Intestinal microbiota is a plastic factorresponding to environmental changesMarco Candela, Elena Biagi, Simone Maccaferri, Silvia Turroni and Patrizia Brigidi
Department of Pharmaceutical Sciences, University of Bologna, Bologna, Italy
Review
Traditionally regarded as stable through the entire life-span, the intestinal microbiota has now emerged as anextremely plastic entity, capable of being reconfigured inresponse to different environmental factors. In a mutu-alistic context, these microbiome fluctuations allow thehost to rapidly adjust its metabolic and immunologicperformances in response to environmental changes.Several circumstances can disturb this homeostaticequilibrium, inducing the intestinal microbiota to shiftfrom a mutualistic configuration to a disease-associatedprofile. A mechanistic comprehension of the dynamicsinvolved in this process is needed to deal more rationallywith the role of the human intestinal microbiota inhealth and disease.
Intestinal microbiota, a plastic factor of the humansuper-organismHumans are super-organisms, with 90% of their cellsconsisting of microbial cells [1,2]. A majority of thesemicrobial cells live in the gastrointestinal tract (GIT)and constitute the human intestinal microbiota [1,3]. Witha concentration of 1012 CFU/g of intestinal content, thehuman intestinal microbiota probably represents one ofthe most dense, biodiverse, and rapidly evolving bacterialecosystems on Earth [4]. Its collective genome – the intes-tinal microbiome (Box 1) – provides functional traits thathumans have not evolved by their own, and several of ourmetabolic, physiological, and immunological features de-pend on the mutualistic association with our intestinalmicrobial community [5–8]. For example, the intestinalmicrobiota enhances our digestive efficiency by degradingotherwise indigestible polysaccharides and, at the sametime, represents a fundamental barrier against GIT colo-nization by enteropathogens. Moreover, crosstalk betweenthe immune system and the GIT microbial community isessential for the development, education, and functionalityof our immune system [9,10]. Studies carried out withgerm-free (GF) mouse models revealed that ultrastructuraldevelopment of the GIT depends on its dynamic interactionwith the intestinal microbiota [11]. In a landmark studybased on three mouse models – GF, pathogen-free withnormal gut microbiota and adult conventionalized GFoffspring – Heijtz et al. demonstrated that the intestinalmicrobiota can also affect synaptogenesis during the peri-natal period, modulating brain development and function[12]. Furthermore, other studies carried out in GF mice
Corresponding author: Candela, M. ([email protected])Keywords: human intestinal microbiota; plasticity; dietary habits; immune system;environment.
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indicated that the intestinal microbiota tunes the hostresponse to noxious stimuli [13], interfering with the be-havioral response to nociceptive and stressful insults.These recent findings reinforced hypotheses concerningthe role of intestinal microbiota in the gut–brain axis,extending the array of physiological features affected byour intestinal microbial counterpart to the field of neuro-gastroenterology.
The GIT microbiota shows an immense biodiversity atthe species level. 16S rRNA gene sequence surveys ofthe intestinal microbiota across the human populationdetected up to 1000 different bacterial species [1,9]. How-ever, at a higher phylogenetic level, microbial biocomplex-ity in the human GIT decreases, resulting in a particularphylogenetic tree characterized by only a few brancheswith a large degree of radiance at the ends. Of the 100different bacterial divisions that populate our planet, onlysix colonize the human GIT [14]: Bacteroidetes, Firmi-cutes, Actinobacteria, Proteobacteria, Fusobacteria andVerrucomicrobia. These microbial phyla generally showa well-conserved profile in terms of relative abundancein a healthy human GIT: �65% Firmicutes, �25% Bacter-oidetes, �5% Actinobacteria, up to �8% Proteobacteria,and �1% Fusobacteria and Verrucomicrobia [2,15].
