PerspectiveObesity

Gut Check: Testing a Role for the Intestinal Microbiome in Human Obesity

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Science Translational Medicine  11 Nov 2009:
Vol. 1, Issue 6, pp. 6ps7
DOI: 10.1126/scitranslmed.3000483

Abstract

By using germ-free mice transplanted with human fecal microbiota, scientists show that a high-fat, high-sugar diet durably changes the transplanted microbiome and that this diet-altered microbiome promotes obesity. This model should encourage investigation of the gut microbiome as a contributor to human metabolic disease and permit discovery of targets for the prevention and treatment of these disorders.

The prevalence of obesity in humans is on the rise, with adverse consequences for human health. This situation has stimulated intensive research into pathogenesis and potential therapies. Obesity results when energy intake chronically exceeds energy expenditure, and much has been learned about the complex and interlocking physiological circuits that underlie regulation of systemic energy balance (1, 2). These circuits include systems for sensing energy stores and needs, regulating and mediating ingestive behavior, digesting and assimilating nutrients, and regulating energy expenditure. Genetic factors, many of which affect the aforementioned circuits, play an important role in obesity risk (3), but environmental influences, including changes in food availability, diet content, and physical activity, are viewed as being responsible for the increased prevalence of obesity over the past several decades. In recent years, a completely new dimension for regulating energy balance has emerged: a role for the gut microbiome (4). In fact, this “dimension” resides somewhere between the human genome and the environment (Fig. 1). Although the gut microbiome is derived from the environment and is distinct from the genome within our own cells, it has clearly coevolved with our own genomes (5) in a manner quite distinct from all other environmental influences. The paper by Turnbaugh et al. in this issue of Science Translational Medicine (6) substantially adds to our appreciation of this dimension and presents a new way to apply meta‐genomics (7)—the study of genomes isolated from environmental sources—to the gut microbiome, with the goal of identifying novel therapies for obesity.

Fig. 1 Rules of engagement.

The diagram depicts the relationships among the human genome, the conventional environment, and the gut microbiome.

CREDIT: C. BICKEL/SCIENCE

The microbiota within the gut can realistically be viewed as a microbial metabolic organ of sorts, composed of trillions of largely anaerobic bacteria that coevolved with our own physiology. This organ provides valuable functions to its host, including the capacity to modify the immune system, degrade and promote the absorption of dietary components that would otherwise be undigestible, and presumably mediate other physiological functions that are currently unknown (8). The 500 to 1000 bacterial species estimated to reside in the human colon, many of which cannot be cultured, have combined genomes perhaps 100 times larger than our own, providing enormous capacity for biological innovation (9).

One simple approach to understanding the contributions of the gut microbiome is to examine germ-free mice. Indeed, these mice are not fully healthy. They have defective development of their immune systems and are resistant to obesity induced by high-fat and high-sugar diets, a change that is independent of food intake (8, 10). The mechanism underlying obesity resistance absent a gut flora involves reduced caloric harvest of ingested plant polysaccharides, as well as the less intuitively obvious mechanism of altered expression of host genes that influence energy oxidation and storage (8, 10). Reintroduction of microbiota into the germ-free mice increases fat mass and restores sensitivity to diet-induced obesity (8, 10). These and other data suggest that the gut microbiota is an important internal “environmental” variable in the regulation of energy balance, acting through multiple physiological mechanisms.

Many factors make the microbiome a difficult area of study. These include the complexity of the relevant microbial communities and technical difficulties in characterizing them. Next-generation DNA sequencing methods now allow such populations to be characterized at the meta‐genomic level in a culture-independent manner (9). When such analytical approaches are coupled with germ-free mice into which selected microbes are reintroduced, the framework for a powerful experimental system becomes apparent. Turnbaugh et al. have exploited this heterologous host system ingeniously to explore the human gut microbiome (6).

What are the major conclusions of their study? First, Turnbaugh et al. show that human microbiota derived from fecal material can be transplanted into the guts of germ-free mice, where the microbes stably colonize recipients and, surprisingly, maintain their community complexity. This transplantation can be done with either fresh or frozen human fecal material, a result that will be extremely helpful for future studies. Second, when such stably “humanized” mice are exposed to a high-fat and high-sugar (“Western”) diet that promotes obesity in mice, a rapid change occurs in the population of resident organisms, along with a reproducible change in microbial gene expression patterns. Third, mice with a gut microbiome that is humanized by the fecal-transplantation method have increased body fat relative to mice that do not have the humanized gut microbiome. Remarkably, transplantation of microbiota from high-fat–fed humanized mice (as opposed to low-fat–fed humanized mice) into a new cohort of germ-free mice produced mice with increased fat mass even when they are fed low-fat diets. This result suggests that the microbiota from high-fat–fed humanized mice is, at least under these conditions, sufficient to induce obesity in a germ-free mouse.

