Olmstead, MD
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The Scope of the Problem
Obesity and type 2 diabetes mellitus are pandemic metabolic disorders.1,2 Over 40% of Americans are obese.3 Over 10% of the world’s population is obese.4 Across the globe, the prevalence of diabetes has soared nearly fourfold, rising to 21.1 million in 2001.2 Worldwide, diabetes is projected to affect 592 million people by the year 2035, nearly 7% of the earth’s population. Metabolic syndrome is the concurrence of central or visceral obesity with insulin resistance, high blood pressure, elevated triglycerides, reduced high density lipoprotein (HDL) cholesterol levels, and a pro-inflammatory, prothrombotic milieu.5 People with metabolic syndrome have double the risk of developing cardiovascular disease (CVD).6 They are 3 to 4 times more likely to have a heart attack, while the risk of stroke is 2- to 4-fold higher in metabolic syndrome.5 When people with metabolic syndrome suffer a myocardial infarction or stroke, they are twice as likely to die.6 In addition to CVD, people with obesity and metabolic syndrome are at significantly increased risk for cancer of the breast, pancreas, and prostate, as well as a variety of diseases affecting the eyes, liver, kidney, skin, and reproductive system.6 Obesity and metabolic syndrome are major health challenges yet to be successfully met by the medical community.

Conventional Approaches to Obesity and Metabolic Syndrome
Obesity is the major impetus for the rising prevalence of metabolic disorders.1 Conventional approaches to obesity and metabolic syndrome have focused on weight loss primarily through diet and exercise.7 While the merits of low-carbohydrate diets versus low-fat diets are contentiously debated, a daily reduction in calorie intake is essential to successful weight loss.1,8 The daily energy deficit should be about 500 calories to sustain consistent weight reduction. Even modest weight loss delivers numerous metabolic health benefits such as reduced blood pressure, improved insulin sensitivity, decreased triglyceride levels, and increased HDL-cholesterol.9 Low-carbohydrate diets favorably affect triglyceride (TG) and HDL-cholesterol levels.10 There is also evidence that they improve glucose tolerance in people with diabetes. Exercise is vital for initial weight loss and healthful weight maintenance.11 There is evidence that exercise promotes visceral fat loss.12 Even without weight loss, exercise can improve insulin sensitivity in people who have been sedentary.13 Once simplistically considered a disorder caused by an imbalance of caloric intake versus energy expenditure, obesity is now understood to be a complex, multifaceted systemic inflammatory disease.

Eat Less, Exercise More – Easier Said Than Done
Although the approach of an energy-restricted diet and exercise for obesity and metabolic syndrome is simple and straightforward, in clinical practice it is difficult for people to maintain a diet and exercise regimen. Even when people are diligent, modest weight loss is usually the best expected outcome from participation in a structured diet program.8,14 Commitment and adherence to a change in diet and lifestyle are often insurmountable barriers to successful and sustained weight loss.15 Even when initial weight loss is accomplished, long-term maintenance of a more healthful weight is usually a major challenge.8 Clearly additional interventions are needed to make diet and exercise more effective in metabolic disorders. A novel approach to support a healthful weight and metabolism is the use of probiotics and prebiotics to address the gastrointestinal dysbiosis associated with obesity, type 2 diabetes mellitus, and metabolic syndrome. Probiotics and prebiotics are optimally combined with exercise, an energy-reduced diet, and supplements that reduce dietary starch and fat absorption.

Obesity-Associated Gastrointestinal Dysbiosis
The understanding of the pathogenesis of obesity and metabolic syndrome was radically transformed in 2004 when investigators reported that intestinal microorganisms transplanted from normal mice into germ-free mice not only led to weight gain but also promoted body fat accumulation and insulin resistance even with calorie restriction.16 Transplantation of gut microbes from genetically obese rodents into germ-free animals resulted in significantly greater weight gain than microbiota harvested from lean mice.17 Human studies found that the gut microbiota of obese people contained greater microbial populations in the phylum Firmicutes and fewer in the phylum Bacteroidetes compared with microbiota in lean people.18 Interestingly, after a carbohydrate- or fat-restricted, low-calorie diet, the ratio of Firmicutes to Bacteroidetes in obese individuals approached that found in lean subjects. The link between diminished Bacteroidetes numbers and obesity is controversial. While some studies confirm reduced gut Bacteroidetes populations in obese humans, others find increased numbers of Bacteroidetes in obese people.17,19 Yet others fail to find any association between Bacteroidetes and obesity.20,21 The focus on the phyla Bacteroidetes and Firmicutes ignores the important role of other microbes such as Bifidobacterium in the phylum Actinobacteria. Bifidobacterium populations are much higher during infancy in children who have a normal weight in later childhood than in obese children.22 Diminished Bifidobacterium numbers have also been described in overweight women compared with lean women. Low gut Bifidobacterium populations are associated with excessive weight gain during pregnancy and are depressed in people with type 2 diabetes.23,24 While a definitive link between obesity and relative proportions of Bacteroidetes and Firmicutes has yet to be established and may not exist, it is clear that obesity, type 2 diabetes, and metabolic syndrome are associated with complex gastrointestinal dysbiosis. The important microbiota disturbances appear to be at the genus and species levels and in reduced microbiota diversity.

