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glossary
Commensal relationship Nash equilibrium Pathogen
An intimate, although generally benign, relationship In game theory, a solution concept in which players in a In medicine, any organism that causes disease. In biological
between a resident microorganism and its host. Probably game are aware of the strategies of the other players but terms, a pathogen is a microorganism that has the inherent
the product of a long evolutionary interplay between the do not deviate from their own, because they do not have capacity to cross anatomical barriers and resist host
microorganism and the host. The relationship need not be anything to gain; it will be disadvantageous to deviate defences that ordinarily restrict most other microorganisms.
symbiotic. (to ‘cheat’).
Symbiont
Gene transfer Pan-genome An organism that has a biological relationship with one or
The transfer of individual genes or their components, islands The set of all of the genes that are found in members of a more organisms that leads to mutual benefit.
of genes, entire organisms, or communities of organisms single species.
from parent to offspring (vertical transfer) or between Syntrophic interactions
individuals not in a direct lineage (horizontal transfer). Parasite Interactions in which organisms do more together than alone.
An organism that diminishes the reproductive fitness of
Microbiome another organism or benefits from another organism Virulence
The collective genomes of the microorganisms that reside without reciprocity. A quantitative estimate of the ability of one organism to
in an environmental niche. harm another.
Table 1 | Changes in human ecology that might affect microbiota composition The ‘disappearing microbiota’ hypothesis
In general, it seems that the human micro-
change consequence biota and their hosts evolved their equilibria
clean water reduced faecal transmission together, in an orderly way10, as diet, geogra-
Increase in caesarean sections reduced vaginal transmission phy and occasional ecological disturbances
Increased use of pre-term antibiotics reduced vaginal transmission
had their effects on distinct, albeit diverse,
human genetic backgrounds43. Our complex
reduced breastfeeding reduced cutaneous transmission and a protective commensal microbiota facilitate
changed immunological environment
nutrient and vitamin acquisition, promote
smaller family size reduced early life transmission tissue development and integrity, and
Widespread antibiotic use selection for a changing composition stimulate multiple aspects of immunity 18–22.
Increased bathing, showering and use of antibacterial soaps selection for a changing composition However, in the face of modern global
ecological changes, has there been stability
Increased use of mercury-amalgam dental fillings selection for a changing composition
for the descendents of the microbiota that
colonized humans during the ~2 million
composition of the microbiota deliberately of opportunists, invaders and cheaters. In years that they lived in small groups as
or inadvertently. The use of molecular Koch’s steady state, the equilibria form a continuum, hunter–gatherers?
postulates30 may assist in this risk assessment. analogous to a Mobius strip, with no begin- As human health and longevity have
ning or end. This population structure per- improved in developed countries, new
How are the microbiota stabilized? mits the co-evolution of competing organisms diseases have arisen without obvious
Is there any underlying biological regulation (for example, host and microorganism) that explanation. The ‘disappearing microbiota’
that stabilizes the diverse microbial popula- would otherwise lead to an ‘arms race’39 and hypothesis44,45 has been advanced to explain
tions that we carry, even in the face of host the destruction of one organism or the other. the rise and fall of several common diseases
immunity, competing organisms and the daily However, even in such a derived evolutionar- in developed countries. beginning in the
continuous flux of newly introduced microor- ily stable strategy 40, all is not fixed. The equi- nineteenth century and accelerating in the
ganisms? Cooperation between competing life librium has sufficient elasticity for invasions twentieth century, there have been dra-
forms is a challenging concept and, although (by pathogens or ‘cheaters’) to be contained matic changes in human ecology (TABLE 1),
much of the literature on microorganisms under normal conditions of flux. However, including cleaner water, smaller families, an
focuses on the evolution of virulence31,32, there even with such capacitance, there must be increase in the number of Caesarian sections,
is an increasing focus on the rules that govern boundaries beyond which the systems lose increased use of pre-term antibiotics, lower
the evolution of cooperation33,34. equilibria and descend towards the extinction rates of breastfeeding and more than 60 years
In an earlier report, a hypothesis was of one partner or the other. of widespread antibiotic use, particularly
presented that Nash equilibria enable patho- In the human biosphere, the boundaries in young children. How have these changes
gens such as Mycobacterium tuberculosis and for flux are unknown. Even a catastrophe like affected the transmission and maintenance of
Salmonella enterica subsp. enterica serovar the AIds epidemic has so far been contained the indigenous microbiota44?
