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.
ALTERED GUT MICROBIOTA IN OBESITY
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).
MICROBIAL REGULATION OF OBESITY
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.
MECHANISMS FOR MICROBIAL REGULATION OF HOST METABOLISM
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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