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Changes in Intestinal Microflora in Obesity: Cause or Consequence?

Bäckhed, Fredrik

Journal of Pediatric Gastroenterology and Nutrition: April 2009 - Volume 48 - Issue - p S56–S57
doi: 10.1097/MPG.0b013e3181a11851
Original Articles

Obesity and the associated metabolic disorders, such as diabetes and metabolic syndrome, have become major public health issues worldwide. Obesity results from a positive energy balance and is associated with decreased microbial diversity in the human gut with lower levels of Bacteroidetes. However, whether changes in the gut microbiota are a cause or consequence in obesity remains to be definitively proven. Experiments using germ-free mice have begun to reveal some mechanisms by which the gut microbiota may affect the development of obesity.

Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden

Address correspondence and reprint requests to Fredrik Bäckhed, PhD, Wallenberg Laboratory, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden (e-mail:

The author reports no conflicts of interest.

The adult intestine contains approximately 100 trillion microbes—a number 10 times greater than the number of cells in the human body. The gut microbiota is established at birth and is modulated by a number of environmental factors both during infancy and later in life. The gut microbiota has coevolved with the host and provides us with metabolic features that are vital to human health, such as vitamin synthesis and xenobiotic metabolism (1). However, not all microbial functions are beneficial, and we recently proposed that the gut microbiota could act as an environmental factor that regulates obesity (2). However, it still remains to be shown whether gut microbial alterations early in life contribute to the development of obesity and metabolic diseases.

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The incidence of obesity has increased exponentially over the past 3 decades and cannot exclusively be explained by genetic factors. Could the gut microbial community contribute to the obesity epidemic? Although the majority of mouse gut species are unique, mouse and human microbiota are dominated by the same major groups of bacteria: Bacteroidetes and Firmicutes. Recent studies have shown that obese mice have dramatically higher levels of Firmicutes and lower levels of Bacteroidetes compared with their lean counterparts (3). Interestingly, a recent twin study showed that the gut microbiota of obese humans is characterized by phylum-level changes (eg, reduced levels of Bacteroidetes), reduced diversity, and an increased capacity to absorb energy from the diet (4). Kalliomaki et al (5) recently showed that decreased levels of bifidobacteria during infancy may predict overweight. Taken together, these results suggest that variations in the gut microbiota early in life may confer an increased risk of developing obesity later in life.

Altering the gut microbiota in genetically obese mice by adding antibiotics reduced body weight, improved fasting glycemia, and glucose tolerance, which suggest that the gut microbiota could be a novel target for treating metabolic diseases (6). Interestingly, the improved glycemic control could not simply be explained by decreased food intake or adiposity because pair-fed ob/ob mice were as glucose intolerant as the control ob/ob mice (7).

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We have demonstrated that conventionally raised mice have significantly more body fat than germ-free counterparts, and germ-free mice are protected from diet-induced obesity (2,8). These results further support the role of the gut microbiota in regulating obesity. Moreover, we identified an essential role of angiopoietin-like protein 4 (Angptl4, also known as fasting-induced adipose factor) in regulating peripheral metabolism (8). Colonization of germ-free mice with a normal gut microbiota rapidly suppresses the intestinal expression of Angptl4, which results in decreased fatty acid oxidation in muscle and increased triglyceride storage in adipose tissue. We confirmed an essential role for Angptl4 in mediating protection against diet-induced obesity in germ-free mice by rederiving Angptl4−/− mice as germ-free and feeding them a high-energy Western diet. We found that these germ-free Angptl4−/− mice gained as much weight as the conventionally raised mice. Thus, the gut microbiota regulates both energy harvest and peripheral metabolism via distinct mechanisms.

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To understand how the gut microbiota affects host physiology, we recently investigated how the gut microbiota regulates the metabolome and transcriptome in germ-free and conventionally raised mice. Metabolomic analysis revealed that the gut microbiota affects several important metabolic processes including energy metabolism, amino acid, and lipid metabolism. The serum metabolome was associated with increased hepatic transcription of genes involved in proteolysis, energy, and xenometabolism. Surprisingly, we detected increased levels of neurotransmitters in serum of conventionally raised animals, which suggests that the gut microbiota may affect animal behavior. Taken together, these results suggest that variations in an individual's gut microbiota may have profound effects on host metabolism and physiology and will be an important factor when considering personalized medicine.

The major areas of research are related to the following: how the gut microbiota is altered in obesity, what is known about perturbations of the gut microbiota early in life, and the underlying mechanisms that provide a link between gut microbiota, metabolism, and obesity.

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1. Bäckhed F, Ley RE, Sonnenburg JL, et al. Host-bacterial mutualism in the human intestine. Science 2005; 307:1915–1920.
2. Bäckhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A 2004; 101:15718–15723.
3. Ley RE, Bäckhed F, Turnbaugh PJ, et al. Obesity alters gut microbial ecology. Proc Natl Acad Sci USA 2005; 102:11070–11075.
4. Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut microbiome in obese and lean twins. Nature 2009; 457:480–484.
5. Kalliomaki M, Collado MC, Salminen S, et al. Early differences in fecal microbiota composition in children may predict overweight. Am J Clin Nutr 2008; 87:534–538.
6. Cani PD, Bibiloni R, Knauf C, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008; 57:1470–1481.
7. Membrez M, Blancher F, Jaquet M, et al. Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice. Faseb J 2008; 22:2416–2426.
8. Bäckhed F, Manchester JK, Semenkovich CF, et al. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci USA 2007; 104:979–984.

Gut microbiota; Obesity; Metabolism

© 2009 Lippincott Williams & Wilkins, Inc.