Typhi to persist35. such a view has also been within the overall population, in part because We postulate that the important factor
applied to Helicobacter pylori, the dominant of the inefficiencies of HIv transmission41. in modern allergic and metabolic diseases
member of the gastric microbiota16. In game However, scenarios involving more transmis- might not be our decreased sampling of the
theory, a nash equilibrium represents a sible agents in a ‘smaller world’ in which pop- microorganisms in food, air, water or soil, as
particular circumstance in which any player ulation connectivity selects for virulence and has been postulated by the ‘hygiene hypoth-
who deviates from the rules of the game is in the ecosystem has been perturbed are wor- esis’ (REF. 46), but instead could reflect the
an inferior position compared to those who risome42. This is directly germane to consid- loss of our ancestral microorganisms. As the
have played by the rules36,37. such conditions erations of the stability of the microbiota. On representation of particular species dimin-
can exist in a limited number of situations the basis of humanity’s long association with ishes in one generation, the potential for
in nature, and biological co-evolution is a our indigenous microorganisms and their vertical transmission to the next generation47
prime example. conservation4,10, the equilibria that maintain can decrease in a stepwise manner (FIG. 1).
For any equilibrium to function, there the composition of our microbiota should be diminished horizontal transmission result-
must be boundary conditions or limits and considered to be major pillars of our biologi- ing from changes in human ecology (TABLE 1)
strong penalties against transgressors that, in cal stability. seen from this view, pathogens makes it more difficult to overcome losses in
net, remove any advantage from ‘cheating’38. that arise are ‘cheaters’ that can break the vertical transmission, and this then manifests
This is characteristic of a nash equilibrium, equilibria. In principle, ‘cheaters’ can cause as a birth cohort phenomenon. We believe
but the complex evolved biology of metazo- the extinction of the microorganism, the host that alterations in human macroecology have
ans such as humans requires solutions that or even both, although in reality variants progressively affected the composition of our
operate on multiple scales. A series of nested usually emerge and equilibria ultimately rule. indigenous microbiota, which in turn has
dynamic equilibria was envisioned, in which For example, if the host-mediated penalties affected human physiology and, ultimately,
each stratum contributes to creating the against ‘cheating’ (such as host immunity to disease risk. The increases that have occurred
boundary conditions for the others35. This is the microorganism or the microorganism’s in recent years in the prevalence of condi-
made possible, in part, by the fractal nature of loss of a niche in the host) are sufficiently tions such as obesity and asthma, as well
biological communities, in which ecosystems high, then less virulent variants that can as oesophageal disorders that are a conse-
nest within one another, a structure that pro- evade biological surveillance can become quence of reflux, have been so rapid that an
vides both stability and resilience in a world successful. environmental cause must be present 48–50. Is
illustrate the concept that the loss of an indig- differ in H. pylori-positive and H. pylori-
Representation of a
75
enous microorganism will have consequences negative hosts72–74. This might be expected,
for the host. as the H. pylori-negative stomach has a
50 diminished presence of the cellular elements
Loss of H. pylori. H. pylori colonization of the immune system and reduced cytokine
and the response that it induces in the host traffic, whereas the H. pylori-positive stom-
25 affects the regulation of gastric hormones, ach has a rich population of immune cells
including gastrin and somatostatin58. As (FIG. 3). The enhanced T cell populations
0
such, H. pylori status affects gastric pH in H. pylori-positive hosts include greater
0 20 40 60 80 and its regulation55. Over the decades of proportions of particular T cell subsets,
Time (years) H. pylori colonization, the mass of gastric including cells expressing forkhead box pro-
Figure 1 | The effect of maternal status on the acid-secreting glands in the host progressively tein P3 (FOXP3), which regulate immune
resident microbiota of the next generation. We decreases, owing to the long-term effects functions73,74. The stomachs of H. pylori-
propose that, since the earliest days of the evolu- of inflammation58,59. Although the rates of negative hosts have much lower numbers
tion of mammals, thereNature
hasReviews | Microbiology
been major maternal glandular decrease reflect both host-specific of these cells, which have systemic, as well
transmission of microbiota to their offspring (verti-
and population-specific factors, overall there as local, activities. several epidemiologi-
cal transmission). However, loss of the conserved
is a progressive decrease in acid production60 cal studies (reviewed in REF. 75) show that
microbiota in one generation leads to its loss in the
next. For humans, until recently, horizontal micro- that is greater than the decrease observed in H. pylori-positive individuals (especially
bial transmission also occurred and could compen- H. pylori-negative hosts60,61. The increasing individuals carrying cag-positive strains)
sate for the loss of vertical transmission. Members gastric atrophy and hypochlorhydria that are have lower risks of childhood asthma, allergic
of the microbiota were horizontally transmitted associated with the presence of H. pylori 60–62 rhinitis and skin allergies than those without
through faecally contaminated drinking and bath- contribute to the risk of gastric cancer 63,64, H. pylori 56,76,77. The rise in childhood asthma
ing water, and high physical contact as a result of but the sustained acidity in H. pylori-negative and related disorders has occurred while
social crowding and large families; in many modern hosts increases the risk of gastroesophageal H. pylori has been disappearing; the loss of
societies, these routes have diminished. The pro- reflux disease (GErd) and its consequences, gastric T cell populations and their systemic
gressive loss of vertically transmitted microorgan-
including oesophageal and gastric cardia effects could provide a mechanism for these
isms without horizontal replacement represents a
adenocarcinomas64,65. allergic diseases78,79.
