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English to Italian: The Microbiome: The Trillions of Microorganisms That Maintain Health and Cause Disease in Humans and Companion Animals General field: Medical Detailed field: Livestock / Animal Husbandry
Source text - English Review
The Microbiome: The Trillions of Microorganisms That Maintain Health and Cause Disease in Humans and Companion Animals
A. Rodrigues Hoffmann1, L. M. Proctor2, M. G. Surette3, and J. S. Suchodolski4
Veterinary Pathology
2016, Vol. 53(1) 10-21
ª The Author(s) 2015
Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0300985815595517 vet.sagepub.com
Abstract
The microbiome is the complex collection of microorganisms, their genes, and their metabolites, colonizing the human and animal mucosal surfaces, digestive tract, and skin. It is now well known that the microbiome interacts with its host, assisting in digestion and detoxification, supporting immunity, protecting against pathogens, and maintaining health. Studies published to date have demonstrated that healthy individuals are often colonized with different microbiomes than those with disease involving various organ systems. This review covers a brief history of the development of the microbiome field, the main objectives of the Human Microbiome Project, and the most common microbiomes inhabiting the human respiratory tract, companion animal digestive tract, and skin in humans and companion animals. The main changes in the microbiomes in patients with pulmonary, gastro- intestinal, and cutaneous lesions are described.
Keywords
microbiome, microbial ecology, human microbiome project, respiratory, gastrointestinal, skin
The various microorganisms (fungi, protozoa, bacteria, archaea, bacteriophages, and viruses of eukaryotes) that live in and on the bodies of humans and other animals are more than a simple collection of microbes. The microbiome encompasses the full complement of microorganisms, their genes, and their metabolites. The microbiome has co-evolved with humans and animals, thereby assisting in digestion and detoxification, sup- porting immunity, protecting against invading pathogens, and maintaining overall health. At 1014 species, comprising at least
20 million unique microbial genes, the microbiome constitutes the largest genetic component of the human and animal super- organism. Microbial ecologists who studied microorganisms and microbial communities in the environment recognized early on that most microorganisms in nature were not readily culturable and so developed alternate approaches to the study of microbial communities. An early and broadly adopted approach for investigating microorganisms in the environ- ment was the use of the 16 S ribosomal RNA (rRNA) gene as a taxonomic marker for interrogating bacterial diversity in nature.71 With the growth of non–culture-based molecular techniques to study environmental microorganisms and com- munities, some medical microbiologists started using these tools to study the human body and found far greater microbial diversity than expected, even in well-studied sites such as the oral cavity.7,15,70
In the infectious diseases field, recognition was growing that many diseases could not satisfy Koch’s postulates as their pathogenesis appeared to involve multiple microorganisms. The term polymicrobial diseases was coined to describe these diseases resulting from concurrent infection with multiple infectious agents,11 as seen with abscesses, AIDS-related opportunistic infections, conjunctivitis, gastroenteritis, hepati- tis, otitis media, periodontal diseases, respiratory diseases, and genital infections. However, we now recognize added com- plexity in these diseases, as we see these as entire microbial
1Department of Veterinary Pathobiology, College of Veterinary Medicine and
Biomedical Sciences, Texas A&M University, College Station, TX, USA
2National Human Genome Research Institute, National Institute of Health, Bethesda, MD, USA
3Department of Medicine, Department of Biochemistry and Biomedical Sci-
ences, Faculty of Health Sciences, Farncombe Family Digestive Health Research
Institute, McMaster University, Hamilton, ON, Canada
4Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
Corresponding Author:
A. Rodrigues Hoffmann, Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.
Email: [email protected]
communities and begin to understand how the bacteria that comprise them interact with each other and with the host. In an essay on the history of microbiology and infectious disease, Lederberg73 coined the term microbiome and called for ‘‘a
Table 1. Major objectives of the Human Microbiome Project divided into 2 phases.
Phase 1
more ecologically-informed metaphor’’ to understand the rela- tionship between humans and microbes.
This review includes an introduction to the National Insti- tutes of Health (NIH) Human Microbiome Project (HMP) and considers the microbiota inhabiting the human respiratory tract, the digestive tract in companion animals, and the skin in humans and dogs in health and disease.
The NIH Human Microbiome Project
In order to better evaluate the role of the microbiome in health and disease, the NIH launched the HMP, which focused on surveying microbiomes present in different organ systems (www.commonfund.nih.gov/hmp). The NIH-HMP was divided into 2 phases: Phase 1 surveyed the microbiomes of major body regions in healthy individuals and in those with disease, and Phase 2 focused on the biological properties of these microbiomes. The initial studies focused on the diges- tive tract23,39 and demonstrated the tremendous complexity as well as the functional potential of the human microbiome.
