Do You Have the Right Guts? Obesity and the Gut Microbiome

| January 1, 2015

This column is written by medical students and is dedicated to reviewing the science behind obesity and bariatric surgery.

Column Editor: Daniel B. Jones, MD, MS, FACS
Professor of Surgery, Harvard Medical School, Vice Chair, Beth Israel Deaconess Medical Center, Boston, Massachusetts

This month: Do You Have the Right Guts? Obesity and the Gut Microbiome
by Wendy W. Liu, PhD, Medical Student, Harvard Medical School, Boston, Massachusetts

Bariatric Times. 2015;12(1):21–22.


The Gut Microbiome
Although we may be unaware, all of us are colonized by microorganisms both inside and out. There are around 1.5kg of bacteria in our gut, and many more that cover our skin. In fact, 90 percent of cells in our body are microbial cells.[1] It has been increasingly recognized that the gut microbiome can have an important contribution to health and disease. Gut bacteria produce molecules that enter the bloodstream via the enterohepatic circulation or through damaged gut mucosa. Some bacteria are beneficial, producing anti-inflammatory factors, analgesic compounds, antioxidants, and vitamins. Conversely, other bacteria create toxins that can damage DNA and affect the nervous and immune systems.[2]

The Link to Obesity
Gut bacteria can also have a profound effect on energy extraction and metabolism, and has been associated with diseases such as type 2 diabetes mellitus (T2DM) and obesity.[3,4] Initial studies comparing the distal gut microbiota of genetically obese mice to that of lean wild-type mice revealed that obesity is associated with the relative abundance of the two dominant bacterial divisions: the Firmicutes and the Bacteroidetes. Obese mice had more Firmicutes and fewer Bacteroidetes.[5] Subsequent metagenomic and biochemical analyses showed that this “obese microbiota” has a greater capacity to harvest energy from the diet. The structure of the gut microbiota can be rapidly altered by diet. Diets high in fat and sugar favor the growth of bacteria that contribute to increased adiposity.[6–8] This trait can, moreover, be transmitted. When germ-free mice are colonized with microbes from obese donors, they have significantly more body fat than when colonized with microbes from lean donors, despite equivalent food intake.[9] Studies in humans have also confirmed that decreased abundance of Bacteroidetes relative to Firmicutes in individuals with obesity. This proportion increases with weight loss on two types of low calorie diets.[10] These results suggest that the composition of gut microbiota can contribute to the pathogenesis of obesity, and that manipulation of gut microbiota could be a potential approach in the treatment of obesity.

Microbial Gene Richness
More recently, the cataloguing of microbial genes from the human gut has enabled analysis at the gene and species level of how the gut microbiome correlates with obesity.[11] Obesity was found to be correlated with the number of gut microbial genes in the microbiome, or microbial gene richness. Individuals with low gene richness had a higher level of body fat and inflammation-associated characteristics compared to those with high gene richness, suggesting a higher risk of metabolic diseases. Furthermore, individuals with obesity with lower gene richness tended to gain more body weight, indicating the presence of inflammation-associated microbiota.[12] Interestingly, dietary intervention improved microbial gene richness and systemic metabolic status but seems to be less efficient for reducing inflammation in individuals with lower gene richness.[13] Hence, microbial gene richness may help stratify individuals into different metabolic risk profiles, and predict the efficacy of intervention.

Changes in Gut Microbiota after Gastric Bypass
Roux-en-Y gastric bypass (RYGB) is the current gold standard for treatment of severe obesity, resulting in a significant and sustained loss of around 70 percent of excess body weight and fat mass.[14] While its mechanism was initially thought to be restrictive and malabsorptive, recent data suggests that RYGB changes the physiology of energy metabolism in ways that can be independent of weight loss.[15] These include alterations in gut hormone profiles, improvement in glucose homeostasis, and increases in energy expenditure.[16–20] Studies in humans and rats have shown that RYGB causes marked alteration in the gut microbiota.[21–23] In a mouse model, RYGB caused a rapid and sustained increase in the relative abundance of Gammaproteobacteria and Verrucomicrobia that was independent of weight change and caloric restriction. Transfer of the gut microbiota from RYGB-treated mice to germ-free, nonoperated mice resulted in weight loss and decreased adiposity, suggesting that changes in gut microbiota contribute to regulation of host physiology and energy balance after RYGB.[24]