These studies raise many important questions relevant to human obesity. First, are there specific human gut microbiomes that characterize or predispose individuals to the obese state? Limited studies using various techniques have begun to suggest that obese rodents and humans display a distinct microbiome relative to nonobese subjects, but data are preliminary and, so far, not fully consistent (4, 1114). Much more research is needed to clarify this important question. If microbiomes characteristic of obesity (versus leanness) are found, even in a subset of patients, they could be the result or a cause of obesity (or leanness). A causal role would, of course, be far more provocative, although obesity-dependent changes in the microbiome could also have important physiological or pathological consequences. The system described by Turnbaugh et al. makes it possible to test such hypotheses. If the human microbiota is capable of playing a causative role in obesity, it would be critical to identify the responsible mechanisms. Specific microbiota could enhance energy absorption or exert obesity-promoting effects on other host physiological pathways, such as those regulating appetite, energy expenditure, energy storage, inflammation, and neuromuscular activity (for example, intestinal mobility).

How might the gut microbiome influence host pathways? Prior studies in a mouse model suggested that the ability of the microbiome to influence energy balance is dependent on the capacity of the microbes to suppress expression of fiaf, a gut-derived circulating inhibitor of human lipoprotein lipase—a key regulatory enzyme that frees fatty acids from triglycerides in lipoprotein complexes so that they can be used or stored by organs. These two functions thus link the gut microbiome to the host’s capacity to accumulate lipid in specific tissues (8, 10). The mechanism for such microbial regulation of gut fiaf expression is as yet unknown. Many other such interactions between specific microbes and host physiology might exist. Whatever the details of these interactions, the existence of such collaborations suggests that it is possible to intervene against obesity by targeting specific microbial species or species-specific biochemical pathways required for or mediating the microbes’ effects on human physiology.

The model described by Turnbaugh et al., in which germ-free mice are colonized by human gut microbiota, can be explored with donor microbiota from individuals with distinct physiologies or before or after various nutritional, pharmacological, or even surgical therapies, such as gastric bypass. A recent study suggests that even brief antibiotic prophylaxis can produce a durable change in human gut microbiome lasting 6 months (15). It would be fascinating to explore in germ-free mice the “founder effects” of a microbiome derived from donors before and after antibiotic treatment. This type of experiment will be invaluable, both to characterize the resulting microbiota and to test their abilities to transfer a metabolic phenotype to transplanted mice. As mechanisms for the interrelationship between the microbiota and host metabolism are defined, one can imagine several levels of interventions that might be explored in this model (Fig. 2). For example, custom founder microbial consortia or mutants of particular bacterial species could be explored in this model as a way of defining the microbial genome content that is associated with obesity induced by the Western diet. Microbial group-, species-, or gene-specific linkages to changes in the metabolic phenotype might be definitively established in this way, setting the stage for human clinical trials of appropriate interventions.

Fig. 2 Define intervention.

The arrows indicate possible points of intervention between factors that influence interplay among the environment, the host, and the microbiome.

CREDIT: C. BICKEL/SCIENCE

One approach could involve searching for nutritional interventions to modify specific gut microbial species. Dietary components (prebiotics) might be found that alter growth of specific microbial species capable of affecting host physiology (16), and the Turnbaugh model can be used to pinpoint these elements and decipher the mechanisms of the host-microbe collaboration. Dietary ingestion of live microorganisms (probiotics) has been used to alter microbial gut flora with the intention of conferring favorable effects on the host (17). The germ-free mouse system could be used to explore the actions and efficacy of novel probiotics. From the microbial side of the problem, it seems likely that narrow-spectrum (indeed group-, genus-, or even species-specific) antibiotics hold obvious promise. In this regard, progress has also recently been made in understanding which bacterial genes are required by commensal microbes to establish themselves as normal flora in gnotobiotic mice (18). Thus, a proof of concept might emerge from these studies in the form of antibacterial drugs that target gene products required for commensal association of bacterial species, which in turn are implicated in adverse metabolic changes in the host. Lastly, the gut microbiota is a still largely untapped source of novel drugs or leads for future drug discovery (16, 17, 1921). Bacterial natural products include antibiotics and quorum-sensing autoinducers associated with intra- and interspecies microbial interactions as well as small and macromolecular ligands for receptors of the innate immune system (for example, pathogen-associated molecular patterns or PAMPs) (2225). The model described by Turnbaugh et al. (6) will provide a powerful means for the discovery of commensal (26) or microbiota-associated molecular patterns that may in turn provide a pharmacological basis for the influence of the microbiota on host physiology and even feeding behavior.

It is ironic and somewhat discouraging that the prevalence of obesity is increasing coincident with a period of knowledge explosion surrounding the genetics and systems biology of weight-regulatory pathways. This discordance between knowledge and disease burden should encourage scientists to seek entirely new avenues for understanding the causes of and discovering potential therapies for obesity. The gut microbiome seems poised to serve as such a promising new scientific platform. It is important, however, to keep this new knowledge in perspective. There are as yet no data indicating that the human gut microbiome, sitting at the interface of our own genes and the apparently toxic modern environment, is an important contributor to the obesity epidemic or a likely route to novel therapies. But the paper by Turnbaugh et al. (6) and other work in this field make it clear that gaining answers to key questions concerning the role of the microbiota in metabolic disease is now possible.

Footnotes

  • Citation: J. S. Flier, J. J. Mekalanos, Gut check: Testing a role for the intestinal microbiome in human obesity. Sci. Transl. Med. 1, 6ps7 (2009).

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