Each healthy human subject possesses a specific subsetof hundreds of species out of the thousands that constitutethe human intestinal microbiota [16]. According to Turn-baugh et al., 70% of the phylotypes of individual microbiotaare subject-specific and no phylotype is present at morethan 0.5% abundance in all subjects [17]. As a result of bothnature and nurture, an adult-type intestinal microbiota isstabilized after weaning following an extremely dynamicprocess of colonization that begins at birth (Box 2) [18].
The phylogenetic and functional composition of the indi-vidual microbiota has been traditionally thought of as rela-tively stable throughout adulthood [19,20]. However, therecent adoption of longitudinal approaches in studyingmicrobiota in the human intestinal ecosystem has suggesteda new and more dynamic view of the human intestinalmicrobiota [21,22]. Molecular studies have been specificallydesigned to investigate the intestinal microbiota dynamicsin response to different environmental variables, and havedemonstrated an unexpected degree of plasticity in responseto diet [15,21,23,24], exposure to environmental bacteria[25], geographic origins [26,27], and climate change [28].Recently, McNulty et al. evaluated the extent of the dynam-ics of the microbiota in 14 people [29]. Their fecal microbiotawas characterized every 2 weeks for 120 days. Some 74.6% ofphylotypes and 36% of the genes identified in the individual
6/j.tim.2012.05.003 Trends in Microbiology, August 2012, Vol. 20, No. 8 385
Box 1. The human microbiome
The collective genome of the human intestinal microbiota (micro-
biome) has been estimated to contain 100 times more genes than the
2.85 billion base pairs in the human genome [1,64]. Its functional
assignment revealed that it is generally enriched for clusters of
orthologous groups (COG) and Kyoto Encyclopedia of Genes and
Genomes (KEGG) categories involved in metabolism [5,17]. In
particular, pathways involved in carbohydrate metabolism, energy
metabolism, generation of short-chain fatty acids, amino acid
metabolism, biosynthesis of secondary metabolites, and metabolism
of cofactors and vitamins are highly represented in the human
intestinal microbiome. Interestingly, the percentage of sequences
assigned to carbohydrate-active enzymes (CAZymes) is greater than
for all the other KEGG pathways. A total of 156 CAZy families have
been found within at least one human gut microbiome [17]. This high
glycobiome complexity confers to the human intestinal microbiota
the capacity to degrade several glycans that cannot be metabolized by
the human host, ranging from the host glycans enclosed in mucus to
the array of glycans contained in plant polysaccharides, and supports
the limited saccharolytic diversity encoded by the human genome.
Characterization of the human microbiome is still in its infancy.
According to the most recent reports, its functional assignment rate
is approximately 60% [18,31], showing that a significant fraction of
the microbiome is not represented in any of the 1511 published
reference genomes. Moreover, the open pan-genome curves for 151
intestinal isolates, together with the outstanding degree of novelty
shown by their genomes with respect to non-intestinal bacteria,
highlight the remarkable functional diversity of this microbial
ecosystem and indicate that the unassigned fraction of the human
microbiome is probably greater than estimated [60].
Even if it is commonly accepted that all individuals share a core
microbiome [18,30] encoding genes involved in key metabolic
functions, a comparative analysis of intestinal microbiomes re-
vealed that each subject also possesses considerable microbiome
variability, comprising a unique set of subject-specific functional
genes that corresponds to 25% of the total genes in the microbiome
[61]. Although much of this genetic diversity is still unassigned and
its impact on the human physiological phenotype is unknown, the
variable microbiome undoubtedly provides an expanded view of
the genetic variability of the human super-organism. Its complete
functional attribution will allow the final limits of genetic variation in
humans to be computed.
Review Trends in Microbiology August 2012, Vol. 20, No. 8
microbiota complement were variable in a period of 4months, demonstrating the relevant degree of phylogeneticand functional plasticity of the human intestinal microbiota.
