Microbiology._Fighting_obesity_with_bacteria.1

https://www.wendangku.net/doc/8711858726.html, SCIENCE VOL 341 6 SEPTEMBER 2013

1069

Fighting Obesity with Bacteria

MICROBIOLOGY

Alan W. Walker and Julian Parkhill

Intestinal bacteria from lean humans can confer protection against fat gain in experimental mice.

T

he human large intestine harbors a complex community of microorgan-isms (microbiota) that affect many aspects of our physiology and health ( 1). Numerous lines of evidence, particularly from rodent models, have suggested that the intestinal microbiota may play a role in the development of obesity. On page 1079 of this issue, Ridaura et al . ( 2) demonstrate that the microbiota from lean or obese humans induces similar phenotypes in mice and, more remarkably, that the microbiota from lean donors can invade and reduce adiposity gain in the obese-recipient mice if the mice are fed an appropriate diet.

Ridaura et al . recruited four human female twin pairs discordant for obesity and transferred the intestinal microbiota in fecal samples from each of them into the intestines of germ-free mice. Animals receiving a trans-plant from the obese (Ob) twin donors devel-oped increased adiposity compared to those receiving transplants from lean (Ln) twin donors. Differences in mouse adiposity could also be reproduced after inoculation of germ-free mice with collections of cultured bacte-ria grown from twin-pair fecal samples. Co-housing of mice harboring cultured bacteria from an obese twin (Ob ch ) with mice harbor-ing cultured bacteria from a lean twin (Ln ch ) prevented the development of increased adi-posity in the Ob ch mice. This occurred in tan-dem with successful colonization of Ob ch intestines by bacteria from the Ln ch mice. By contrast, Ob ch microbes did not transmit to Ln ch mice, and these animals remained lean. This indicated that transmissibility of intesti-nal microbes and adiposity phenotype were tightly linked.

Analysis of the bacterial communities showed that members of the Bacteroidetes phylum, particularly Bacteroides spp., could pass from the Ln ch mice and colonize the Ob ch mice, suggesting that these bacteria were larg ely responsible for protection ag ainst increased adiposity. However, cohousing of Ob ch mice with lean mice inoculated with a relatively simple mix of just 39 de? ned bac-terial strains, including many of the Bacteroi-des species that were previously correlated

with reduced adiposity, did not reduce adi-posity in the Ob ch mice. This indicates that more complex bacterial interactions underlie protection against increased body mass and associated metabolic disturbance.Ridaura et al . also identi? ed diet as an important factor in the transmission of micro-biota and associated host phenotype. Lean twin–derived bacterial strains effectively colonized and ameliorated excess adiposity in Ob ch mice when the recipients were fed a low-fat, high-? ber diet. This was not the case when the mice were fed a diet that was high in saturated fat but low in ? ber.The finding s support some emerg ing

hypotheses regarding potential mechanisms by which the microbiota can affect host weight gain. One of the main activities of the intestinal microbiota is to break down and ferment dietary ? bers into short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate. The host absorbs these acids, and humans obtain perhaps 5 to 10% of daily energy requirements from them ( 3). Ridaura et al . show that the microbiota in Ln mice produces greater amounts of SCFAs, partic-ularly propionate and butyrate, and digests more of the plant ? ber present in the mouse’s

Obese twin

Lean twin

Microbiota transplant

Recipient mice

Increased adiposity

Lean

A

B

Low-fat,high-fiber diet

Low-fat,high-fiber diet

Low-fat, high-fiber diet

High-fat,low-fiber diet

Ine ffe cti ve mic i b rob i ot iot a tra nsm ss iss i ion o

Ine ffe cti ve e mic rob iot a tra nsm iss ion

Please pass the microbiota. (A ) Germ-free mice inoculated with microbiota from obese or lean human twins take on the microbiota characteristics of the donor. Those receiving the obese microbiota (red outline) had an increase in adiposity, whereas those receiving the lean microbiota (blue outline) remained lean. (B ) If fed an appropriate diet, mice harboring the obese microbiota, when cohoused with mice harboring the lean microbiota, are invaded by the lean microbiota and do not develop increased adiposity (blue and red outline). By contrast, the obese microbiota does not effectively colonize mice harboring the lean microbiota, and these mice remain lean.

C R E

D I T : V . A L T O U N I A N /S C I

E N C E

Pathogen Genomics Group, Wellcome Trust Sanger Insti-tute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK. E-mail: parkhill@https://www.wendangku.net/doc/8711858726.html,

Published by AAAS

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6 SEPTEMBER 2013 VOL 341 SCIENCE https://www.wendangku.net/doc/8711858726.html,

1070PERSPECTIVES

Reducing Earthquake Risk

GEOPHYSICS

Brian E. Tucker

How can a higher level of earthquake prepared-ness be achieved, particularly in developing nations?

diet than the microbiota of Ob mice. Thus, increased weight gain in Ob mice does not result from increased energy harvest. Rather, the ? nding supports previous studies showing that although SCFAs are a source of energy, they promote leanness by inhibiting fat accu-mulation in adipose tissue, raising energy expenditure, and enhancing production of hormones associated with feelings of satiety ( 4– 6). Other putative mechanisms include a role for the microbiota in metabolizing bile acids, branched-chain amino acids, and acyl-carnitines, which have all been linked to either insulin resistance or obesity in humans and mice.

