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Obesity is an ever-growing and ravaging disease with numerous associated disorders, deteriorating life quality and life expectancy. Traditional explanations of obesity’s causes have focused on genetic and environmental factors, higher caloric intake along with a sedentary lifestyle, and overindulgence in a high-fat, high-carb Western diet (5). However, a new line of inquiry contends that calories, genes, and lifestyle are half of the obesity puzzle. Now more than ever, researchers are elucidating compelling evidence that our changing microflora, well-known for its role in host homeostasis and immune function (6), is strongly linked to shifts in our metabolic potential, levels of inflammation, gut permeability, and ultimately, the upsurge in obesity.
Several studies have demonstrated that differing microbial compositions correlate with obese and lean phenotypes. One study found that genetically obese mice have fewer Bacteriodetes and more Firmicutes than their lean littermates; these microbial shifts could not be justified merely by differences in total body mass and food consumption (6). Other studies found that germ-free mice were 40% leaner than conventionalized mice (e.g. mice living with normal microbiota), despite the latter eating 30% less chow than the former. Similar findings in the gut’s microbial composition have been evidenced in humans.
During a year-long weight loss program, obese individuals with greater weight loss displayed a dramatic increase in Bacteriodetes and reduction in Firmicutes (4). Additionally, a longitudinal study revealed that obese children (who were followed from infancy to seven years of age) had fewer Bifidobacteria and more Staphylococcus aureus bacteria as infants than children of normal weight (3). Collectively, these findings convincingly suggest that a certain microbial constitution—or the ratio of health-promoting bacteria to health-endangering bacteria—predispose or protect an individual from obesity and its concomitant metabolic disorders.
There is also increasing evidence that our microbiome plays a role in changing critical components in our metabolism. Most crucially, several enzymes are selectively targeted and modulated by the microbiota. FIAF (fasting induced adipose factor), an enzyme which reduces fatty acid release from circulating triglycerols, is actively suppressed by gut microbiota in conventionalized mice and results in increased fat storage (1). In contrast, lean germ-free mice have elevated levels of FIAF along with reduced body fat deposition (1). AMPK (AMP-activated protein kinase), which pivotally maintains body weight, is reduced by obese microbiota. Conversely, unimpaired AMPK activity equips germ-free mice with obesity resistance despite a high-fat diet (1). Even the microbial ecology of obese mice displays an enrichment of fermenting enzymes, such as glycoside hydrolases, which foster greater energy extraction from the diet (6). Beyond down-regulating and up-regulating particular enzymes, obese microbiota also raises glucose levels, increase lipogenesis, and reduce calories deposited in the stool (6). In essence, lean mice and germ-free mice transplanted with ‘obese microbiota’ become obese. These complex metabolic modifications—from enzymatic regulation to heightened efficiency of energy extraction – have compellingly implicated the transforming microbiome as a potent influence on metabolism and obesity.
Lipopolysaccharide (LPS), a bacterial endotoxin, has also been linked to the low-grade inflammation characteristic of obesity. For example, mice fed high-fat meals showed substantially increased plasma LPS levels compared to normal chow-fed mice (2). In another experiment, mice chronically infused with LPS not only developed endotoxemia, but they also had appreciable increases in inflammation, insulin resistance, and subcutaneous and visceral mass (1). Analogously, healthy human subjects eating high-fat meals developed metabolic endotoxemia and varying degrees of inflammation (2). Furthermore, increases in gut permeability (e.g. via changes in the distribution and localization of tight junction proteins) are strongly associated with alterations in the microbiota (1). Interestingly, these changes allow for enhanced absorption of LPS and intestinal monosaccharides under high-fat conditions, and a resultant propensity toward obesity (1). In sum, our increasingly fatty diets appear to be inducing unhealthy levels of bacterial toxins in our bodies, provoking hazardous inflammatory responses and reengineering our microbiome into a factory of obesity.
The most striking evidence linking our changing microbiota to obesity, however, is rooted in the long-lasting uses of prebiotics (stimulants of beneficial microorganisms), probiotics (or health-conferring bacteria), and antibiotics. For instance, the prolonged use of probiotics as cattle growth promoters has been implicated as a potential manipulator of our gut's microbial composition, and an unwitting contributor to obesity in society(6). Similarly, many scientists contend that the introduction of high fructose corn syrup into the US diet may have caused a drift toward a Firmicutes-dominated microbiome, optimizing energy extraction and weight gain (6). In an opposite vein, experimental manipulations of the gut microbiota with prebiotics and antibiotics have revealed anti-obesity effects. These studies discovered that prebiotics improve gut permeability, combat inflammation, and diminish adipose tissue and body weight (1).
Correspondingly, antibiotic treatment lowers LPS levels, reduces glucose intolerance, and minimizes body weight gain (7). Clearly, our ability to manipulate the microbiota’s composition, purposefully or indiscriminately, indicates that our microbiome is also susceptible to change by non-laboratory factors currently beyond our control. We can only wonder – how else have we manipulated the microbiota and consequently predisposed ourselves to obesity?
Unraveling the causal complexity of obesity will take promethean effort. A plethora of scientific evidence suggests that obesity is a multi-pronged and multidimensional disease. It is influenced not only by caloric intake, energy expenditures, and environmental and genetic factors, but also by our gut’s shifting microbial configurations. While the relative contribution of microbiota to obesity is not yet known, we can be certain that our changing microbiome works in tandem with many factors to enhance the efficiency of caloric extraction, trigger systemic inflammation, modify the gut's permeability, and increase fat deposition.
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3. Delzenna NM, Cani PD: Nutritional modulation of gut microbiota in the context of obesity and insulin resistance: potential interest of prebiotics. International Dairy Journal 2010, 20:277-280.
4. Manco M, Putignani L, Bottazzo GF: Gut microbiota, lipopolysaccharides, and innate immunity in the pathogenesis of obesity and cardiovascular risk. Endocrine Reviews 2010, 31:817-844.
5. Tilg H: Obesity, metabolic syndrome, and microbiota multiple interactions. Journal of Clinical Gastroenterology 2010, 44 Supp 1: S16-8.
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7. Tsukuno DM, Carvalho BM, Carvalho-Filho MA, Saad MJ: Translational research into gut microbiota: new horizons in obesity treatment. Arq Bras Endocrinol Metab 2009, 53:139-144.
Copyright © 2013 Mentis
About the author:
Candice Carpenter is a first year medical student. She is deeply interested in issues related to bioethics, medical entrepreneurship, social justice, patient empowerment, educational innovation, as well as integrative medicine.
About the artwork:
"Reclining Figure, 1975" is an etching by Henry Moore.