Probiotics in Obesity and Metabolic Syndrome
While these are early days for the use of probiotics to support a healthful weight, given the current knowledge base, a reasonable approach is to use a formula that combines probiotics species with evidence for weight loss, healthful weight maintenance, and balanced glucose metabolism. These probiotics include Lactobacillus acidophilus, L. gasseri, L. plantarum, L. rhamnosus, and a robust mix of Bifidobacterium species including B. bifidum, B. breve, and B. lactis. A clinical trial performed at Stanford University showed that L. acidophilus supplementation was associated with significantly more weight loss following Roux-en-Y gastric bypass surgery.25 People receiving the probiotic had significantly greater weight loss up to 6 months postoperatively. In a randomized, controlled, double-blind study, L. acidophilus in yogurt together with B. lactis and L. casei significantly reduced body mass index (BMI), fat percentage, and leptin levels in overweight and obese adults.26 L. acidophilus has also been shown to improve insulin sensitivity and reduce markers of systemic inflammation in people with both normal and impaired glucose tolerance.27 And a randomized, double-blind, placebo-controlled study has evaluated the antiobesity effects of Lactobacillus gasseri.28 A fermented milk beverage with or without 100 billion CFU/day of L. gasseri was administered to 87 obese men and women. After 12 weeks, participants in the L. gasseri group experienced significant reductions in BMI, waist-to-hip ratio, total body fat mass, and abdominal visceral fat area compared with control subjects who experienced mild to moderate increases in each of these metrics. L. plantarum consistently reduces gains in total body, liver, and fat pad weight in rodents fed high-cholesterol diets.29 In mice L. plantarum has been shown to reduce obesity through production of active conjugated linoleic acid (CLA) isomers.30 In a small double-blind, controlled study involving people with obesity and hypertension, L. plantarum administered in a probiotic cheese significantly reduced BMI.31 There was a trend for L. plantarum to lower blood pressure. Women who received dietary counseling plus L. rhamnosus and B. lactis during their first trimester of pregnancy were significantly less likely to develop central adiposity after delivery than women who only received dietary counseling.32 L. rhamnosus and B. lactis supplementation in pregnant women has also been shown to reduce the risk of gestational diabetes.33 Consumption of a symbiotic shake containing B. bifidum together with L. acidophilus and oligofructans by elderly diabetics significantly reduces blood glucose and increases HDL-cholesterol levels.34 B. breve strains have been shown to reduce weight gain in rats fed a high-fat, adipogenic diet.35 In a randomized, double-blind, placebo-controlled trial involving people with a tendency to obesity, after 12 weeks B. breve significantly reduced fat mass compared with the placebo.36 Improvements in liver function and diminished inflammation were indicated by reductions in g-glutamyl-transpeptidase and high-sensitivity C-reactive protein levels.

Prebiotics in Obesity and Metabolic Syndrome
While the data are thin, evidence from animal models suggests pre­biotics may be used to modify the gut microbiota and promote a healthful weight. Feeding inulin-type fructans to genetically obese mice significantly elevates cecal Bifidobacterium and Lactobacillus populations while decreasing intestinal permeability, plasma lipopolysaccharide (LPS) levels, inflammatory mediators, and fat deposition in visceral, epididymal, and subcutaneous adipose tissues.37 Rats fed a standard diet enriched with 10% oligofructose for 4 weeks lose significantly more weight than rats fed the same diet alone.38 There are few human intervention trials studying prebiotics and weight maintenance. In a study of adolescent males, intake of 8 g/day of inulin-type fructans was associated with less weight gain and reduced total fat mass, especially in those with adequate calcium intake.39 In another study, obese, dyslipidemic, premenopausal women were given daily doses of a syrup containing 0.14 g/kg of inulin-type fructans, which led to a reduction in weight, body mass index (BMI), fasting insulin levels, and LDL-cholesterol.40 In a double-blind, randomized, controlled clinical trial examining the effects of prebiotics on weight loss, 21 g/day of oligofructose or an equicaloric control was administered to obese and overweight individuals.41 After 12 weeks, the group receiving oligofructose lost approximately 1 kg of body weight, most of it fat mass from the trunk region, while slight increases in weight and fat mass were recorded for the placebo group. Additionally, beneficial satiety hormone changes were observed with an increase in peptide-YY and a decrease in ghrelin. Prebiotics represent a vastly underused modality to favorably modulate the gut microbiota to support health. Inulin-type prebiotics, especially in combination with probiotics, are worth consideration in the setting of obesity and metabolic syndrome.