Phase 1 Healthy Adult Cohort Study
During the first phase of HMP (2007–2012), the major objec- tives were to (1) survey the microbiomes of healthy adults to produce a reference data set, (2) develop a catalog of genome sequences of microbial reference strains, and (3) evaluate the properties of microbiomes associated with specific diseases in a collection of HMP Demonstration Projects (Table 1).96
The microbiomes were surveyed in 5 major body regions of healthy adults (airway, skin, oral cavity, digestive tract, and vagina). From these studies, the HMP Consortium pub- lished 2 landmark papers in 2012 describing the range of nor-
(1) Survey the microbiomes of healthy adults—produce a reference data set of microbiomes
(2) Develop a catalog of microbial genome sequences of reference strains
(3) Resource of metagenomic sequence data from healthy cohort study
(4) Evaluate specific microbiome-
associated diseases
Phase 2
Develop a data set of multiple biological properties of the microbiome and host— metagenomic analysis of predicted metabolic pathways in these microbiomes
Five major body regions of healthy adults—airway, skin, oral
cavity, gastrointestinal tract, and vagina
Over 2600 bacterial genomes and
100 bacteriophages and eukaryotic viruses sequenced, assembled, annotated, and deposited at NCBI
Five major body regions of healthy adults
Models of microbiome-associated diseases or conditions, focusing on the microbiome and host (mother and child) from pregnant women, inflammatory bowel disease cohorts, and patients transitioning from the prediabetic state to type 2 diabetes
mal microbial variation among healthy adults in a Western population.49,50 One major finding was that even though microbial community structure varied greatly between body habitats, the potential metabolic capabilities encoded in these communities’ metagenomes were much more constant. That is, although microbial taxonomic composition varied among healthy individuals, their collective metabolic functions remained remarkably stable within each body site.1
Another key resource from this phase was the HMP refer- ence microbial genome sequence catalog, which includes the largest collection of human-associated microbial genomes sequences, including bacteria, bacteriophages, viruses of eukaryotes, and microbial eukaryotes (NCBI, http://www.ncbi. nlm.nih.gov/bioproject/43021; Bioproject PRJNA28331). Nonetheless, with tens of thousands of bacterial strains and unknown numbers of fungal, viral, and protists in the human microbiome, much work remains to create a com- plete catalog of reference genomes.31 Approximately 15% of the samples collected in the healthy cohort study were
sequenced by whole genome shotgun (WGS) sequencing
to produce metagenomic sequences for the 5 major body regions of the study.
To evaluate and compare the healthy cohort study with other individuals, 15 Demonstration Project studies were launched focusing on gastrointestinal diseases (Crohn’s disease, ulcera- tive colitis, pediatric inflammatory bowel syndrome, neonatal necrotizing enterocolitis, esophageal adenocarcinoma, and idiopathic pediatric fever), urogenital conditions (bacterial vaginosis, men with circumcision), skin diseases (eczema, psoriasis, and acne), and patients with obesity.
The outcomes from Phase 1 accomplished many things for the field though it also raised new questions about the best approaches for identifying characteristic signature phenotypes. It was noted that in many cases, taxonomic composition of the microbiomes alone was not sufficient to define a core micro- biome associated with specific diseases or states of health. Rather, predicted metabolic pathways of these microbiomes appeared to move us closer to this goal.
Phase 2 of the HMP (2013–2015)
Phase 2 of the HMP (2013–2015) focused on developing a data set of multiple biological properties of the microbiome and host
microbiota of the upper airways includes many pathogenic bacteria that colonize asymptomatically such as Streptococ- cus pneumoniae, Staphylococcus aureus, Moraxella catar-
35
from well-characterized cohort studies (www.hmp2.org). A
rhalis, and Haemophilus influenzae.
For these organisms,
cardinal property of microbes is their versatile metabolic cap- abilities, which are not taxon specific. In other words, more than 2 unrelated microbes may have the ability to break down a common component in our diet, and this can mean that micro-
the distinction between commensal and opportunistic patho-
gen is blurred. When host defense at these sites and in the lower respiratory tract (LRT) are compromised, aspiration of bacteria from the URT into the lungs can result in severe
27,103
bial community makeup may not be the best biomarker prop-
respiratory infection.
In addition to pathogens, the com-
erty to characterize specific human conditions. Therefore,
mensal microbiota can also be a reservoir of antibiotic resis-
35,76
Phase 2 was designed to collect multi-omic biological proper-
tance and virulence genes.
