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Can your Microbiome Make you Fat?

Posted on November 9th, 2016 by in Pharma R&D

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This is a story about fecal microbiota transplant (FMT): FMT is a procedure in which fecal matter is collected from a healthy donor and placed in a recipient, typically by colonoscopy. The purpose? To suppress the growth of Clostridium difficile. In this case, a lean women undergoing treatment for recurring Clostridium difficile infection receives  FMT from her daughter who was experiencing significant weight gain at the time of the donation. After receiving the fecal donation, the patient undergoes rapid, unintentional weight gain. The authors concluded that the fecal donation had a microbiota that caused obesity in the recipient (ref 1).

Obesity, and its sidekick, Type 2 diabetes, is an epidemic public health problem and growing.  Diet plans, fad diets, drugs, behavior modification, and surgery are available with drawbacks. According to the CDC (ref 2), about 37% of U.S adults are obese and about 70% are overweight. Enter the microbiome, which may provide an explanation for weight gain in some individuals. Microbiome refers to the total collection of microorganisms and their genetic material in the host, and therapeutics using the microbiome may be just around the corner (ref 3).

How does the gut microbiome control how many calories an individual extracts from food? Disease causes a decrease in diversity of the microbiota, leading to a state called “dysbiosis.” In the dysbiotic state, the normal microflora and metabolic pathways are significantly changed. One hypothesis is that a high ratio of Firmicutes to Bacteroidetes bacteria favors obesity. Another says that an overabundance of Christensenellaceae keeps the fat off. Central to these hypotheses is the contention that a shift in the microbiota leads to a greater extraction of calories from food. Experiments with mice (ref 4) demonstrate that germ-free mice are protected against obesity that develops after consuming a Western diet rich in fat and sugar.

Low-grade Inflammation, mediated by a dysbiotic microbiota, is associated with obesity and Type 2 diabetes. Inflammation, fueled by bacterial cell-wall components (lipopolysaccharides), gives rise to a leaking gut, cytokine release, and insulin resistance.

Overuse of antibiotics is a strong contributing factor to obesity. Not just overuse of antibiotics we are prescribed to fight infection, but from the chronic consumption from meat in our food supply. Antibiotics are added to livestock feed as a prophylaxis for infection. Fed in low doses, antibiotics promote growth. Cho and Blaser (ref 5) conducted an experiment where mice were given a dose of antibiotic, similar to the amount in our meat supply. The antibiotic-treated mice became obese, even though the calorie intake was controlled. These results suggest that antibiotics cause a gut dysbiosis, increasing calorie extraction, all leading to inflammation, obesity, and insulin resistance.

Human and animal research publications with microbiome and obesity do not have consistent findings. One reason is because the methods for identifying bacteria are inconsistent. Traditionally, great pains went to isolating and culturing microorganisms with varying success. Now, next generation sequencing (NGS) and bioinformatics show an incredibly complex community of microorganisms. Additionally, there are shifts in the metabolic machinery (metabolome) and gene expression (metatranscriptome) with dietary change. Overall, the research is fairly consistent showing a tight interplay between diet, microbial population, and metabolic shifts.

Several metabolic mediators are thought to play a role as both bacteria respond to an obesity-producing diet. Angiopoietin-like Protein (Angpt14) or Fasting Induced Adipose Factor (Fiaf), a regulator fat metabolism in adipose and muscle, is modulated by gut bacteria. Another is short chained fatty acids (SCFA) such as butyrate, propionate, and acetate, originating from bacterial fermentation of dietary fiber may be protective against weight gain – however some studies find some SCFAs are pro obesity. Generally, the obese individual is characterized with a high fecal SCFA level, high expression of bacterial genes responsible for polysaccharide metabolism, and an increased energy extraction from food.

Returning to FMT, certain characteristics that are influenced by the microbiota can be transferred by fecal transplant. Fecal transplant is a popular research approach to understanding the role of microbiota in obesity. Fecal microbiota transplantation (FMT) may be a future therapeutic option for some diseases beyond fighting GI infection. In one interesting experiment, fecal microbiota from adult female twins, one lean, the other obese, were transplanted into germ-free mice (ref 6). The obesity phenotype was transferred to the lean mouse, similar to the opening story.

Looking to the future, the microbiome will be one of the most exciting platforms for providing new drug candidates and also new treatment modalities such as manipulation of the microbiome.

References:

  1. Open Forum Infect Dis (Winter 2015), BRIEF REPORTS: Editor’s Choice: Weight Gain After Fecal Microbiota Transplantation, Alang, N and Kelly CR.
  1. CDC: http://www.cdc.gov/nchs/fastats/obesity-overweight.htm
  1. http://www.vedantabio.com/06-27-2013/
  1. Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):979-84. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Bäckhed F, Manchester JK, Semenkovich CF, Gordon JI.
  1. 2012 Aug 30;488(7413):621-6. Antibiotics in early life alter the murine colonic microbiome and adiposity. Cho I, Yamanishi S, Cox L, Methé BA, et al.
  1. Science  06 Sep 2013:Vol. 341, Issue 6150. Gut Microbiota from Twins Discordant for Obesity Modulate Metabolism in Mice. Riaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, et al.

To keep up on the latest research on obesity and microbiome (together and separately), visit ScienceDirect.

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