a staggering number of microbes reside in and upon the human body ( dethlefsen et al . , 2007 ) . our co - evolution with this microbiota has resulted in the integration of microbially derived developmental cues and metabolic capacities into human biology ( backhed et al . , the vast majority of the 10100 trillion microbial cells that inhabit the human body are found within the distal digestive tract . an altered intestinal microbiota composition has been linked to numerous pathologic states such as inflammatory bowel diseases and obesity in mouse models and in humans ( ley et al . , 2005 , 2006 ; frank et al . , 2007 ) . in some cases an etiological relationship between the microbiota and disease state has been established ( turnbaugh et al . , 2006 ; garrett et al . , 2007 ; vijay - kumar et al . , 2010 ) . thus , human biology and health are intimately intertwined with the biology of our microbial inhabitants . ongoing large - scale sequencing efforts are providing a comprehensive sequence - based definition of this intestinal microbiota ( qin et al . , 2010 ) . typically two bacterial phyla dominate the healthy western adult intestine , the firmicutes and bacteroidetes compose > 90% of the bacterial cells . proteobacterium and bifidobacterium and a handful of other bacterial phyla make up the remainder of the community , along with members of archaea and eukaryota . despite the limited representation of bacterial phyla , at finer scales of phylogenetic resolution , such as species and strain , the intestinal microbiota is highly diverse and exhibits substantial compositional variability between people , and thus represents an  individualized fingerprint . in addition to inter - individual variability , the microbiota exhibits temporal variability , likely due to the numerous factors that continually perturb this dynamic microbial ecosystem , such as changes in host diet and introduction of orally acquired pathogens . the tremendous foundation of microbiome sequencing data is propelling human microbiota studies into a second phase focused on function and mechanism . recently published metagenomic data highlight the overlap and conservation of core functionalities within the intestinal microbiome of different individuals ( turnbaugh et al . this similarity embedded within the combined genomes of different consortia reveals that each person 's gut is endowed with a core set of genes ( a core microbiome ) that carry out functions common to the human intestine . this new phase of investigation , which is focused on the emergent properties of the host  microbial super - organism , is attracting biomedical scientists from diverse fields , including virologists . the ability of an orally acquired pathogen to cause disease is dependant upon multiple steps that the microbiota may influence . a pathogen must navigate through the dense community of microbes , gain access to the epithelial surface , and manage the ensuing immune response . commensal microbes present significant competition for nutrients ( sonnenburg et al . , 2006 ) , secrete microbicidal proteins ( corr et al . , 2007 ) , and elicit host responses that are fundamental to the development and maintenance of the mucosal innate and adaptive immune system ( cebra , 1999 ; hooper et al . , 2001 ; despite this seemingly inhospitable environment , pathogens can gain access to host tissue and cause disease . the role of the intestinal microbiota in reducing host susceptibility to enteric bacterial pathogens is commonly referred to as  colonization resistance ,  although the underlying mechanisms are poorly understood . the increased susceptibility of oral antibiotic - treated mice or humans to enteric infection nicely illustrates the potential impact of microbiota perturbation on pathogen emergence ( pavia et al . , 1990 ; barthel et al . , 2003 ; doorduyn et al . , 2006 ; lawley et al . , 2009 ) . furthermore , treating infectious diarrheas with live microbial supplements ( i.e. , probiotics ) has proven successful in decreasing the duration of symptoms , but the mechanisms of action and whether such treatment is more effective for certain causative agents ( e.g. , bacterial vs. viral ) remain obscure ( servin , 2004 ; vandenplas et al . , 2007 ; guandalini , 2008 ; allen et al . , together , these data support that alterations in host - associated microbial communities can impact an ensuing interaction with a pathogen . the gut microbiota influences the status of the host immune system during development and throughout life . the host typically maintains a dynamic and attenuated physiological state of inflammation in the mucosa that is tuned to the membership of the adjacent microbial community ( cebra , 1999 ) . for example , in an experimental model of chemically induced intestinal epithelial injury , cell damage is exacerbated in the absence of a microbiota or if the mice are deficient in myd88 , an adaptor protein