α-Cyclodextrin: A Novel Soluble Dietary Fiber
A viscous soluble dietary fiber called α-cyclodextrin offering significant potential benefits to people with obesity and metabolic syndrome is available as a dietary supplement. α-cyclodextrins are naturally occurring oligosaccharides consisting of 6 D-glucose molecules linked end to end by a-1,4 glycosidic bonds to form a doughnut or truncated cone.42 It is highly water soluble, its glycosidic bonds are resistant to hydrolysis by human salivary and pancreatic α-amylase, and the hydrophobic interior space of the doughnut or truncated cone complexes with the bi- and triglycerides that constitute most dietary fat.42 When α-cyclodextrin is ingested with a meal containing fat, it complexes the fat at up to a 1:9 w/w ratio forming microemulsions.43 Due to its high water solubility and resistance to salivary and pancreatic α-amylase, an ingested dose of α-cyclodextrin can pass intact and in solution through the stomach and small intestine into the colon.44 α-cyclodextrin interferes with fat absorption by preventing the hydrolysis of bi- and triglycerides into free fatty acids and glycerol. One gram of α-cyclodextrin can complex up to 9 grams of dietary fat. In human studies, α-cyclodextrin has been shown to stabilize weight in obese people with diabetes mellitus without any change in diet.45 When weight change was normalized for dietary energy intake, people receiving α-cyclodextrin lost weight. In a double-blind study involving healthy but overweight adults, α-cyclodextrin alone facilitated significant weight loss over 2 months without diet or exercise.46 If dyslipidemia is present, α-cyclodextrin significantly lowers cholesterol and LDL-cholesterol levels and blunts postprandial hypertriglyceridemia.45-47 Among healthy but overweight people, α-cyclodextrin reduced insulin levels by nearly 9.5%, indicating improved insulin sensitivity.46 In people with obesity and diabetes, α-cyclodextrin increases adiponectin levels especially in those not using insulin.45 Higher adiponectin levels favorably impact insulin tolerance, glucose regulation, and weight reduction.48 α-cyclodextrin is an effective adjunct to an energy-reduced diet as well as providing support to glucose and lipid metabolism.

α-Amylase Inhibitors from White Bean (Phaseolus Vulgaris)
White bean contains a variety of α-amylase inhibitor isoforms.49 A standardized water extract of non-GMO white kidney beans is available as the branded preparation Phase 2 that has been well documented to inhibit salivary, intraduodenal, and intraileal α-amylase.49 Human studies document significant reductions in postprandial glucose and insulin levels.50 In a randomized, double-blind, placebo-controlled trial involving overweight and obese people, those receiving the white bean α-amylase inhibitor lost weight over 12 weeks, while those receiving placebo gained weight.49 In a study involving mildly overweight people, the white bean α-amylase inhibitor plus 0.5 mg/d of chromium picolinate experienced a significant reduction in body weight, BMI, fat mass, adipose tissue thickness, and waist, hip and thigh circumferences while maintaining lean body mass.51 In conjunction with a 1200 calorie/day, low-fat diet, white bean α-amylase inhibitor combined with inulin and Garcinia cambogia extract resulted in significant drop in weight BMI and percent body fat compared with baseline, while there was no significant change in these parameters in the placebo group.52

Conventional approaches to obesity and metabolic syndrome are generally acknowledged to have limited success. The fundamentally moralistic view that obesity is an imbalance between excessive dietary intake and inadequate activity has been demonstrated to be exceedingly simplistic. The appreciation that the pathogenesis of obesity, type 2 diabetes mellitus, and metabolic syndrome involves gastrointestinal dysbiosis and systemic inflammation may well prove transformative to the management of weight and metabolism. While low-carbohydrate and low-fat diets may have similar long-term effects on weight, low-carbohydrate diets appear to offer additional benefits for glucose and lipid metabolism. Probiotics and prebiotics offer exciting modalities to favorably modify gut dysbiosis and reduce systemic inflammation, thereby promoting healthful weight and metabolism. α-cyclodextrin and white bean α-amylase inhibitors offer ways to safely reduce absorption of dietary fat and starch, thereby promoting weight loss and healthful glucose and lipid levels.

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