On the basis of static comparisons of the intestinalmicrobiota among groups of subjects having a differenthealth status, traditional studies have allowed microbiol-ogists to detect a core microbiome, defined as a constantand shared fraction of the human microbiome, fundamen-tal in supporting the mutualistic symbiotic relationshipwith the host [30]. However, longitudinal studieshighlighted that the intestinal microbiota of each individ-ual is an extremely dynamic entity [21,22,29], raisingquestions about how significant this degree of plasticityis for human health and homeostasis. This review sum-marizes the most recent and significant studies on theintestinal microbiota, highlighting its dynamic nature inrelation to different environmental stressors. In addition,the importance of this plasticity for human health ishighlighted by describing situations in which this dynamichomeostasis is compromised, resulting in disease. Thesereported findings and hypotheses could strengthen thedirection in which research in intestinal microbial ecologyis moving, shifting from a static view to a dynamic, andperhaps pliable, vision of the intestinal ecosystem.
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Dynamics of the intestinal microbiota in response todiet, environmental microorganisms and geographyThe most remarkable example of plasticity of the gutmicrobiota is provided by its capacity to rapidly respondto dietary changes (Table 1). In fact, an individual’s micro-biota is able to both compositionally and functionallyadapt itself to changes in diet in a 1–3-day period[21,23]. A molecular study of diet-dependent microbiotadynamics in 14 overweight men revealed that the individ-ual microbiota adapts its phylogenetic profile in responseto the main types of ingested fermentable carbohydrates.Interestingly, these fluctuations were influenced by theindividual’s complement of microbial species, showingsubject-specific diet-dependent changes in the microbiotaphylotypes [23]. In a second dynamic study, the intestinalmicrobiota of lean subjects under caloric restriction wasinvestigated for a 4-day period [15]. Subjects enrolled inthe study recorded all components of their diets daily,allowing correlation to the adaptation of their intestinalmicrobiota to macro- and micronutrient consumption. Asignificant association was observed between the phylo-genetic and functional structure of the intestinal micro-biota and fiber and protein intake. In a recent publication,Wu et al. differentiated long- and short-term dietaryresponses of the human intestinal microbiota [24]. Theimpact of a long-term dietary habit on the intestinalmicrobiota was studied in a cohort of 98 healthy volun-teers. Focusing on 78 taxa showing �0.2% abundance in atleast one sample and appearing in more than 10% of thesamples, the authors evaluated the association betweenbacterial taxon abundance and the intake of specific nu-trient classes. This taxon–nutrient correlation analysisrevealed that the human intestinal microbiota is character-ized by bacterial groups showing a reciprocal inverse asso-ciation with nutrients from fat and plant products.Analogous taxon–nutrient inverse correlations were ob-served for proteins versus carbohydrates, and fat versuscarbohydrates. Within the same study, 10 subjects weresequestered in a hospital environment and enrolled in ashort-term controlled feeding study by randomization tohigh-fat and low-fiber or low-fat and high-fiber diets.Changes in their intestinal microbiota were significantwithin the first 24 h of the controlled dietary regime, con-firming the data reported by Walker et al. [23]. Identicalshort-term diets did not overcome the inter-individualvariations, preserving the high degree of inter-individualvariability of the human intestinal microbiota. Interesting-ly, the comparison between long- and short-term dietarychanges revealed that the intestinal microbiota consists ofbacterial groups affected by short-term dietary changes andothers that are exclusively modulated by long-term dietaryhabits, such as those referred to as human enterotypes [31].In the context of these recent findings, a hypothesis regard-ing how the dietary habits of the USA within the past 30years have shaped the human intestinal microbiota hasbeen advanced [21]. According to the authors, the increasein total caloric intake has prompted a general reduction inthe phylogenetic and functional complexity of the humanintestinal microbiota.