critical for toll - like , receptor - mediated recognition of the commensal microbiota ( rakoff - nahoum et al . , 2004 ) . similarly , salmonella - induced inflammation becomes more severe in the absence of an intestinal microbial community ( stecher et al . , 2005 ) . antimicrobial protein secretion ( hooper et al . , 2001 ) , induction of secretory iga ( moreau et al . , 1978 ; shroff et al . , 1995 ) , th1:th2 bias ( mazmanian et al . , 2005 ) , and recruitment of the myeloid and lymphoid cell lineages to the gut ( cebra et al . , 1998 ; therefore , aspects of mucosal and systemic immunity are similar in concept to a rheostat , with the microbiota playing a significant role in modulating the set - point . the concept that microbial modulation of the immune system can alter pathogen susceptibility is illustrated in a mouse model of latent herpesvirus infection . in this model , the latent virus is capable of elevating steady state levels of ifn- , effectively altering the set - point of the immune system and decreasing the host susceptibility to intracellular bacterial pathogens ( barton et al . , 2007 ) . the increased resistance to listeria monocytogenes and yersinia pestis of mice harboring latent herpesvirus implies that such dormant viruses ( most humans possess several such herpesviruses ) may be viewed as symbionts with mutualistic potential . these data are also suggestive that these same principles may apply to the microbiota : specifically , host immune status may be modulated by commensal microbes prior to pathogen exposure to alter host resistance to infection . since the vast majority of infections begin at the mucosal surface , it is not surprising that pathogen susceptibility may be impacted by the presence or absence of resident microbes that are capable of influencing local and systemic aspects of immunity . segmented filamentous bacteria ( sfb ) , an intestinal resident of mice , were recently identified as necessary and sufficient to induce th17 development in the gut ( ivanov et al . , 2009 ) . in this same study , the presence of sfb proved critical in minimizing the inflammation caused by a colitis - inducing bacterial pathogen , citrobacter rodentium . similarly , alteration in host susceptibility to respiratory infection following intestinal exposure to a specific microbe has been reported . in an experimental model of cryptococcus neoformans - induced pulmonary eosinophilia , the th2-driven pathology can be abrogated by prior introduction of c. rodentium into the digestive tract ( williams et al . , 2006 ) . c. rodentium inflammation induces a th1-response , which reduces the th2-skewing and c. neoformans - associated pulmonary inflammation . this protective effect is lost if mice are colonized with a mutant strain of c. rodentium that is deficient in the intimin receptor , and therefore is incapable of attaching to the host colonic epithelium and unable to induce a th1 response . similarly , multiple studies have illustrated the ability of either chronic or acute parasitic infection in the intestine to influence immune responses in the lung , specifically decreasing allergic airway inflammation ( wilson et al . the ability of a group of clostridium species to induce regulatory t - cells in the colon and decrease the severity of colitis and ige responses in a mouse model further affirms the role of gut microbes in modulating aspects of mucosal and systemic immune function ( atarashi et al . in addition to acting through the immune system , the intestinal microbiota may impact pathogens more directly . the emergence of bacterial pathogens , such as clostridium difficile and salmonella spp . , during or shortly after antibiotic treatment , suggests the loss of inhibitory effects of the microbiota upon antibiotic - induced disruption . several bacterial pathogens , such as salmonella and citrobacter , appear to subvert the host immune response within the intestine causing persistent microbiota disruption thus aiding their own proliferation ( lupp et al . , 2007 ; competing for nutrients , physically obstructing access to the mucosa , and producing antimicrobial proteins have all been proposed as mechanisms that contribute to colonization resistance ( stecher and hardt , 2008 ) . the bacteriocin , abp118 , produced by a lactobacillus salivarius strain , is capable of killing l. monocytogenes , and its production in vivo is required to protect the host in a murine model of oral listeria infection ( corr et al . , 2007 ) . this example provides a glimpse of the type of warfare that can take place amongst and between permanent and transient gut residents . alternatively , egg hatching of trichuris muris , a nematode that invades the intestinal epithelium of mice , is enhanced in the presence of the microbiota - derived microbes in vitro , and t. muris burden is decreased after antibiotic knock - down of the microbiota ( hayes et al . , 2010 ) . the ability of multiple pathogens to infect in the absence of apparent microbiota disruption ( i.e. , not all orally acquired pathogens require antibiotic treatment to emerge and cause disease ) suggests that several infectious agents may be adapted to and benefit from the microbiota in a normal state . in general , the microbiota may enhance viral infection , reduce viral infection , or have no effect on viral infection . in instances when the microbiota influences viral infection , it may be via direct mechanisms , such as virion modification , or indirect mechanisms , such as host cell modification . direct effects of the microbiota on viruses are likely to occur locally , whereas indirect effects may occur locally or systemically . several studies have shown that the microbiota has the potential to reduce viral infection and disease . first , germ - free mice have enhanced susceptibility to influenza a virus ( dolowy and muldoon , 1964 ) , coxsackie b virus ( schaffer et al . , 1963 ) , and friend virus ( mirand and grace , 1963 ) , which suggests that the microbiota directly or indirectly limits disease in mice with a conventional flora . second , while dengue virus is a blood - borne pathogen in mammals , it initiates mosquito infection through the enteric route . interestingly , dengue virus replication is enhanced in the midguts of antibiotic - treated mosquitoes , which suggests that the insect microbiota limits viral replication . these effects may occur indirectly via microbiota - mediated anti - viral immune activation through the toll pathway ( xi et al . , 2008 ) . third , adenovirus replication is inhibited by defensins , which are antimicrobial peptides produced by the host in response to the microbiota ( gropp et al . , 1999 ) . defensins directly bind adenovirus virions and limit replication in vitro ( smith and nemerow , 2008 ) . therefore , the microbiota may limit adenovirus infection through induction of host defense mechanisms , although the effects of defensins on enteric viruses in vivo is unknown . conversely , several studies have shown that microbial products can indirectly enhance viral replication and disease . first , persistence of mouse mammary tumor virus is enhanced by lipopolysaccharide ( lps ) , a component of gram - negative bacteria . lps activates the innate immune pathways culminating in il-10-mediated tolerance and viral persistence in mice ( jude et al . second , theiler 's murine encephalitis virus - induced replication and disease in the central nervous system is enhanced by treatment with lps . these effects likely occur through indirect mechanisms involving increased inflammation in the central nervous system , which promotes viral replication ( pullen et al . , 1995 ) . in future work , it will be important to determine whether native microbiota - derived lps , rather than experimentally administered lps , is sufficient to promote viral infection . third , human immunodeficiency virus ( hiv ) pathogenesis and progression to acquired immunodeficiency syndrome ( aids ) is enhanced by lps - mediated chronic immune activation from microbial translocation through the intestinal wall ( brenchley et al . , 2006 ) . therefore , the microbiota may indirectly enhance progression to aids through indirect immune activation mechanisms . when considering effects of the microbiota on viruses , it is important to be mindful of the evolutionary potential of viruses , particularly rna viruses . viruses have error frequencies up to a million - fold higher than bacteria or mammals and likely evolved to replicate in their respective niches , including niches containing a microbiota . thus , the hypothesis that some viruses will generally fare worse in the absence of the microbiota with which they have evolved will be important to test using microbiota - deficient mice . clearly , it is important to understand how the microbiota influences viral infections , but what are the major questions to address ? the questions will be shaped by virus type . for example , the intestinal microbiota may have direct and indirect effects for enteric viruses that directly encounter them in the intestinal lumen ( enterovirus , rotavirus , norwalk virus , astrovirus , etc . ) . however , the intestinal microbiota may also impact non - enteric viruses through indirect mechanisms . several viruses encounter host  microbiota at other body sites , such as skin and the genital tract ( hiv , papilloma virus , herpes simplex virus , etc . ) . therefore , microbiota may affect a wide variety of viruses through diverse mechanisms ( figure 1 ) . potential roles that commensal microbes within the intestine may play in host susceptibility to virus . ( a ) a commensal may inhibit a virus ( top left panel ) directly ( a ) , or indirectly at a local site ( b ) , or at a peripheral site such as the lung ( c ) . conversely , this same commensal may promote viral infectivity ( lower left panel ) via these same mechanisms , such as directly activating the virus ( a ) , recruiting leukocytes that promote / permit viral replication ( b ) , or setting systemic immune parameters that are permissive for viral replication at a distant site ( c ) . ( b ) other commensals may have opposite effects on the same viruses , and alterations in microbiota composition or functional state may shift the balance in favor of the first or second scenario . the first step is to determine the impact of the microbiota on various viruses by depleting the microbiota and quantifying viral replication and pathogenesis . mouse models will be very useful for these experiments , provided that there is an appropriate mouse model for the virus of interest . mice are naturally resistant to many pathogens , including viruses , often requiring the use of immunodeficient or neonatal mice for pathogenesis studies . microbiota depletion can be accomplished with broad - spectrum antibiotic treatment or the use of germ - free animals . antibiotic treatment is an attractive option since it is relatively simple and inexpensive and can be used with any animal model . however , in antibiotic - treated animals , microbiota clearance is incomplete , the ratios of various species are altered , and the antibiotics can indirectly alter the host via microbiota - independent effects ( rakoff - nahoum et al . , 2004 ) . another negative is that antibiotic - mediated microbiota clearance requires 1  week or more , and since neonatal mice are required for some viral pathogenesis models , the antibiotic model is not ideal . germ - free mice are completely microbiologically sterile , eliminating background and allowing recolonization with specific microbes to examine specificity of microbiota effects . however , germ - free mice require highly specialized facilities , are expensive , and a limited number of germ - free mouse strains are available . additionally , germ - free mice have immature immune systems and altered intestinal physiology , which may complicate interpretation of experiments ( smith et al . , 2007 ) . a combination of experiments with antibiotic - treated mice and germ - free mice may be necessary to paint a complete picture of microbiota effects on viruses . retrospective and/or prospective studies on humans treated with antibiotics and their incidence of viral infections may also be useful in evaluating microbiota effects on viruses . once the impact of the microbiota has been established for a given virus , the second step is to determine whether effects occur through direct or indirect mechanisms . the microbiota may directly alter the infectivity of viral particles through virion modification or processing . it is also possible that virions may  hitchhike  on motile bacteria to access host cells . for example , the microbiota may promote or limit viral replication by altering innate and/or adaptive immune responses , changing the susceptibility of host cells , or altering viral receptor expression . a variety of experimental systems will be useful to determine the nature of microbiota effects on viruses . for example , direct effects of microbiota on virions can be examined through in vitro mixing experiments and infectivity assays . indirect microbiota effects on viruses mediated by innate immune responses can be examined in mouse strains lacking components of the innate response . the specificity of microbiota effects can be examined by colonizing germ - free mice with specific types of bacteria to determine whether a particular type of bacteria is sufficient to affect the virus of interest . together , these types of experiments will reveal the basics of microbiota  virus interactions and will provide information for detailed mechanistic studies in the future . it is clear that the microbiota provides a major source of biological variation between individuals , and it is a contributor to numerous biological processes . microbiota plasticity , which is significantly greater than that of our own genome , may be harnessed to modulate aspects of human health , such as optimizing resistance to certain pathogens . the link between microbiota perturbation and enteric pathogen emergence illustrates that investigation into the factors that govern microbiota stability could have great significance for humans . alternatively , if certain members of the microbiota , or certain functions encoded within the microbiota , are co - opted by viruses and are required for invasion of host tissue , this set of interactions presents new therapeutic targets . the possibility of leveraging the microbiota 's role in infectious disease as a platform to alter the course of infections presents many important questions . can we rationally and reproducibly manipulate the composition and function of our intestinal microbiota ? can this manipulation be performed in ways that prevent or ameliorate