As many commensals and
ties of the microbiome, such as the gene expression profiles (ie, the metatranscriptome),33,48,128 protein profiles (ie, the meta-
pathogens of the respiratory tract are naturally competent,
namely, have the ability to take up exogenous DNA (eg,
56,58
proteome),127 profiles of metabolites from host and microbome
Streptococcus, Haemophilus, Neisseria),
under selective
(ie, the metabolome),16 and related relevant host properties from well-characterized cohorts. These studies are focusing on the microbiome and host (mother and child) for pregnant
pressure, antibiotic resistance can likely spread rapidly
through this community.
Most studies on the URT microbiota have focused on
14,24,74
women at risk for preterm birth, the gut microbiomes of cohorts
healthy adults.
However, it is important to consider that
at risk for inflammatory bowel disease (IBD), and the gut and
the groups most susceptible to respiratory infections are the
nasal microbiomes from cohorts at risk for type 2 diabetes.54
very young and the elderly.3,60
Bogaert et al10
looked in depth
These data and the resultant integrated data set, which will be deposited in public databases, will allow the scientific com- munity to evaluate microbiome properties or combinations of
at children under 2 years of age in the Netherlands and
observed 4 clusters, 3 dominated by a single operational taxo- nomic unit (Moraxella, Haemophilus, or Streptococcus) and 1
10
properties and provide new insights into the role of the micro-
that was mixed.
Similar results were observed in a recent
biome in health and in disease.
The Respiratory Tract Microbiome
The Upper Respiratory Tract Microbiome
The human upper respiratory tract (URT), including the nose, throat, and oral cavities, is colonized by a complex and dynamic microbial community. Collectively, the upper air- ways, in particular the oral cavity, represents the most diverse microbiome site in the body, even harboring more bacterial species richness than the digestive tract.51,75,111 As the site of initial interactions with many environmental microbes through breathing and ingestion, an important role of the commensal microbiota is the first line of defense against pathogens by out- competing potential colonizing pathogens (microbial antagon- ism).65,82 Essentially, by occupying all binding sites in the URT, any invading pathogen must somehow contend with these organisms, in addition to the host defenses. Importantly, the microbiota of the airways, like those at other mucosal sur- faces, are integral in priming and educating the immune sys- tem72 and regulating immunity in the lung in response to infection.52 To date, most of the research has used 16 S rRNA gene sequencing to characterize the bacterial communities of the respiratory tract. Fungal and viral communities have not been studied, with the exception of pathogen-focused studies.
The nasal passages and oropharynx harbor a distinct micro- biota. In healthy adults, the nasal passages are typically domi- nated by Actinobacteria (Propionibacterium, Corynebacterium) and Firmicutes (Staphylococcus), whereas Firmicutes (Veillo- nella, Streptococcus, Staphylococcus) are more prevalent in the oropharynx (Fig. 1).14,51,74 Importantly, the resident
study of healthy children from a Canadian city, except that a
Haemophilus-dominant group was not observed.110 The micro- biota of young children (65) showed marked differences between the microbiota of this age group compared to younger healthy adults (age 18–43).125 While there is a clear distinction between the nasal and oropharyngeal microbiota in younger adults14,51,74 and even young children,111 this topographic dif- ference is lost in the elderly.125 Overall, there was an increased relative abundance of streptococci (specifically species of the Streptococcus salivarius group but not Streptococcus pneumo- niae) in the oropharynx of elderly.
These studies on the URT microbiota of the young and elderly, the group most vulnerable to respiratory infections, suggest that the changing microbiota, in combination with a
Figure 1. Different microbial communities colonize the upper and lower respiratory tract in humans. Individuals with chronic infections are colonized by obligate anaerobes, pathogenic bacteria, and bacteria found in the upper respiratory tract. Modified from Marieb EN, Hoehn K. Human Anatomy and Physiology. 8th ed. 2010. Printed and electronically reproduced by permission of Pearson Education, Inc, Upper Saddle River, New Jersey.
maturing and senescing immune system in the very young and elderly, respectively, play a role in this susceptibility. This will not be unique to humans but likely occurs in all mammals.