Taken together, current research on microbiota plasticityin response to diet leads to a dynamic view in which the
Table 1. Response of the human intestinal microbiota to different dietary interventions
Study design Type of diet or nutrients Microbiota response Refs
Randomized crossover study:
14 overweight subjects,
3-week intervention
Diet high in resistant
starch (type III RS)
No changes at phylum level
"Ruminococcaceae
"Firmicutes spp. belonging to Roseburia genus, Eubacterium
rectale group and relatives
At phylotype level: "Ruminococcus bromii, "E. rectale,
"Oscillibacter valericigenes
[23]
Reduced carbohydrate
weight-loss diet (high
protein diet)
No changes at phylum level
#Firmicutes spp. belonging to Roseburia genus, Eubacterium
rectale group and relatives
At phylotype level: #Collinsella aerofaciens,
"Oscillibacter valericigenes
Cross-sectional study (COMBO)
to assess long-term dietary habits:
food frequency questionnaire,
98 healthy subjects
Fats "Bacteroidetes, Actinobacteria
#Firmicutes, Proteobacteria
[24]
Fiber #Bacteroidetes, Actinobacteria
"Firmicutes, Proteobacteria
Animal proteins Positively associated with the Bacteroidetes enterotype
Carbohydrates and
simple sugars
Positively associated with the Prevotella enterotype
Controlled feeding study (CASE)
to assess short-term dietary habits:
randomization to specific diets,
10 healthy subjects, 10 day intervention
High-fat low-fiber versus
low-fat high-fiber
Changes in microbiome composition are detectable within
the first 24 h of controlled feeding
Bacterial functional categories change significantly in
response to diet
No reduction in UniFrac distance between individuals fed
the same diet
No significant changes in Archaea, Bacteria and Eukarya
concentrations
No stable switching between Bacteroidetes enterotype and
Prevotella enterotype after 10 days of controlled feeding
Caloric restriction: 18 lean subjects,
4 day dietary record
Proteins Protein intake is significantly associated with KEGG orthology
groups
[15]
Insoluble dietary fibers Insoluble dietary fiber intake is significantly associated with
bacterial operational taxonomic unit (OTU) content
Review Trends in Microbiology August 2012, Vol. 20, No. 8
intestinal microbiota continuously changes in response tolong- and short-term dietary habits [32]. Through selectionof microbial populations that optimally degrade the avail-able substrates, these continuous microbiota fluctuationsprovide the host with the capability to readily adapt todietary changes. Supporting this hypothesis, in a milestonepublication, Hehemann et al. reported the first experimentalevidence that the consumption of foods containing environ-mental bacteria is the most likely mechanism that promotescarbohydrate-active enzyme (CAZyme) update in the GITmicrobiome [33]. According to the authors, the microbiomein Japanese people recently acquired the porphyrinase genefrom the seaweed-associated marine bacterium Zobelliagalactanivorans from a lateral gene transfer event favoredby consumption of non-roasted dietary seaweed in Japanesesushi. The presence of CAZyme porphyrinase in their micro-biome complement allows Japanese people to extract energyfrom the red marine algal porphyrin by means of the bacte-rial fermentation of this indigestible polysaccharide toshort-chain fatty acids in the gut. These findings highlightthe key role of the intestinal microbiome as a plastic andadaptable factor that improves the metabolic capacity of thehuman super-organism for more efficient extraction of en-ergy from the diet.
The human intestinal microbiota shows a second degreeof plasticity with regard to its response to constant exposureto environmental bacteria. The continuous interaction be-tween intestinal microbiota and environmental microorgan-isms during the entire course of human life is emerging as astrategic factor for the modulation of our immune functions
[8,11,22,34]. In particular, microbiota fluctuations in re-sponse to key environmental microbes during infancy arefundamental for proper development and education of theimmune system. According to the ‘old friend hypothesis’,exposure to environmental microbes from contaminatedfoods, feces, or livestock, which have been present through-out mammalian evolution, is necessary to prime the physi-ology of our immune system [25,34–36]. Recently, studiescarried out in mice demonstrated a role in programmingmany aspects of effector CD4+T cell and B cell differentiationfor specific intestinal microbial groups, such as segmentedfilamentous bacteria – Clostridium-related symbionts in theintestinal microbiota [37] – and Clostridium leptum andClostridium coccoides [8,37,38]. By orchestrating T cell dif-ferentiation into various pro- and anti-inflammatory sub-sets, such as T helper 2 (TH2), TH17, and regulatory T cells,these microorganisms can fine-tune our immune systemfrom the earliest stages of life [10,11,38].