cumulative birth cohort phenomenon.
As H. pylori is disappearing from human
populations, reflecting both diminishing Subtherapeutic antibiotic treatment. In the
one of these causes the loss of one or more transmission and increasing antibiotic early 1950s, not long after the discovery of
constituents of the indigenous microbiota? treatment (TABLE 1), both ‘idiopathic’ peptic antibiotics, scientists found that feeding
H. pylori, an ancient member of the ulcer disease and gastric cancer rates are low doses of antibiotics (termed subthera-
human microbiota51, generally dominates diminishing 66,67, which is clearly salutary. peutic antibiotic treatment (sTAT)) to farm
the gastric niche (BOX 3). Accordingly, its However, oesophageal reflux, barrett’s animals increased their rate of growth
presence can be used as a means to assess oesophagus and adenocarcinoma are and ability to convert food into body mass
the status of our microbiota. surprisingly, increasing, which is clearly deleterious50,66. (otherwise known as their ‘feed efficiency’;
H. pylori has been progressively disappear- Are these reciprocal phenomena? The cag reviewed in REF. 80). The younger the ani-
ing 52–54 from individuals in developed coun- pathogenicity island55 (or perhaps a better mals are when sTAT is started, the stronger
tries (FIG. 2) during the twentieth century, term would be the cag ecological fitness the effect 80. The fact that several antibiotics
with secondary alterations in gastric secre- island68) status of the H. pylori population can produce this effect in poultry, cattle and
tory, hormonal and immune physiology 55,56. has a strong influence on the development swine80–82 has led to the widespread usage
These alterations have been associated of barrett’s oesophagus and adenocarci- of antibiotics as animal feed supplements in
with a progressively declining incidence of noma, as predicted by the strong interac- the united states and other developed coun-
important illnesses with long latent periods, tion between cag-positive strains and host tries (this practice has now been banned by
such as gastric cancer. We now have multiple cells60,63,69,70. The stomach also produces the European union because of the spread
tools to detect H. pylori 57. but if a lesser the hormones ghrelin and leptin, both of of antibiotic-resistant bacteria).
known ancestral indigenous microorganism which have multiple roles in energy home- Why does giving sTAT change energy
disappeared in the colon, mouth, skin or ostasis55. Patients in whom antibiotic treat- homeostasis in this broad group of verte-
vagina, could we identify that change and, ment eliminates H. pylori have increased brates? As growth promotion can be induced
crucially, could such a change (whether it circulating ghrelin levels71. Investigations by many different antibacterial (but not
was a loss or a replacement and subsequent are ongoing, but it is already clear that in antifungal) agents, this activity is not a side
‘overgrowth’ by a different indigenous com- recent generations of children growing up in effect but a consequence of the antibacterial
ponent) contribute to some of the diseases developed countries there has been little gas- activities of these agents, which presum-
that are becoming more prevalent? The tric H. pylori-mediated56 regulation of these ably affect the microbiota of the exposed
Human Microbiome Project6 should begin adipokines at the developmental stage, when animals82. However, the affected microbial
to address such questions (BOX 1). long-term adiposity is being programmed. populations and metabolic pathways are
a Males b Females
70 70
1925
H. pylori prevalence
50 50
1995 1995
0 0
70–79 60–69 50–59 40–49 30–39 20–29 10–19 <10 70–79 60–69 50–59 40–49 30–39 20–29 10–19 <10
Age (years) Age (years)
Figure 2 | Helicobacter pylori prevalence in the United States by age effect52–54 in which H. pylori acquisition, and thus prevalence, has been
and year of birth. Helicobacter pylori prevalence in males (a) and females declining in industrialized countries for >100 years. The numbers next
(b) was determined in two large national studies (the National Health and to each point represent the midpoint Nature
yearReviews | Microbiology
of birth for each group of
Nutrition survey (NHANEs) III and NHANEs Iv), which were conducted survey subjects (with each group covering one decade of births).