Microbiome studies in companion animals focusing on the upper and lower respiratory tract in young, adult, and aged ani- mals are currently lacking. Of the few studies published to date, Moraxella sp. was frequently identified in samples from the nostril and oral cavity of healthy dogs,99,112 accounting for approximately 33% of the bacteria colonizing the nostril. Bac- teria in the genus Moraxella were also isolated from oral swabs from healthy dogs61 and from bronchial samples from dogs with tracheal collapse.57
The Lower Respiratory Tract Microbiome
The lower airways have been considered to be a sterile site in healthy individuals or more appropriately an effectively sterile site. During normal breathing, the lower airways in an adult human are exposed to 105 microorganisms per day through
aerosols. These were thought to be effectively dealt with by the airway immune defense.9,21 However, this continued exposure to microbes has prompted investigations of the lower airways in healthy individuals and led to questions of whether there may be a viable microbial colonization of the lungs. The chal- lenge for studies addressing these questions is contamination of the sample during bronchoscopy and the suggestion that the diverse community observed represents contamination rather than true colonization of the lower airways. To address this, oral microbiota profiles were compared to bronchoalveolar lavage (BAL).6 If there were a true lower airway community, it is predicted that the composition would look different than the oral microbiota in the same individuals. Even if the lower airways were colonized from the upper airways, as a different ecological environment, some but not all species would be sim- ilar, and they would differ in their relative abundances. The data from recent human studies suggest a lower airway micro- biome, but it was certainly not convincing in all samples.77,90
These 2 studies compared oral washes to BAL fluid and
observed distinct differences in the microbiome composition, with Enterobacteriaceae, Haemophilus, Methyllobacterium, and Ralstonia being disproportionally more abundant in the lungs. Surprisingly, there were no statistical differences in the microbiota between healthy individuals and smokers. Another unexpected finding was the prevalence of Tropheryma whip- plei in the samples from the lower airways.77,90 T. whipplei is the causative agent of Whipple’s disease, a rare systemic dis- ease primarily associated with gastointestinal infections.28 The clinical significance of these findings is unknown. Another study examining the LRT microbiota using similar compari- sons but carried out on BAL obtained through the nasal route to minimize oropharyngeal contamination observed URT microbiota in some but not all individuals.104 In other samples, bacterial DNA was detected but most likely represented low- level DNA contaminants in the BAL fluid. More importantly, low-level inflammation was detected in the BAL fluids when the URT microbiota signature was recovered, providing further support for the presence of bacteria in the lower airways. No T. whipplei was reported in this study.
These studies provide evidence for presence of bacteria in the LRT of healthy human individuals. They do not provide evidence of a stable unique lower airway microbiome, how- ever. Indeed, the results of Segal et al104 are consistent with these microbiota in the LRT being transient in healthy individ- uals. Furthermore, like all molecular studies, they provide evi- dence for bacterial DNA and not necessarily viable organisms. Bacterial products would be sufficient to induce an immune response independent of the presence of viable organisms. However, these studies do indicate that the LRT are constantly exposed and any compromise to host defense or immune sup- pression could result in rapid development of LRT infections. Stress-mediated suppression of the immune system in shipping fever of cattle is an example.46 LRT infections are often responsible for high morbidity and mortality in both the devel- oped and developing world. For patients with severe pneumo- nia, even when carefully diagnosed, an etiological agent (bacterial or viral) is identified in less than 50% of cases.6,12,84
Commensal microbiota are often recovered but dismissed clini- cally as contamination. It is possible that we may be underes- timating the pathogenic potential of organisms we dismiss as commensals of the upper repiratory tract.
In the case of chronic lower airway disease (eg, in cystic fibrosis [CF],80 chronic obstructive pulmonary disease, and asthma) and even in more acute infections in humans, it is now
widely accepted that the lower airway colonization is polymi- crobial (Fig. 1).9,47,79,97,120 These communities include many members of the upper airway microbiome in addition to the expected LRT pathogens. In disease states, such as in CF, sev- eral studies have shown that the sputum or BAL microbiome is distinct in microbial composition and relative abundance com- pared to the oral microbiome,100 ruling out contamination as a major source of these organisms. Importantly, obligate anae- robes make up a significant portion of these lower airway microbiomes. Even in the studies of the LRT microbiome from healthy individuals, obligate anaerobes (eg, Prevotella and
Veillonella) are among the most common bacteria detected.77,90,104 The role of these additional microbes in dis- ease is not understood. Using animal models, it has been shown that bacteria isolated from the airways of CF patients, which have little or no pathogenic potential, can synergize with patho- gens to enhance virulence, suggesting a role for polymicrobial interactions in disease progression.22,105 This synergy involves microbe-microbe interactions that result in the modulation of bacterial virulence factor gene expression.105 It is likely that most lower airway infections are polymicrobial.80,107 Whether this will influence the progression of disease is not known.