Interestingly, it has been reported that the humanintestinal microbiota shows a surprising degree of plastici-ty in response to climate change and geography. In alongitudinal study of 15 healthy Finnish subjects for7 weeks, overseas travel was associated with a high de-crease in similarity between samples from the samesubject [28]. Changes in diet and exposure to new environ-mental microbes, as well as a different climate and stress,can account for this travel-related plasticity of the intesti-nal microbiota. The impact of geographic origin on intesti-nal microbiota composition was demonstrated in anextensive comparative analysis of intestinal microbiota
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Box 2. Acquisition and aging of the intestinal microbiota
We are born sterile in a microbial world. During the neonatal period
we are involved in a complex and dynamic interplay with environ-
mental microbes that, after weaning, culminates in the acquisition
of an adult-type intestinal microbial community [65,66].
Perinatal events and early environmental exposure play a pivotal
role in determining the acquisition of the infant microbiota and have
lasting effects on the phylogenetic structure of the later adult
intestinal ecosystem. The mother’s vagina is regarded as the first
microbial source for the microbiota of the newborn [67]. However, the
biodiversity of the vaginal ecosystem is relatively low, dominated by
Lactobacillus species, so the environment encountered by the infant
at and immediately after birth, such as the mother’s skin and fecal
microbiota, living conditions and child-rearing practices, is of
great importance [21,68]. Moreover, by modulating the early
Bifidobacterium-dominated architecture of the infant gut microbiota,
the mother’s milk has a relevant role in the process of microbiota
assembly [69]. In this key period of our life, the intestinal microbiota
dramatically fluctuates in response to stochastic microbial exposure.
At weaning, with the introduction of a solid diet, developmental
changes in the gut mucosa and maturation of the intestinal immune
system stabilize the ecosystem, which converges to a more constant,
adult-like phylogenetic architecture, with progressively increasing
functional and taxonomic complexity [65,70].
In this scenario, if and how human genetics plays a role in the
process of assembly of the individual intestinal microbiota is still
controversial. According to Turnbaugh et al., monozygotic and
dizygotic twins showed a comparable degree of similarity between
their intestinal microbial communities, demonstrating that host
genotype is secondary to environmental exposure in shaping gut
microbial ecology [17]. However, another study showed a slightly
reduced microbiota similarity profile in dizygotic compared to
monozygotic twins [71]. Moreover, in a recent study in murine
models, Benson et al. identified 18 host quantitative trait loci showing
a significant linkage to intestinal microbial taxa [72]. In conclusion, the
intestinal microbiota can be viewed as a factor that is in part vertically
inherited from the mother, in part horizontally transferred from the
environment, and in part controlled by host genetic factors.
The crosstalk with its microbial counterpart accompanies the
human host throughout adulthood, until aging and its related
pathophysiological conditions start to affect this mutualistic rela-
tionship. Changes in lifestyle and diet, as well as immunosenes-
cence, lead to increased intestinal permeability and decreased
motility, and strongly impact on the intestinal microbiota, favoring
proinflammatory pathobionts (Enterobacteriaceae) to the detriment
of immunomodulatory bacterial groups (Clostridium cluster IV and
XIVa, Bifidobacterium). This aged-type microbiota could play a role
in consolidating the ‘inflamm-aging’ process by establishing a self-
sustained inflammatory loop detrimental for host health [40,73].
However, from an ecological perspective, the ability of the host to
re-establish a mutualistic relationship with this compromised
microbial community may represent a necessary step for the human
host to maintain health and reach longevity.
