NEWS AND VIEWS
Human and microbe: united we stand Inna Sekirov & B Brett Finlay
Only about ten percent of the cells in our bodies are truly human: the vast majority are microbial. Almost all of these bacteria are unculturable1 but molecular methods can give us a good glimpse of this diverse community. Gill et al.2 have now examined the collective genomes—the ‘microbiome’—of the bacteria in the large intestine, where the vast majority of flora reside. They compared this collection to other microbial and human genomes, revealing that the human gut microbiome encodes numerous metabolic pathways important for normal human metabolism. The microbiome encodes a larger proportion of these pathways that are important for human life than the human genome itself. These findings highlight just how much we depend on our resident microbiota, and lay the groundwork for further exploring this relationship in health and disease. Colonization of the gastrointestinal tract with intestinal microbiota occurs immediately after birth and lasts a lifetime. The microbe ecosystem is very stable, but its structure is influenced by regional variations along the gastrointestinal tract, including pH, oxygen and nutrient availability. Factors, such as genotype, age, diet and health status, can also affect the microbial community3. At the gross level, the microbiota composition is very similar not only between human subjects, but also between different mammalian species, including mice4. However, at a more detailed level, the interpersonal and interspecies variations in the intestinal microbiota are considerably greater, perhaps representing an evolutionary adaptation of the host-microbe relationship5. The stability of this long-term relationship implies that it is symbiotic in nature. Indeed, germ-free rodents have impaired gastrointestinal and immune functions6–8. Although the specifics of this mutualism are poorly understood, Bacteroides thetaiotaomicron, a prominent member of the colonic
The authors are in the Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z4. e-mail:
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community, provides an excellent example of a symbiont. B. thetaiotaomicron is highly efficient in glycan metabolism, allowing the host to harvest additional energy from otherwise indigestible sugars such as galactose and mannose9.
Gill et al. analyzed the microbial composition of fecal samples of two healthy adult human subjects, one male and one female. Random DNA libraries were created for each of the subjects, and the species composition of the DNA libraries was determined by comparison to
a Healthy host • Balance of intestinal mucosa • Normal function of connected organ systems
Inflammation Infection Toxicosis, etc.
Host GI system Microbiota
Antibiotics Chemotherapy etc.
Toxin degradation Micronutrient synthesis Glycan and amino acid metabolism (Balanced)
b Antinflammatories Fluids Electrolytes
Probiotics Prebiotics
Sick host • Disruption of homeostasis at intestinal mucosa • Effects on other organ systems
Toxin degradation Micronutrient synthesis Glycan and amino acid metabolism (Imbalanced)
Kim Caesar
© 2006 Nature Publishing Group http://www.nature.com/naturemedicine
A metagenomic analysis of the microbes in the human gut reveals their diversity and just how interdependent we are on them. Together with our microbes we are a human-bacterial superorganism with immense metabolic diversity and capacity.
Figure 1 Intestinal homeostasis: a human-microbe balancing act. (a) Gill et al. demonstrate that humans are superorganisms whose metabolism represents a fusion of host and bacterial attributes. In a healthy person, both the human genome and the microbiome contribute to a variety of metabolic pathways indicated by arrows. The arrow thickness represents relative enrichment of the specified metabolic pathways in the human genome and its collective distal gut microbiome. (b) A new model stems from the findings of Gill and colleagues, supported by other experimental data in the field. An assault on either the host or its microbiota will lead to a disruption in the intestinal ecosystem and an imbalance in the metabolic processes that are jointly supported by the host and its resident bacteria. Treatment targeting the host or the microbiota or both will in turn lead to the restoration of the hostbacterial balance and a return to a healthy state.