The Microbiome in the Digestive Tract
The Digestive Tract Microbiome in Health
An estimated 1010 to 1014 microbial cells are present in the intestine of mammals, which is approximately 10 times more than the number of host cells. Sequence analysis of 16 S rRNA genes has revealed a highly complex ecosystem within the human,123 canine,43,44,114 and feline44 GI tract. This complex intestinal microbiota has a significant impact on health and dis- ease. Several reviews have covered the human digestive tract microbiome in depth.64,109,123 This section will focus primarily on the digestive tract microbiome of companion animals.
The exact number of bacterial species in the digestive tract remains unknown, mostly due to the technical difficulties in accurately describing this complex ecosystem. Generally, the composition of the gut microbiota is to some extent similar across humans, dogs, and cats. At least 200 bacterial phylo- types are estimated to be present in the canine small intestine, while the canine colon harbors a few hundred to thousand bac- terial phylotypes.44,114 The Firmicutes and Bacteroidetes are the major bacterial phyla in the gut of dogs and cats (Fig.
2).2,3 Less abundant phyla in dogs are Proteobacteria, Acti-
nobacteria, Spirochaetes, Fusobacteria, Tenericutes, Ver- rucomicrobia, Cyanobacteria, and Chloroflexi. The phylum Firmicutes comprises many distinct bacterial groups. Of those, Clostridium clusters XIVa and IV are the most abundant and encompass many important short-chain fatty acid–producing bacterial groups (ie, Lachnospiraceae, Ruminococcus, Faecali- bacterium, Dorea). There is a gradual increase in species rich- ness and abundance of bacteria from the small to the large intestine. The canine stomach harbors a microbiome that is often dominated by Helicobacter spp., which comprised 99% of 16 S rRNA sequences in one study.34 Bacterial counts in the canine and feline duodenum typically range from 102 to 105 colony forming unit per gram (cfu/g) of content. However, up to 109 cfu/g have been reported in healthy dogs and cats.37,59
The total bacterial count in the colon ranges between approxi- mately 109 and 1011 cfu/g.
The digestive tract harbors not only bacteria but also var- ious fungi, archaea, protozoa, and viruses. Recent studies have provided more in-depth analysis about the diversity of these microorganisms in healthy individuals, but their inter- actions, influences on the host, and role in disease remain
Figure 2. The most common bacteria identified in the digestive tract and feces in healthy dogs and cats and those with acute and chronic gas- trointestinal disease. Figure 3. The most common phyla and families of bacteria identified in the skin of healthy and allergic dogs. Modified from Rodrigues Hoffmann et al.99
unclear. Analysis by fluorescence in-situ hybridization (FISH) and DNA shotgun sequencing analysis of fecal DNA obtained from healthy humans and canines have estimated that bacteria make up approximately 98% of all sequences, and fungal organisms and archaea together make up
Translation - Italian Revisione
Il Microbioma: trilioni di microorganismi, che mantengono la salute e causano le malattie negli esseri umani e negli animali da compagnia
A. Rodrigues Hoffmann (1), L. M. Proctor (2), M. G. Surette (3), and J. S. Suchodolski (4)
1 Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
2 National Human Genome Research Institute, National Institute of Health, Bethesda, MD, USA
3 Department of Medicine, Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
4 Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
Corresponding Author: A. Rodrigues Hoffmann, Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.
Email: [email protected]
Riassunto
Il microbioma è il complesso insieme dei microrganismi, dei loro geni e dei loro metaboliti, che colonizzano le superfici mucosali umane e animali, l’apparato digerente e la pelle. È ormai noto che il microbioma interagisce con il suo ospite, assistendolo nella digestione e nella disintossicazione, sostenendolo nell’immunità, proteggendolo contro gli agenti patogeni, e mantenendo la salute.
Gli studi finora pubblicati hanno dimostrato che gli individui sani sono spesso colonizzati con microbiomi differenti, rispetto a quelli con malattie che coinvolgono vari apparati.
Questa recensione riguarda una breve storia dello sviluppo del campo del microbioma, gli obiettivi principali dello Human Microbiome Project (Progetto del Microbioma Umano), ed i microbiomi più comuni che abitano il tratto respiratorio umano, il tratto digestivo degli animali da compagnia, e la pelle, negli esseri umani e negli animali da compagnia.
Essa descrive i principali cambiamenti nel microbioma di pazienti con lesioni polmonari, gastrointestinali e cutanee.
Parole-chiave:
microbioma, ecologia microbica, progetto del microbioma umano, respiratorio, gastrointestinale, pelle
I diversi microrganismi (funghi, protozoi, batteri, archaea, batteriofagi, e virus di eucarioti), che vivono nel corpo e sul corpo degli esseri umani e degli altri animali, sono più di una semplice collezione di microbi.
Il microbioma comprende la serie completa dei microrganismi, dei loro geni e dei loro metaboliti.
