Escolar Documentos
Profissional Documentos
Cultura Documentos
era currently included in probiotic prepara- hyperoxaluria and its often accompanying tion can be unpredictable. As prebiotics have
tions. Most probiotic organisms are adapted calcium oxalate kidney stones (Fig. 2) (14). considerable therapeutic potential—and the
to live within fermented foods (such as yo- Prebiotics are compounds administered to human diet is, in essence, a mix of poorly un-
CREDIT: C. BICKEL/SCIENCE TRANSLATIONAL MEDICINE
gurt) and are temporary or low-abundance a microbial community to selectively stimu- derstood prebiotics—the molecular effects of
members of the gut community. Strains of late growth of a specific subset of microbes. these molecules on the gut community should
the two dominant intestinal phyla, Bacte- The study of prebiotic compounds has largely be explored in a way that promotes predict-
roidetes and Firmicutes, may prove to be been confined to purified plant polysaccha- ability by connecting prebiotic molecules to
more effective as probiotics at conferring rides (for example, inulin) that resist host di- the microbiotal gene products that metabo-
health benefits than the currently popular gestion and reach the distal gut. Enrichment lize them. In certain instances, it will be nec-
Lactobacillus species. Likewise, strains cho- of a specific prebiotic polysaccharide in one’s essary to also understand the bioactive small
sen for carrying out a specific function may diet may permit preferential expansion of a molecules that are produced as a function of
be useful as agents for personalized thera- microbial group that is well adapted to its use, prebiotic-stimulated secondary metabolism.
py. For example, Oxalobacter formigines, a but because patterns of prebiotic metabolism Prebiotics may benefit from the co-adminis-
resident gut species that degrades dietary by resident gut microbiota are not well under- tration of probiotics, and both prebiotic and
oxalates, is associated with protection from stood the outcomes of prebiotic administra- probiotic therapies would benefit from know-
O
inactive glucuronide of SN-38, a
A O O HO B
OH OH
OH
cancer chemotherapeutic drug, to
Short-chain fatty acids Lactic acid the active aglycone in the intestine,
Synthesis O Catabolism
Dietary O Primary causing severe diarrhea. Wallace et
metabolites O O metabolites
HO N O al. recently showed that inhibiting
n Oxalate the bacterial glycosidase responsible
N O
O H for this conversion prevents the re-
Vitamin K2 Tyrvalin generation of SN-38 from its gluc-
C O O
uronide in the intestine, decreasing
O
O O O
its toxicity (20). This result proves
OH OH OH the principle that using microbio-
OH H H
O
OH H
Conversion H
H ta-targeted drugs to achieve ends
HO
O
OH Conversion H
O
O O H OH H OH H OH
other than killing (21) or inhibiting
OH O
OH H HO
H HO
H
virulence (22) could be a fruitful ap-
OH
proach for altering human physiol-
Digoxin Digoxigenin Dihydrodigoxigenin
Inactive Active Inactive
ogy by changing gut-community
function.
Lastly, several recent studies
host factors. Because the microbiota reside For example, gut bacteria convert the prodrug ing robust interventions such as fecal bacte-
on exposed surfaces of the human body, they digoxin to the active product digoxigenin by riotherapy to eliminate Clostridium difficile
provide a wealth of previously unidentified glycoside hydrolysis (18). In ~10% of patients, from the gut community (27). After milder
drug targets that are easily accessed; indeed, digoxigenin is reduced by a gut species, Eu- perturbations, microbial communities can
gut bacteria routinely encounter orally ad- bacterium, to dihydrodigoxigenin, an inac- exhibit resilience—the property of returning
ministered drugs prior to absorption. This tive molecule, leading to as much as a twofold to the preexisting stable state—or they may
phenomenon is important for two reasons. reduction in the serum concentrations of di- settle in a distinct stable state (28). When such
First, promising lead compounds that target goxigenin (Fig. 2). Co-administration of the a state is reinforced through feedback from
the microbiota are less likely to suffer from antibiotic erythromycin decreases or elimi- the environment (for example, chronic in-
problems with absorption, metabolism, dis- nates the production of dihydrodigoxigenin flammation), the recalcitrance of the system
tribution, and excretion. Lipinski’s Rule of in these subjects (19). Gut bacterial glycoside may be formidable. Can principles of evolu-
Five, which establishes chemical guidelines hydrolysis is responsible for converting the tionary dynamics be exploited to target key
nodes in the population network? Will the molecules that trigger host signaling pathways microorganisms to treat and prevent disease?