VOLUME 12 | NUMBER 7 | JULY 2006 NATURE MEDICINE
microbial genome databases. The proportion of the various microbial species was inferred from the relative abundance of DNA. The analysis showed that, similar to other studies, only two major bacterial divisions and one archaeal member were represented in the samples. After analyzing the fecal microbial community, the authors scanned the DNA libraries for the sequences of enzymes that participate in known metabolic pathways. In previous analyses, the scanned enzyme sequences were only compared to other microbial genomes. Gill and colleagues, however, compared the enzyme sequences to the human (that is, the host) genome. Compared to the human genome, the microbiome was highly enriched in metabolic pathways that facilitate degradation of plant polysaccharides, synthesize short-chain fatty acids (such as butyryl–coenzyme A, a principal energy source for colonocytes), remove toxic products of bacterial fermentation and xenobiotic compounds, and synthesize vitamin and isoprenoid precursors (Fig. 1a). As expected, statistically significant intersubject variability was found, as flora varies between individuals. Taken together, these findings emphasize the important contributions the gut microbiome makes to our existence. The microbiome affects host metabolism by enhancing energy production and maximizing the energy value in food, contributes to biosynthetic pathways and promotes host homeostasis, and decontaminates the intestine, thereby minimizing exposure to toxic substances that could result in malignan-
cies or other problems. Symbiosis with resident bacteria endows us with a colossal metabolic diversity and capacity. This study supports the theory that we are in fact ‘superorganisms’ whose metabolism integrates microbial and human features. To further elucidate the details of this composite ‘supermetabolism’, deeper sequencing analysis of additional subjects will need to be performed. The experimental approach taken by the authors can now be used to answer several key questions about the function of microbiota in health and disease. Microbiota has been implicated in various disease states, such as obesity10, inflammatory bowel disease11, cardiovascular disease12 and late-onset autism13. Animal models and metagenomic comparisons such as this one will help flesh out the details. They will also aid in understanding how an imbalance in the carefully calibrated microbial community could lead to disease or be disrupted by it. As we learn more about the interdependence on our resident bacteria, new therapeutic avenues may come into sight. Drug development efforts could be directed toward discovery of high-tech prebiotics with narrow and specific target ranges, and advances in bacterial isolation and culturing techniques could allow creation of probiotic cocktails suited for individual diseases and disorders. Additionally, individual differences in microbiota composition—such as that between the two subjects in this study— could be evaluated using the metagenomic comparison, and used to fine-tune dietary
recommendations and therapeutic regimens. Individualized medicine will only become truly individualized when all aspects of an individual, human and bacterial alike, can be considered. A potential model is emerging, in which a disruption in the microbiome results in a functional imbalance, contributing to a pathological state (Fig. 1b). Treatments such as drugs, changes in diet or re-seeding efforts could facilitate a return to the steady state between the human body and resident microbiota, thereby restoring the functions of supermetabolism. We are just beginning to realize the implications of being a superorganism, and the benefits of better knowing our intestinal inhabitants. 1. Eckburg, P.B. et al. Science 308, 1635–1638 (2005). 2. Gill, S.R. et al. Science 312, 1355–1359 (2006). 3. Lupp, C. & Finlay, B.B. Curr. Biol. 15, R235–R236 (2005). 4. Ley, R.E., Peterson, D. & Gordon, J.I. Cell 124, 837– 848 (2006). 5. Backhed, F. et al. Science 307, 1915–1920 (2005). 6. Alam, M., Midtvedt, T. & Uribe, A. Scand. J. Gastroenterol. 29, 445–451 (1994). 7. Gustafsson, B.E., Midtvedt, T. & Strandberg, K. Scand. J. Gastroenterol. 5, 309–314 (1970). 8. Husebye, E., Hellstrom, P.M. & Midtvedt, T. Dig. Dis. Sci. 39, 946–956 (1994). 9. Sonnenburg, J.L. et al. Science 307, 1955–1959 (2005). 10. Ley, R.E. et al. Proc. Natl. Acad. Sci. USA 102, 11070– 11075 (2005). 11. Guarner, F. & Malagelada, J. Lancet 361, 512–519 (2003). 12. Ordovas, J.M. & Mooser, V. Curr. Opin. Lipidol. 17, 157–161 (2006). 13. Song, Y., Liu,C. & Finegold, S.M. Appl. Environ. Microbiol. 70, 6459–6465 (2004).
Microbes plump up mice Interactions among the microbes in our gut could contribute to obesity, suggest findings by Buck Samuel and Jeffrey Gordon (Proc. Natl. Acad. Sci. USA 103, 10011– 10016). Gordon and his colleagues had previously found that germ-free mice gained fat after they were inoculated with a suite of gut microbes. To ask why, the researchers inoculated germ-free mice with only a few species. These included two common inhabitants of the human large intestine, the polysaccharide-munching bacterium Bacteroides thetaiotaomicron (shown here) and the archaeal species Methanobrevibacter smithii. Mice inoculated with both species did not gain weight—but they got 50 percent fatter. They also had 100–1,000-fold more microbes in their gut than mice inoculated with either microbe alone. Clearly, the microbes were somehow interacting. The researchers found that M. smithii influenced the metabolism of B. thetaiotaomicron, prompting it to consume mainly fructose-containing polysaccharides that break down into several substances, including formate—the preferred food of M. smithii. Exactly why the mice get fatter is unclear. But the findings suggest that the collaboration between the microbes increases the efficiency of polysaccharide metabolism— increasing the yields of short-chain fatty acids such as acetate, which are used by the mouse to stimulate fat production and storage. The authors say that differences in our gut microbial communities may affect our predisposition to obesity. For some people, a diet rich in certain polysaccharides, such as fructose-containing sweeteners, could expand the waistline.
Charlotte Schubert
NATURE MEDICINE VOLUME 12 | NUMBER 7 | JULY 2006
Justin Sonnenburg, Jaime Dant, Jeffrey Gordon; AAAS
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