Il microbioma si è co-sviluppato con gli esseri umani ed animali, aiutandoli in tal modo nella digestione e nella disintossicazione, supportando l'immunità, proteggendoli contro gli agenti patogeni invasori, e mantenendone la salute globale.
Con 1014 specie, comprendenti almeno 20 milioni di geni microbici unici, il microbioma costituisce la più grande componente genetica del super-organismo umano ed animale. Gli ecologisti microbici, che hanno studiato i microrganismi e le comunità microbiche nell’ambiente, hanno subito riconosciuto che la maggior parte dei microrganismi in natura non era facilmente colturabile, e così hanno sviluppato approcci alternativi allo studio delle comunità microbiche.
Un approccio precoce ed ampiamente adottato, per indagare i microrganismi nell’ambiente, è stato quello dell'uso del gene 16S dell’RNA ribosomiale (rRNA) come marker tassonomico, per investigare la diversità batterica in natura 71. Con la crescita delle tecniche molecolari basate sulla non-coltura, per studiare i microrganismi e le comunità ambientali, alcuni medici microbiologi hanno iniziato a utilizzare questi strumenti per studiare il corpo umano, ed hanno trovato una diversità microbica molto maggiore del previsto, anche in siti ben studiati, come la cavità orale 7,15,70.
Nel campo delle malattie infettive, cresceva il riconoscimento che molte malattie non potevano soddisfare i postulati di Koch, poiché la loro patogenesi sembrava coinvolgere più microrganismi.
Il termine “malattie polimicrobiche” è stato coniato per descrivere queste malattie derivanti da un’infezione concomitante con più agenti infettivi 11, come si è visto per gli ascessi, le infezioni opportunistiche legate all'AIDS, la congiuntivite, la gastroenterite, l’epatite, l’otite media, le malattie periodontali, le malattie respiratorie e le infezioni genitali. Tuttavia, ora riconosciamo la complessità aggiunta in queste malattie, posto che le vediamo come intere comunità microbiche, e cominciamo a capire come i batteri, che le compongono, interagiscano tra loro e con l'ospite.
In un saggio sulla storia della microbiologia e delle malattie infettive, Lederberg 73 ha coniato il termine “microbioma”, ed ha chiesto una “metafora più ecologico-informata’’ per capire il rapporto tra gli esseri umani ed i microbi.
Questa revisione include un'introduzione al Progetto del Microbioma Umano (HMP) degli Istituti Nazionali della Salute (NIH), e considera il microbiota che abita il tratto respiratorio umano, l'apparato digerente negli animali da compagnia, e la pelle negli esseri umani e nei cani, in salute e malattia.
Il progetto sul microbioma umano (HMP) del NIH
Al fine di valutare meglio il ruolo del microbioma nella salute e nella malattia, il NIH ha lanciato il HMP, che si è concentrato sul rilevamento dei microbiomi presenti nei diversi sistemi di organi (www.commonfund.nih.gov/hmp).
Il NIH-HMP è stato diviso in 2 fasi:
• La Fase 1 ha esaminato i microbiomi delle principali regioni del corpo, in individui sani ed in pazienti malati,
• La Fase 2 ha esaminato le proprietà biologiche di questi microbiomi.
Gli studi iniziali si sono focalizzati sul tratto digestivo 23,39, ed hanno dimostrato l'enorme complessità, così come il potenziale funzionale, del microbioma umano.
Fase 1 – Studio sulla coorte di adulti sani
Durante la prima fase dello HMP (2007-2012), i principali obiettivi erano:
1) l’esame dei microbiomi di adulti sani, per produrre un set di dati di riferimento
2) lo sviluppo di un catalogo di sequenze genomiche dei ceppi microbici di riferimento
3) la valutazione delle caratteristiche dei microbiomi associati a malattie specifiche, in una raccolta di progetti di dimostrazione HMP (Tabella 1) 96.
Sono stati esaminati i microbiomi in 5 grandi regioni del corpo di adulti sani (vie respiratorie, pelle, cavità orale, tratto digerente e vagina).
Da questi studi, il Consorzio HMP ha pubblicato 2 documenti fondamentali nel 2012, che descrivono la gamma della normale variazione microbica tra gli adulti sani, in una popolazione occidentale 49,50. Una scoperta importante è stata quella per cui, anche se la struttura della comunità microbica varia notevolmente tra gli habitat del corpo, le potenziali capacità metaboliche codificate nei metagenomi di queste comunità erano molto più costanti. Vale a dire: anche se la composizione tassonomica microbica variava tra gli individui sani, le loro funzioni metaboliche collettive rimanevano notevolmente stabili, all'interno di ciascun sito del corpo 1.