Review Trends in Microbiology August 2012, Vol. 20, No. 8
among people from Korea, China, Japan and the USA [27].Data analysis revealed that gut microbiota profiles clus-tered according to geographic origin. In particular, Amer-icans were characterized by higher abundance ofFirmicutes, Japanese had more Actinobacteria, andKoreans and Chinese showed a Bacteroidetes-rich gutmicrobiota. Analogously, a comparative study between chil-dren from Europe and Burkina Faso showed significantcountry-related differences in the fecal microbial communi-ty [26]. Children from Burkina Faso were enriched in Bac-teroidetes and Actinobacteria, and depleted in Firmicutesand Proteobacteria compared to the European children.According to the authors, these country-related differencesin intestinal microbiota profiles can result from hostgenetics, as well as several environmental variables, such
388
as climate and particular dietary habits and lifestyle of thosein each country.
The recent adoption of longitudinal approaches instudying the human intestinal microbiota highlighted anunexpected degree of phylogenetic and functional plastici-ty of our symbiont microbial counterpart. This dynamicnature is strategic for several important features of humanbiology, such as adaptation to different diets and environ-ments and modulation of the immune system.
Disturbance of the microbiota–host mutualisticrelationshipUnder some circumstances, diet and other environmentalfactors, as well as factors of endogenous origin, such aschronic inflammation [9,39] and aging [40,41] (Box 2), canforce the intestinal microbiota to shift from a mutualisticconfiguration supporting health and homeostasis to adisease-associated profile, usually characterized by alower level of phylogenetic and functional biodiversity(Figure 1). The unbalanced intestinal microbiota observedin obese people [17] and the progressive loss of key intestinalmicrobial groups as a result of a Westernized lifestyle [21]provide two remarkable examples of disturbance of themicrobiota–host mutualism triggered by environmentalstressors.
The recent pandemic of obesity in Westernizedcountries reflects environmental and lifestyle changes,among which dietary factors play a major role [42–45].In this scenario, diet-dependent changes in the microbiotaare perceived as probably being involved in the etiologyand severity of obesity [17,30,46,47]. High-fat dietaryhabits can have a dramatic impact on the intestinal micro-bial community. To explain this phenomenon, Turnbaughet al. suggested an intriguing metaphor by comparing theobese gut microbiota to fertilized runoff, whereby, withrespect to the high diversity of a rainforest, a low-diversitycommunity blooms on application of an abnormal energyinput [17]. According to the authors, compared to leancontrols, the intestinal microbiota of obese people is sig-nificantly less diverse and generally characterized byhigher abundance of Firmicutes and Actinobacteria anda corresponding decrease in Bacteroidetes. However, Dun-can et al. reported conflicting results, failing to detect anyrelationship between the proportion of Bacteroidetes infecal samples and obesity [48]. This lack of consensussuggested that the link between microbiota and obesityis probably more complex than the mere phylum-levelBacteroidetes:Firmicutes ratio. The latter hypothesishas been recently reinforced by a comparative analysisof gene-level and network-level topological differences be-tween lean and obese microbiomes [49]. As a result ofadaptation to a low-diversity environment, the obesemicrobiome is characterized by reduced modularity andthe enrichment of peripheral enzymes with a low cluster-ing coefficient. According to the authors, this variation incommunity-level metabolism may be induced by an in-crease or decrease in relative abundance of a small subsetof species, which changes the way in which the microbiomeinterfaces with the environment and the host.
The functional annotation of the obese microbiomerevealed that the obese-type microbial community
Bio
div
ersi
ty
Disease
Homeostasis
Disease
1 2 3 n
Environmental/endogenous stressors
TRENDS in Microbiology
Figure 1. Dynamics that force disturbance of the microbiota–host mutualism. Under certain conditions, environmental stressors (diet and/or other environmental factors,
such as infection, hygiene, and sanitization) and factors of endogenous origin (such as inflammation or aging) can force the intestinal microbiota to shift from the
mutualistic configuration that supports homeostasis (from 1 to n) to a disease-associated profile, generally characterized by a lower level of phylogenetic and functional
biodiversity. Different healthy configurations are represented, showing the variability within and between individuals.