in 1988–1991 and 1999–2000, respectively. These data, involving 15,000 Image is modified, with permission, from REF. 56 © (2008) University of
subjects, are consistent with a now well-recognized birth cohort chicago Press.
organisms that are acquired during ongoing through the dairy section of any super- than the role of single microorganisms, espe-
environmental exposure. The transmis- market in the Western world would lead cially for the development of new approaches
sion potential will determine whether the one to believe so. nonetheless, translating for maintaining or restoring health. Thus,
replacement organisms will be host-specific this marketing concept into scientifically under some circumstances, restoration of
populations or emergent, highly selected based beneficial activities is limited by sev- communities might be more appropriate than
organisms that are common between hosts. eral outstanding questions. These include: replacing single microorganisms.
A potential consequence of the third sce- which particular microorganisms should
nario is the emergence of a highly transmis- be replaced; what will their sources be; Conclusions
sible microorganism that is well-adapted for and what will the timing of their replace- It is predictable that social and medical
the now sparsely populated niche. because ment be? We should begin to think about progress that affects the composition of the
in this situation selection is based on the these options and their expected outcomes. microbiota will also have consequences for
ability to transmit to new hosts, a range replacement will necessarily lead to the our physiology and health. However, the spe-
of virulence is possible, with the potential development of new classes of probiot- cific outcomes will only be learned empiri-
for positive selection for virulence104. This ics; we speculate that one day we will see cally, as the human ecosystem is too complex
could be dangerous, because the next main microbial additives that are specific for par- for anything more than the most superficial
inhabitant of the gastric niche might not ticular hosts, for specific durations of expo- predictions. Improving our prognostication
be as benign as H. pylori, which has co- sure and eradication. This is one vision for is an important technical challenge.
evolved with humans at a moderate level of the future, but it will require a much deeper Is the selective disappearance of the
virulence. A newly acquired organism that understanding of the metabolic, hormonal microbiota contributing to oesophageal dis-
evolved to colonize and efficiently use the and immunological interactions with our eases, obesity and its consequences, asthma
resources would probably be more viru- microbiota (FIG. 3). and related disorders, and the epidemic
lent105 and could selectively sweep through One emerging concept in microbial patho- spread of high-grade pathogens? Further
the population. genesis is the notion of the ‘community as a investigation will clarify these points,
These possibilities are not gastric specific pathogen’, in which a conserved broad swathe but the theoretical basis exists: ecological
but represent the general consequences that of the microbial community, rather than any changes involving our ancient microbiota
might accompany the extinction of species one specific member, contributes to disease. have the power to affect physiology and,
from the microbiota of any niche. The more This concept might be relevant to a range ultimately, health. Individuals who are
dominant the species that are lost, the larger of inflammatory processes of the skin and ‘normal’ in modern societies might be rep-
the void and the greater the potential risk of mucosa, including inflammatory bowel dis- resentative of the population at large but
replacement with a highly virulent organism. ease and chronic periodontitis. It suggests that not of our historical heritage106. studies of
studies of pathogenesis should consider the persons who are indigenous to those devel-
Future therapeutics? tgeneral properties of microbial communities, oping countries that have had little impact
Will there be cases in which human health such as resilience, or conserved functional from modern health practices (including
is improved by the replacement of some interactions, such as syntrophic interactions exposure to antibiotics) could be ideal to
of the lost microbiota? Certainly, a trip and the importance of gene transfer, rather define our historic ‘norms’.
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