Un'altra risorsa chiave di questa fase è stata il catalogo della sequenza microbica del genoma di riferimento HMP, che comprende la più grande collezione di sequenze genomiche microbiche umane-associate, tra cui batteri, batteriofagi, virus di eucarioti ed eucarioti microbici (NCBI, http://www.ncbi.nlm.nih.gov/bioproject/43021; Bioproject PRJNA28331).
Ciononostante, con decine di migliaia di ceppi batterici, e con un numero imprecisato di ceppi fungini, virali e protisti nel microbioma umano, resta molto lavoro da fare, per creare un catalogo completo dei genomi di riferimento 31.
Circa il 15% dei campioni raccolti nello studio sulla coorte dei sani sono stati sequenziati col sequenziamento completo del genoma shotgun (WGS), per produrre sequenze metagenomiche per le 5 principali regioni del corpo nello studio. Per valutare e confrontare lo studio della coorte dei sani con altri individui, sono stati lanciati 15 studi di Progetto Dimostrativo, concentrati sulle malattie gastrointestinali (morbo di Crohn, colite ulcerosa, sindrome infiammatoria intestinale pediatrica, enterocolite necrotizzante neonatale, adenocarcinoma esofageo, e febbre pediatrica idiopatica), sulle condizioni urogenitali (vaginosi batterica, uomini con circoncisione), sulle malattie della pelle (eczema, psoriasi, acne), e sui pazienti con obesità.
I risultati della Fase 1 hanno compiuto molte cose per questo “campo”, anche se hanno sollevato anche nuove domande circa i migliori approcci per l'identificazione dei fenotipi a firma caratteristica. È stato osservato che, in molti casi, la composizione tassonomica dei soli microbiomi non era sufficiente a definire un “core microbiome” (“microbioma di nucleo”, “microbioma centrale”) associato a specifiche malattie o a stati di salute.
Piuttosto, le predette vie metaboliche di questi microbiomi sembravano avvicinarci a questo obiettivo.
Tabella 1. Obiettivi principali del Progetto del Microbioma Umano, divisi in 2 fasi.
Fase 1
1) Esaminare i microbiomi di adulti sani - produrre una serie di dati di riferimento dei microbiomi.
Cinque principali regioni del corpo di adulti sani - vie aeree, pelle, cavità orale, tratto gastrointestinale e vagina.
2) predisporre un catalogo delle sequenze genomiche microbiche dei ceppi di riferimento.
Oltre 2600 genomi batterici e 100 virus batteriofagi ed eucariotici sono stati sequenziati, assemblati, annotati e depositati presso il NCBI.
3) Risorsa dei dati di sequenza metagenomica dallo studio della coorte dei sani:
Cinque grandi regioni del corpo di adulti sani.
4) Valutare specifiche malattie associate al microbioma:
Malattie gastrointestinali: morbo di Crohn, colite ulcerosa, sindrome infiammatoria intestinale pediatrica, enterocolite necrotizzante neonatale, adenocarcinoma esofageo, obesità, febbre pediatrica idiopatica.
Condizioni urogenitali: vaginosi batterica, storia riproduttiva, storia sessuale, circoncisione.
Malattie della pelle: eczema, psoriasi, acne.
Fase 2
Sviluppare un insieme di dati sulle molteplici proprietà biologiche del microbioma, ed analisi metagenomica dell’ospite in merito alle predette vie metaboliche in questi microbiomi.
Modelli di malattie o condizioni, associate al microbioma, ponendo l’attenzione sul microbioma e l’ospite (madre e bambino) da donne in gravidanza, da coorti con malattie infiammatorie intestinali, e da pazienti in transizione dallo stato prediabetico al diabete di tipo 2.
Fase 2 del HMP (2013-2015)
La Fase 2 del HMP (2013-2015) si è focalizzata sullo sviluppo di un insieme di dati di molteplici proprietà biologiche del microbioma e dell’ospite, da studi ben caratterizzati sulla coorte (www.hmp2.org).
Una proprietà cardinale dei microbi è la loro versatile capacità metabolica, che non è specifica del taxon.
In altre parole, più di 2 microbi indipendenti possono avere la capacità di scomporre un componente comune nella nostra dieta, e questo può significare che la composizione della comunità microbica potrebbe non essere la migliore proprietà del biomarcatore per caratterizzare le condizioni umane specifiche. Pertanto, la Fase 2 è stata progettata per raccogliere le proprietà biologiche multi-omiche del microbioma, quali i profili di espressione genica (cioè, il metatranscriptoma) 33,48,128, i profili proteici (cioè, il metaproteoma) 127 , i profili dei metaboliti dell’ospite ed il microboma (cioè, il metaboloma) 16, e relative proprietà pertinenti dell'ospite, da coorti ben caratterizzate.