human disease ? to address these questions , it is critical to lay a foundation of basic research that will establish the fundamental principles that govern this complex set of interactions . highly controlled studies in model system are needed to establish how the gut microbiota may be manipulated rationally through the use of orally administered microbes ( probiotics ) , dietary supplementation ( prebiotics ) , and/or microbiota - targeted small molecules to optimize host resistance to infectious disease . as we expand our understanding of pathogens that possess diverse routes of invasion , tropisms , and/or toxins , and we investigate how this biology intersects with the host  microbiota interaction , strategies for using this information to improve human health for example , interferon ( ifn ) signaling is an important part of the immune response to many viral infections ; however , this system is a target for inhibition by many viruses . identifying a microbiota manipulation ( e.g. , dietary change or probiotic administration ) that induces a mild anti - viral - like ifn response suggests a strategy for pre - conditioning the host immune response to provide increased resistance during periods of heightened vulnerability ( e.g. , in infancy or during epidemics ) . tuning the immune rheostat to desired set - points using microbial exposure ( i.e. , colonization status ) provides a promising avenue that may have broad applicability . identification of biomarkers of these host responses , which can be surveyed in feces , urine , or blood , will enable these responses to be tracked and appropriately altered . the ability to modulate the status of the mucosal immune system has implications for improving the efficacy of oral vaccination campaigns . one such example is the global effort to eradicate wild poliovirus , which has stalled in recent years due to the failure of oral polio vaccines to achieve seroconversion of children in developing nations . in the indian states of uttar pradesh and bihar , less than 71% of children are protected against type 1 poliovirus despite an average of 15 oral doses of trivalent vaccine per child before 5  years of age ; 85% protection is achieved with 10 average doses across the rest of india ( grassly et al . , 2006 ) . this failure in protection is seen in several developing regions of the world with poor sanitation and has been linked to diarrhea and the presence of enteric viruses ( myaux et al . , 1996 ) . these studies lend further evidence that the status of the mucosal immune system and/or stability of the microbiota dictates responsiveness to newly encountered agents ( whether vaccines or pathogens ) and places additional importance on pursuing a mechanistic understanding of how the relationship between the microbiota and mucosal immune system may be optimized to reduce viral disease and to improve the efficacy of oral vaccines . a logical and likely extension of personal genomes is the personal microbiome , elucidating the genes encoded by the core species or taxa within an individual 's intestine . with ever the increasing understanding of how the biology of host and microbiota integrate , these two sets of dna sequences will offer insight into current or looming pathologies by identifying potential deleterious combinations of polymorphisms in the genes of host and microbiota . the microbiome offers a set of genes much more amenable to manipulation compared to our human genome . a prerequisite for incorporating the microbiota into personalized , preventative medicine is to attain a mechanistic understanding of microbiota function and to understand how microbes within the intestine affect the resistance and susceptibility to pathogens ( nicholson et al . , 2005 ; zaneveld et al . , the rational manipulation of our  microbial self  will soon be a reality , and it is imperative to understand which manipulations will promote human health . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
many infections start with microbial invasion of mucosal surfaces , which are typically colonized by a community of resident microbes . 
 a growing body of literature demonstrates that the resident microbiota plays a significant role in host susceptibility to pathogens . 
 recent work has largely focused on the considerable effect that the intestinal microbiota can have upon bacterial pathogenesis . 
 these studies reveal many significant gaps in our knowledge about the mechanisms by which the resident community impacts pathogen invasion and the nature of the ensuing host immune response . 
 it is likely that as viral pathogens become the focus of studies that examine microbiota  host interaction , substantial effects of resident communities exerted via diverse mechanisms will be elucidated . here 
 we provide a perspective of the exciting emerging field that examines how the intestinal microbiota influences host susceptibility to viruses .