Summary
There is increasing evidence that the gut microbiota plays an important role in regulating energy balance and the development of obesity along with associated metabolic disorders. The gut microbiota differs in structure and gene content between obese and lean individuals and can be altered by dietary intervention. Microbial gene richness may be a potential marker to identify individuals at higher risk for metabolic disease. Weight loss and improved energy homeostasis after RYGB may be driven in part by changes in gut microbiota. Hence, targeted manipulation of gut microbiota could be a potential avenue for treating obesity. Further studies incorporating metagenomics and dissection of key metabolic pathways with translation to human subjects will expand our understanding of how to reshape the gut microbiome to promote health.

References
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2    Bäckhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism in the human intestine. Science. 2005;307(5717):1915–1920.
3    Bäckhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A. 2007;104(3):979–984. Epub 2007 Jan 8.
4    Cani PD, Amar J, Iglesias MA,et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56(7):1761–1772. Epub 2007 Apr 24.
5    Ley RE, Bäckhed F, Turnbaugh P, et al. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A. 2005;102(31):11070–11075. Epub 2005 Jul 20.
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9    Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444(7122):1027–1031.
10    Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444(7122):1022-–1023.
11    Human Microbiome Jumpstart Reference Strains Consortium, Nelson KE, Weinstock GM, et al. A catalog of reference genomes from the human microbiome. Science. 2010;328(5981):994–999.
12    Le Chatelier E, Nielsen T, Qin J, et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013;500(7464):541–546.
13    Cotillard A, Kennedy SP, Kong LC, et al. Dietary intervention impact on gut microbial gene richness. Nature. 2013;500(7464):585–588.
14    Hatoum IJ, Greenawalt DM, Cotsapas C, et al. Heritability of the weight loss response to gastric bypass surgery. J Clin Endocrinol Metab. 2011;96(10):E1630–E1633.
15    Ahn SM, Pomp A, Rubino, F. Metabolic surgery for type 2 diabetes. Ann N Y Acad Sci. 2010;1212:E37–E45.
16    Rubino F, Gagner M, Gentileschi P, et al. The early effect of the Roux-en-Y gastric bypass on hormones involved in body weight regulation and glucose metabolism. Ann Surg. 2004;240(2):236–242.
17    Thaler JP, Cummings DE. Minireview: Hormonal and metabolic mechanisms of diabetes remission after gastrointestinal surgery. Endocrinology. 2009;150(6):2518–2525.
18    Bueter M, Löwenstein C, Olbers T, et al. Gastric bypass increases energy expenditure in rats. Gastroenterology. 2010;138(5):1845–1853.
19    Nestoridi E, Kvas S, Kucharczyk J, Stylopoulos N. Resting energy expenditure and energetic cost of feeding are augmented after Roux-en-Y gastric bypass in obese mice. Endocrinology. 2012;153(5):2234–2244.
20    Stylopoulos N, Hoppin AG, Kaplan LM. Roux-en-Y gastric bypass enhances energy expenditure and extends lifespan in diet-induced obese rats. Obesity (Silver Spring). 2009;17(10):1839–1847.
21    Furet JP, Kong LC, Tap J, et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes. 2010;59(12):3049–3057.
22    Li JV, Ashrafian H, Bueter M, et al. Metabolic surgery profoundly influences gut microbial-host metabolic cross-talk. Gut. 2011;60(9):1214–1223.
23    Zhang H, DiBaise JK, Zuccolo A,et al. Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci U S A. 2009;106(7):2365–2370.
24    Liou AP, Paziuk M, Luevano JM Jr,et al. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Transl Med. 2013;5(178):178ra41.


FUNDING: No funding was provided for this article.

FINANCIAL DISCLOSURES: The author reports no conflicts of interest relevant to the content of this article.

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