landscape of host biology need to be simul- (for example, quorum-sensing molecules and Early efforts will likely involve engineered
taneously manipulated? Will therapies need ligands for Toll-like receptors, which function probiotics for treating serious diseases with
to be tailored to an individual’s genotype and in innate immunity). Undoubtedly, human- poor standard-of-care treatments. In addi-
microbiotype? Careful ecological study of associated microbes produce a wealth of yet- tion, the risk of unintended colonization may
how natural and unnatural perturbations af- to-be-discovered molecules for the specific need to be mitigated by engineering strains
fect community composition may be the best purpose of manipulating host biology. Co- that undergo a finite number of cell divisions
guide to discovering successful approaches opting such highly adapted signals to tune lo- or are auxotrophic for a co-administered me-
for predictable alteration of the human mi- cal or systemic immune responses could lead tabolite. General acceptance is likely to take a
crobiota composition. to a variety of applications, including decreas- long time; in the meantime, a key challenge
ing susceptibility to pathogens, improving the will be to profile natural gut residents and
ENDOWING THE COMMUNITY WITH efficacy of oral vaccination campaigns, and probiotics to find strains that already perform
NEW FUNCTIONS altering the trajectory of autoimmune condi- some of these functions.
As the focus of human microbiome research tions. Similarly, the gut microbiota may be a
shifts from “Who’s there?” to “What are unique lever by which host energy balance DIAGNOSING DISEASE AND
they doing?” the molecular details of host- can be tuned, either by exerting a direct in- DISEASE RISK
microbe and microbe-microbe interactions fluence on host metabolism or by changing Exploiting new knowledge about connections
are beginning to emerge. These basic science the efficiency of microbiota-facilitated caloric between the microbiota and human health
samples such as fecal matter or skin swabs, intestinal microbiota in the development of Type 1 diabe- P. De Jesus, B. P. Tu, L. Pache, C. Shih, A. Orth, G. Bonamy,
tes. Nature 455, 1109–1113 (2008). L. Miraglia, T. Ideker, A. García-Sastre, J. A. Young, P. Palese,
the bottleneck will be in the data analysis:
5. J. Penders, C. Thijs, P. A. van den Brandt, I. Kummeling, B. M. L. Shaw, S. K. Chanda, Human host factors required for
Can we identify how the abundances of key Snijders, F. Stelma, H. Adams, R. van Ree, E. E. Stobberingh, influenza virus replication. Nature 463, 813–817 (2010).
microbial gene products and metabolites cor- Gut microbiota composition and development of atopic 24. S. D. Allison, J. B. Martiny, Colloquium paper: Resistance, re-
relate with disease state and disease risk? The manifestations in infancy: The KOALA Birth Cohort Study. silience, and redundancy in microbial communities. Proc.
torrent of high-dimensional data is creating Gut 56, 661–667 (2007). Natl. Acad. Sci. U.S.A. 105 (suppl. 1), 11512–11519 (2008).
6. D. N. Frank, A. L. St Amand, R. A. Feldman, E. C. Boedeker, 25. L. Dethlefsen, D. A. Relman, Incomplete recovery and indi-
important challenges and opportunities for N. Harpaz, N. R. Pace, Molecular-phylogenetic character- vidualized responses of the human distal gut microbiota
bioinformaticians, statisticians, and compu- ization of microbial community imbalances in human in- to repeated antibiotic perturbation. Proc. Natl. Acad. Sci.
tational biologists. flammatory bowel diseases. Proc. Natl. Acad. Sci. U.S.A. 104, U.S.A. 108 (suppl. 1), 4554–4561 (2011).
13780–13785 (2007). 26. A. Camilli, B. L. Bassler, Bacterial small-molecule signaling
7. L. Dethlefsen, M. McFall-Ngai, D. A. Relman, An ecological pathways. Science 311, 1113–1116 (2006).
AN EVOLUTIONARY CONTEXT
and evolutionary perspective on human-microbe mutual- 27. A. Khoruts, J. Dicksved, J. K. Jansson, M. J. Sadowsky,
Although human biology is largely the ism and disease. Nature 449, 811–818 (2007). Changes in the composition of the human fecal microbi-
product of mutation and natural selection 8. W. S. Garrett, G. M. Lord, S. Punit, G. Lugo-Villarino, S. K. ome after bacteriotherapy for recurrent Clostridium diffi-
in the ancient past, the contemporary mi- Mazmanian, S. Ito, J. N. Glickman, L. H. Glimcher, Commu- cile-associated diarrhea. J. Clin. Gastroenterol. 44, 354–360
crobiome may deviate substantially from nicable ulcerative colitis induced by T-bet deficiency in the (2010).
innate immune system. Cell 131, 33–45 (2007). 28. L. Dethlefsen, S. Huse, M. L. Sogin, D. A. Relman, The perva-
that of its ancestors as a result of “unnatural” 9. M. Vijay-Kumar, J. D. Aitken, F. A. Carvalho, T. C. Cullender, S. sive effects of an antibiotic on the human gut microbiota,
modern influences. For example, antibiotic Mwangi, S. Srinivasan, S. V. Sitaraman, R. Knight, R. E. Ley, A. as revealed by deep 16S rRNA sequencing. PLoS Biol. 6,
treatment can radically influence the human T. Gewirtz, Metabolic syndrome and altered gut microbio- e280 (2008).