A key question is the translatability of the ? ndings to a human clinical context. Bacte-roides species, correlated with reduced adi-posity by Ridaura et al., have repeatedly been implicated in protection against obesity in mice ( 7). However, evidence from human studies is mixed ( 8). Indeed, Bacteroides , and the propionate that they produce, can be more abundant in overweight and obese indi-viduals than in lean counterparts ( 9). Further-more, Bacteroides have been associated with diets high in animal protein and saturated fats ( 10) and are notably reduced in lean African

individuals consuming diets high in fiber

compared to Europeans consuming typical Western diets ( 11). Given these potential dis-crepancies, it will be important to verify in humans the activity of bacteria that are ben-e? cial in mouse models.

Perhaps the most intriguing finding of Ridaura et al . is that microbial protection from increased adiposity is only possible against the backdrop of a suitable host diet. It may be that future microbiota-based thera-pies for an obese individual will require an alteration in diet to aid colonization by ben-e? cial microbes. This offers a potentially syn-ergistic approach, whereby reduced caloric intake and increased ? ber consumption not only have a positive impact on energy bal-ance but might also promote transplanted microbial communities that are associated with leanness.

Fecal transplants in humans have been used to bene? cially alter the microbiota in a variety of ailments ( 12). Notably, a recent study showed that fecal transplants from lean individuals into obese counterparts improved insulin sensitivity in some obese recipients ( 13). The procedure is not risk free, however, with the potential for introducing pathogens

to the recipient. The mouse model presented by Ridaura et al . is therefore timely, as it offers the potential to test human-derived bacterial strains, and accompanying dietary regimens, within a controlled mammalian host environment. The study is a step toward the ultimate goal of developing relatively simple mixtures of bacteria for testing as anti-obesity therapeutics.

References

1. A. W. Walker, T. D. Lawley, Pharmacol. Res. 69, 75

(2013).

2. V. K. Ridaura et al ., Science 341, 1241214 (2013);

DOI: 10.1126/science.1241214.

3. L. V. Hooper, T. Midtvedt, J. I. Gordon, Annu. Rev. Nutr.

22, 283 (2002).

4. I. Kimura et al ., Nat. Commun. 4, 1829 (2013).

5. Z. Gao et al ., Diabetes 58, 1509 (2009).

6. M. J. Keenan et al ., Obesity (Silver Spring) 14, 1523

(2006).

7. P. J. Turnbaugh et al ., Nature 444, 1027 (2006). 8. S. H. Duncan et al ., Int. J. Obes. 32, 1720 (2008). 9. A. Schwiertz et al ., Obesity (Silver Spring) 18, 190

(2010).

10. G. D. Wu et al ., Science 334, 105 (2011).

11. C. De Filippo et al ., Proc. Natl. Acad. Sci. U.S.A. 107,

14691 (2010).

12. E. van Nood et al ., N. Engl. J. Med. 368, 407 (2013). 13. A. Vrieze et al ., Gastroenterology 143, 913, e7 (2012).

10.1126/science.1243787

T

he preceding Perspectives in this series ( 1– 4) provide snapshots of the earthquake and tsunami risks, haz-ard monitoring and risk mitigation activities,

considerable progress in reducing losses due to earthquakes and tsunamis in some places but of growing and evolving risks in others.In the past two decades, the prevailing approach to reducing the consequences of earthquakes and tsunamis has emphasized raising awareness of these hazards, promot-ing methods of reducing their associated risk,

and incorporating the results of Earth science and earthquake engineering research into post-earthquake reconstruction. The United Nations (UN) International Strategies for

Disaster Reduction serves as a platform to coordinate these efforts and, through its Hyogo Frame-work for Action, has declared the goal “to substantially reduce disaster losses by

2015 by building the resilience of nations and communities to disasters” ( 5).

Despite these diverse and sustained efforts, human and economic losses due to earthquakes are increasing and are projected to continue to rise in the future ( 6, 7). The past decade (2001 to 2012) saw more than three times as many earthquake-related deaths as the preceding two decades (1981 to 2000) ( 8). These losses are increasingly con-centrated in developing countries because of

differences in urban population growth (see

the ? gure) and the quality of seismic-resis-tant construction ( 9– 11). Why is progress so frustratingly slow?

The Importance of Being Prepared

One reason is that historically, far fewer resources have been invested in pre-earth-quake preparedness and risk reduction than in post-earthquake response, reconstruction, and recovery; this is particularly true in devel-oping countries. One study ( 12) suggests that of all international aid for humanitarian assis-tance, less than 10% is directed to disaster pre-vention; a more recent study ( 13) estimates that this ? gure is only 1%. Post-disaster activ-ities are important and reliably garner gener-ous support among individuals, governments, and nonpro? t organizations, appealing to the human impulse to help those in need. Yet a comparison of the consequences of recent earthquakes in developing countries, where preparedness is rare, and industrialized coun-tries, where it is much more common, sug-

GeoHazards International, 687 Bay Road, Menlo Park, CA 94025, USA. E-mail: tucker@https://www.wendangku.net/doc/8711858726.html, Published by AAAS

DOI: 10.1126/science.1243787

, 1069 (2013);

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