Obesogenicmicrobiota
Highfermentative
capacity
High-fat dietaryhabits
Pathophysiologyof obesity
Increase in hostenergy harvest
from diet
• Low phylogenetic an d functional di versity
• Enrichment in genes involved in energy metab olism
TRENDS in Microbiology
Figure 2. Disturbance of the microbiota–host mutualistic interaction in response to
high-fat diet. The massive caloric intake from a high-fat diet forces a reconfiguration
of the intestinal microbiota, reducing its phylogenetic diversity and enriching the
microbiome with genes involved in energy metabolism. Characterized by high
fermentative capacity, this obesogenic microbiota profile increases the host energy
harvest from the diet, contributing to the pathophysiology of obesity.
Review Trends in Microbiology August 2012, Vol. 20, No. 8
possesses a lower level of functional diversity and isenriched in genes involved in carbohydrate, lipid andamino acid metabolism, demonstrating an overall increasein fermentative capacity with respect to the lean-typemicrobiome [17]. Furthermore, transplantation of theobesity-associated intestinal microbiota into GF miceresulted in a greater increase in total body fat than coloni-zation with the lean-type intestinal microbiota [50]. Inagreement with the ‘energy harvest hypothesis’ [51], thesedata indicate that the obesity-associated intestinal micro-biota can significantly contribute to disease severity byincreasing energy harvest from the diet. Moreover, it hasbeen shown that high-fat diet-dependent microbiotaalterations negatively affect intestinal permeability, re-ducing expression of the tight junction proteins zona occlu-dens-1 and occludin [52]. The consequent increase incirculating levels of lipopolysaccharide can significantlycontribute to the development of obesity-related inflamma-tory liver diseases, such as non-alcoholic fatty liver disease,non-alcoholic steatohepatitis, and insulin resistance [53].In conclusion, the abnormal dietary habits of obese peopleresult in a severe intestinal microbiota transition from ahealthy profile to an obesogenic one, which supports obe-sity and associated comorbidities (Figure 2) [46,47].
According to the ‘hygiene hypothesis’, a Westernizedlifestyle compromises the mutualistic relationship betweenhumans and their intestinal microbiota. Antibiotic use, san-itization, bathing, clean water and sterile foods, which aretypical of Western societies, favor a profound decrease in themicrobial biodiversity humans are exposed to over theirlifespan [35]. Even if this has provided numerous benefitsin terms of reduced infant mortality and increased lifeexpectancy, it has also come at a cost of a progressive lossof key bacterial groups from the intestinal microbiota, the so-called old friends, which are essential for the developmentand tuning of our immune system [8]. The lack of immuno-logical crosstalk with these old friends – especially duringinfancy – leads to an immune system inclined to inappropri-ate activation, which is characteristic of emerging chronicinflammatory diseases (Figure 3) [34,54]. Confirming this
hypothesis, allergy, autoimmune disorders, inflammatorybowel diseases, and type 2 diabetes, all resulting from chron-ic inflammatory responses, are dramatically increasing indeveloping countries, where Westernized lifestyles are be-coming more and more common [7,21,22,55,56]. Known asthe ‘disappearing microbiota hypothesis’ [25], this theory hasbeen recently strengthened by a comparative study of theintestinal microbiota from children from Europe and ruralAfrica [26]. According to the authors, European childrenwere deprived of microbial groups that may have a role inhost immune education. Furthermore, a recent extensivestudy carried out on a birth cohort of 411 European childrenat highrisk of allergywho were followed for 6 years by clinicalassessments at 6-month intervals demonstrated that bacte-rial diversity in the early intestinal microbiota is inverselyassociated with the risk of allergic sensitization [57].
