Manipulating Gut Bacteria to Treat Obesity: A New Gene Target

Introduction

Obesity is currently an epidemic in most developed countries and contributes to chronic diseases such as type 2 diabetes, cardiovascular disease, and cancer.[1] The search for a treatment is complex because the etiology of obesity likely involves a combination of genetic predisposition and environmental factors, both of which are not fully understood. One contributor to obesity may be an altered gut microbe population, or microbiome, which has been implicated as a potential site for therapeutic treatments.[2][3][4][5] To effectively target a treatment, the mechanisms behind the microbiome’s effects on metabolism and/or obesity development must be understood. A 2013 publication in Nature Communications has identified the intestinal farnesoid X receptor (FXR), a nuclear receptor that controls genes involved in regulating bile acid, fat, and glucose metabolism, as a possible genetic target through which the gut microbiome can be altered to treat obesity.[6] In this study, Fei Li and colleagues from the National Cancer Institute in Bethesda, MD found that lowering or eliminating intestinal FXR activity through the antioxidant tempol or FXR-knockout models, respectively, changed the gut microbiome and reduced high-fat diet (HFD)-induced weight gain in mice.

Gut Microbiome and Health

The human microbiome is made up of 1013 to 1014 microorganisms,[7] and provides an important link between the genes and the environment. The microbiome of the gut, which predominantly contains the bacterial phyla Firmicutes, Bacteriodetes, Actinobacteria, and Proteobacteria, defines various physiological aspects such as xenobiotic and energy metabolism. Each individual has a unique community of microbes—even identical twins have different microbiomes because food, medication, and other external factors also change microbial communities.[4] bacteriaAlterations in the relative proportions of these phyla (i.e., an individual’s gut microbiome) may be associated with diseases such as colon cancer, obesity, and metabolic syndrome, and inflammatory bowel disease, and they may also influence calorie bioavailability, drug metabolism, and immune system response (for a review see [8]). Therefore, manipulating the gut microbiome may be an important therapeutic target for treating chronic diseases such as obesity and obesity-related disorders by optimizing energy metabolism.

Gut Microbiome and Obesity

The first study to show the link between gut microbiota and obesity found that germ-free C57BL/6 mice had 42% less body fat than their counterparts with conventional microbiota, even though they consumed more food.[2] When the scientists colonized the gut of these germ-free mice with a cecum-derived distal microbial community, total body fat increased by 60%, even though neither food consumption nor energy expenditure changed. Further investigation in humans showed that obese individuals have a lower proportion of Bacteriodetes compared to lean individuals; and both carbohydrate-restricted and fat-restricted weight-loss diets increase the proportion of this phylum,[3] suggesting that weight loss may have a profound impact on the gut microbiome. Additionally, Akkermansia muciniphila, a bacterium that grows within the mucus layer of the intestines, was shown to be higher in non-overweight humans and rodents than in their obese counterparts, and administering the bacterium to mice fed a high-fat diet reduced their obesity and related metabolic disorders.[5] Therefore, the relative proportions of multiple microbial species are likely associated with obesity in both human and rodent models, although the mechanisms by which they work remain to be elucidated.

Intestinal FXR—A Potential Therapeutic Target for Obesity?

Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl), a nitroxide compound that metabolizes a variety of reactive oxygen species, prevents weight gain in mice[9] and alters levels of metabolites generated by gut microbes,[10] according to previous studies. Thus, tempol may adjust the energy metabolism controlled by the gut microbiome either by changing the bacterial composition or its metabolic potential. Li, et al. investigated the mechanisms by which tempol exerts its anti-obesity actions through the gut microbiome.[6] Tempol administration in C57BL/6 mice significantly reduced high-fat diet-induced obesity and insulin resistance compared to vehicle-treated mice. This treatment was associated with a phylum-level shift from Firmacutes to Bacteroidetes; in particular, a reduction was observed in the Lactobacillus populations in the mouse cecum.

Because Lactobacillus populations are involved in the deconjugation of taurine-conjugated bile acids in the intestine,[11] the scientists investigated bile acid composition in the intestine. Tauro-β-muricholic acid (T-β-MCA), an FXR antagonist,[12] was elevated in the intestines of tempol-treated wild-type Fxrfl/fl mice and was associated with reduced FXR signaling. Furthermore, intestine-specific Fxr-null (FxrΔ/E) mice gained less weight on a HFD than their wild-type counterparts (Fxrfl/fl), despite consuming similar quantities of food. Tempol treatment increased intestinal T-β-MCA in both Fxrfl/fl andFxrΔ/E mice but only reduced weight gain in the Fxrfl/fl, suggesting that reduced HFD-induced obesity acts through FXR inhibition.

Conclusions/Future Directions   

The recent findings indicate an association between FXR activity and the reduction of HFD-induced obesity by altering the gut microbiome in mice.[6] Thus, FXR may be a genetic target for obesity-reducing therapeutic agents. The full mechanism by which the intestinal FXR contributes to obesity is not completely understood, but may involve sphingomyelin compounds and metabolites such as ceramide, which have been associated with obesity-related metabolic disorders.[13] Further clarification on the relationship between intestinal FXR activity and obesity, the relationship between FXR activity and obesity in humans, and other potential target genes that affect the gut microbiome is warranted to optimize therapeutic treatment for obesity.

References

  1. K. M. Flegal, B. I. Graubard, D. F. Williamson, and M. H. Gail, Excess deaths associated with underweight, overweight, and obesity, JAMA 293, pp. 1861–1867.
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  3. R. E. Ley, P. J. Turnbaugh, S. Klein, and J. I. Gordon,, Microbial ecology: human gut microbes associated with obesity, Nature 444, pp. 1022–1023.
  4. P. J. Turnbaugh, M. Hamady, T. Yatsunenko, B. L. Cantarel, A. Duncan, R. E. Ley, and M. L. Sogin, et al, A core gut microbiome in obese and lean twins, Nature 457, pp. 480–484.
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  6. F. Li, and C. Jiang, K. W. Krausz, Y. Li, I. Albert, H. Hao, K. M. Fabre, J. B. Mitchell, A. D. Patterson, and F. J. Gonzalez, Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity, Nat. Comm. 4, p. 2384.
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  10. F. Li, X. Pang, W. Krausz, C. Jiang, C. Chen, J. A. Cook, and M. C. Krishna, J. B. Mitchell, F. J. Gonzalez, A. D. Patterson, Stable isotope- and mass spectrometry-based metabolomics as tools in drug metabolism: a study expanding tempol pharmacology, J. Proteome. Res. 12, pp. 1369–1376.
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  13. J. A. Chavez and S. A. Summers, A ceramide-centric view of insulin resistance, Cell Metab 15, pp. 585–594.

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