Research ArticleGenetics and Diet

The Effect of Diet on the Human Gut Microbiome: A Metagenomic Analysis in Humanized Gnotobiotic Mice

Science Translational Medicine  11 Nov 2009:
Vol. 1, Issue 6, pp. 6ra14
DOI: 10.1126/scitranslmed.3000322

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Are You a Man or a Mouse? Answer: Both

Comedian Bill Maher targets obese people with his satire almost as often as he does politicians. But clinical obesity is no joke. The World Health Organization estimates the number of obese people worldwide to be 300 million. Add to that the fact that obesity increases one’s risk for a whole stable of serious illnesses—type II diabetes, stroke, and some cancers—and you have one large global disease burden. Scientists and sociologists cite several hypotheses regarding the causes of the obesity epidemic, such as minimal physical exercise, high-fructose corn syrup, and diets of low-cost, large-portion, fat-filled foods. But pinpointing obesity triggers in humans is hard because of uncontrollable genetic, cultural, and environmental variables. Recently, researchers have thrown another element into the mix: the human gut microbiota.

A massive number of microbes make the human gut their home. Highly diverse and numbering in the tens of trillions, our microbial companions help shape our human physiology, including effects on metabolism. The extent of their influence is now the subject of intense study in large part because high-capacity, moderately priced DNA sequencing has allowed our microbial communities and their collections of genes (“the microbiome”) to be characterized without having to culture the component organisms. However, this is a challenging business: Studying the factors that shape the assembly and operations of these communities is difficult to do in humans, given our varied genotypes, our difficult-to-document choices of what we eat, and our different environmental exposures.

Enter Turnbaugh et al., who add a new tool to the toolbox of translational medicine: mice that only harbor human-derived microbes and that can be reared under conditions where potentially confounding variables encountered in human studies can be controlled. To recreate a model human gut ecosystem, they transplanted human fecal matter into germ-free mice. They show that the transplant was remarkably successful: Recipient animals carried a collection of bacteria that mimicked the human donor’s microbiota. Moreover, the transplanted community could be transmitted from generation to generation of gnotobiotic mice. When these humanized animals were switched from a low-fat, plant-rich diet to a high-fat, high-sugar diet, the microbiota was changed after only 1 day on the junk-food binge. The authors were able to measure microbiome gene content and expression to further understand how the community responded to this diet shift. Like their Homo sapiens counterparts, Western diet–fed humanized mice become obese. Remarkably, this increased adiposity phenotype can be transmitted to other mice, at least for a time, by transplanting their gut microbiota to germ-free recipients.

Human microbiome investigators are seeking to extend their descriptive studies. The humanized mice described by Turnbaugh et al. now provide a well-controlled system not only for assaying the functional properties of gut communities harvested from humans with different phenotypes, but also for conducting proof-of-principle “clinical” trials to show how a “host” of factors, including our diets, may influence our microbiota and how in turn our microbiota shapes our health and disease predispositions.