Questi studi si stanno concentrando sul microbioma e sull’ospite (madre e figlio) per le donne incinte a rischio di parto pre-termine, sui microbiomi intestinali delle coorti a rischio di malattia infiammatoria intestinale (IBD), e sull'intestino e sui microbiomi nasali di coorti a rischio di diabete di tipo 2 54.
Questi dati, e l’insieme risultante integrato di dati, che saranno depositati in banche-dati pubbliche, permetteranno alla comunità scientifica di valutare le proprietà del microbioma o le combinazioni di proprietà, e forniranno nuove informazioni sul ruolo del microbioma nella salute e nella malattia.
Il microbioma del tratto respiratorio superiore
Il tratto respiratorio superiore dell’uomo (URT), che comprende il naso, la gola e la cavità orale, è colonizzato da una comunità microbica complessa e dinamica. Collettivamente, le vie aeree superiori, in particolare la cavità orale, rappresentano il sito del microbioma più vario nel corpo, che ospita anche una ricchezza di specie batteriche maggiore di quella del tratto digestivo 51,75,111.
Quale sito delle interazioni iniziali con molti microbi ambientali, attraverso la respirazione e l'ingestione, un ruolo importante del microbiota commensale è l’essere la prima linea di difesa contro gli agenti patogeni di potenziali patogeni “supercompetenti” e colonizzatori (antagonismo microbico) 65,82.
In sostanza, occupando tutti i siti di legame nel tratto respiratorio superiore (URT), qualsiasi agente patogeno invasore deve in qualche modo combattere con questi organismi, oltre che con le difese dell'ospite.
È importante sottolineare che il microbiota delle vie respiratorie, come quelli di altre superfici mucosali, è solidale nell’adescamento e nell’educazione del sistema immunitario 72 e nel regolare l'immunità nei polmoni in risposta alle infezioni 52. Fino ad oggi, la maggior parte dei ricercatori hanno utilizzato il sequenziamento del gene 16 S rRNA, per caratterizzare le comunità batteriche delle vie respiratorie. Non sono state studiate le comunità fungine e virali, con l'eccezione degli studi focalizzati sui patogeni.
I passaggi del naso e dell'orofaringe ospitano un microbiota distinto. Negli adulti sani, i passaggi nasali sono tipicamente dominati da Actinobacteria (Propionibacterium, Corynebacterium) e Firmicutes (Staphylococcus), mentre i Firmicutes (Veillonella, Streptococcus, Staphylococcus) sono più prevalenti nell’orofaringe 14,51,740 (Fig. 1).
È importante sottolineare che il microbiota residente nelle vie aeree superiori include molti batteri patogeni che colonizzano asintomaticamente, come lo Streptococcus pneumoniae, lo Staphylococcus aureus, la Moraxella catarrhalis, e l’Haemophilus influenzae 35. Per questi organismi, la distinzione tra patogeni commensali e opportunisti è sfocata.
Quando le difese dell’ospite sono compromesse in questi siti e nel tratto respiratorio inferiore (LRT), l’aspirazione di batteri dall’URT nei polmoni può causare gravi infezioni respiratorie 27.103.
Oltre agli agenti patogeni, il microbiota commensale può anche essere un serbatoio di geni di resistenza antibiotica e di virulenza 35,76. Posto che molti commensali e patogeni del tratto respiratorio sono naturalmente competenti, ossia hanno la capacità di accogliere il DNA esogeno (ad esempio, Streptococcus, Haemophilus, Neisseria) 56,58, sotto pressione selettiva, la resistenza agli antibiotici può probabilmente diffondersi rapidamente in questa comunità.
La maggior parte degli studi sul microbiota dell’URT sono stati compiuti su adulti sani 14,24,74. Tuttavia, è importante considerare che i gruppi più a rischio di infezioni respiratorie sono i giovanissimi e gli anziani 3,60.
Bogaert et al. 10 hanno esaminato in profondità i bambini sotto i 2 anni di età nei Paesi Bassi, ed hanno osservato 4 gruppi, 3 dei quali dominati da una singola unità operativa tassonomica (Moraxella, Haemophilus o Streptococcus), ed uno che era misto 10. Risultati simili sono stati osservati in un recente studio su bambini sani di una città canadese, tranne che un gruppo Haemophilus-dominante non osservato 110.
Il microbiota di bambini piccoli (
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