Environmental stressors, such as high-fat dietary habitsor excessive sanitization, can overcome the resilience of
389
Shrinkage of themicrobiota diversity
Westernized lifestyle
Decreased microbialdiversity in living
environments
Inappropriateactivation of theimmune system
Chronic inflammatorydiseases
Susceptible host
TRENDS in Microbiology
Figure 3. Hygiene hypothesis and intestinal microbiota. A Westernized lifestyle
compromises the microbial load and diversity in living environments. This results
in a general shrinkage of the microbiota diversity, with the progressive loss of ‘old
friends’, defined as components of the microbiota essential for the development
and tuning of our immune system. In a susceptible host, a decrease in this key
microbial component results in an immune system that is more prone to
inappropriate activation, a characteristic of emerging chronic inflammatory
diseases in Western countries. In a feedback loop, chronic inflammation affects
the composition of the microbiota, supporting a low-diversity proinflammatory
community that feeds into consolidation of the inflammatory status.
Review Trends in Microbiology August 2012, Vol. 20, No. 8
the dynamic symbiotic relationship between the intestinalmicrobiota and the host, compromising host health andfavoring the onset and/or severity of diseases.
Concluding remarks and future directionsIn a mutualistic context, the plasticity of the human intes-tinal microbiota guarantees rapid adaptation of the meta-bolic performance of the super-organism in response to dietand, at the same time, represents an essential prerequisitefor education of the immune system to homeostasis. Inher-ited from the mother and shaped by the composition of themother’s milk, the human intestinal microbiota could thusbe regarded as an epigenetic factor that, shaped by theenvironment, confers adaptability and resilience to thehuman super-organism. Several circumstances can disturbthis mutualistic interaction and force a shift of the intestinalmicrobiota from a mutualistic configuration to a disease-associated profile. However, to reveal the dynamics involvedin these processes and to understand to what extent theplasticity of the intestinal microbiota affects human homeo-stasis in a changing environment, a better understanding ofthe microbiota–host bionetwork is needed. The entirespecies-level phylogenetic diversity of the human intestinalmicrobiota is still to be determined. Moreover, we need touncover the real extent of the unassigned fraction of thehuman intestinal microbiome and, most importantly, thefunction of this biological dark matter [58]. This informationwill be important in dealing with the impact of intra- andinter-individual microbiome diversity on particular hostphysiological phenotypes.
Even if deep-sequencing approaches allow depiction ofthe broad phylogenetic biodiversity of the human intestinalmicrobiota [14,59], we are still far from comprehending thecorresponding degree of functional complexity [17,31,60,61].
390
Thus, reaching the target of 900 GIT reference genomes forthe Human Microbiome Project is mandatory. Moreover, weneed to improve our capacity to cultivate anaerobic mem-bers of the human intestinal microbiota and unknown mi-crobial genes need to be identified by functional genomicsapproaches involving massive functional screening of GITmetagenome libraries [62,63]. By sampling humans acrossthe globe with a variety of diets and lifestyles, includingancestral hunter–gatherer lifestyles, we can increase ourknowledge of the biodiversity of the human intestinal micro-biota. These studies will help in exploring the limits of thegenetic variability of the human super-organism, allowingcomprehension about the extent to which our co-evolutionwith intestinal microbes could be responsible for our physi-ological diversity and environmental adaptation. Moreover,besides traditional comparative static studies on health anddisease, longitudinal studies of the human intestinal micro-biota should be encouraged, in particular for subjects in-volved in migration fluxes. These observational studies willallow investigation of the plasticity of the intestinal micro-biota in response to environmental changes, and shouldshed some light on the limits of adaptability and resilienceof the human super-organism. A mechanistic comprehen-sion of the impact of the intestinal microbiota on the humanphysiological phenotype, together with a better understand-ing of the dynamics that compromise mutualistic partner-ships with the human host, will allow adoption of a morerational approach in dealing with the role of the humanintestinal microbiota in health and disease.
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