a mature human gut harbors a vast number of bacterial residents referred to as 
 the commensal microflora or more recently as  microbiota . it has been 
 estimated that this microbiota is made up of more than 10 individual 
 bacteria comprising over 500 different species . notably , the composition of the 
 microbiota is individual specific and the type of species residing in the gastrointestinal 
 ( gi ) tract varies with the host organism 's age , diet , and health status . in fact , the total number of microbes 
 in the human gi tract far exceeds ( > 10100 times ) the 
 sum of all our somatic and germ cells . the biological outcome of this vast and 
 complex population of microbes is that their genes ( termed the microbiome ) 
 synthesize about 100 times more proteins than the somatic cells of their host . not 
 surprisingly , the human intestine is more densely populated with microorganisms 
 than any other organ and is a site where they exert a strong influence on human 
 biology . this is because the intestinal 
 mucosa serves as the primary border between the immune system and the external 
 environment , and in addition plays a central role in host - commensal flora 
 interactions . accumulating evidence indicates that the gut microbiota is 
 instrumental in supporting energy metabolism and immune function of the host . more recent studies suggest that the commensal microbiota play an important 
 role in the development of numerous conditions , including obesity [ 4 , 5 ] , diabetes , nonalcoholic fatty liver disease , inflammatory bowel disease , and perhaps cancer . unfortunately , the immense complexity 
 of gut flora together with its highly complicated interactions with intestinal 
 epithelium makes it a recalcitrant system to study . although largely 
 unexplored , our gut microbiota plays an intricate and under - appreciated pivotal 
 role for our health and well - being . in this review we will discuss new 
 developments in the field that highlight the cellular and molecular basis of 
 the crosstalk between the host , the commensal microbiota , and pathogenic 
 bacteria in a healthy as well as a diseased gi tract . the 
 microflora of the intestinal microenvironment as a unit provides important 
 protective , metabolic , and trophic functions . resident bacteria serve a central 
 line of resistance to colonization by exogenous microbes , and thus assist in 
 preventing the potential invasion of the intestinal mucosa by an incoming 
 pathogen . this protective function is known as the barrier effect or colonization 
 resistance and serves a number of important roles . for instance , adherent 
 nonpathogenic bacteria can often prevent attachment and subsequent entry of 
 suspected pathogens into epithelial cells , as well as compete for nutrient 
 availability . the commensal microbiota 
 also helps maintain gi nutrient homeostasis by administering and consuming all 
 resources . for example , dietary 
 nutrients are absorbed by the gut and together with various nonnutrient 
 compounds produced by the microbiota are cometabolize by host enzymes , such as 
 cytochrome p450 and conjugating enzymes in the liver . the resulting metabolites that are 
 derived from both host and microbial processes are returned to the gut by the 
 bile for further metabolism or excretion . this mutual and beneficial relationship 
 helps to dampen unwanted overproduction of nutrients , which could potentially 
 support intrusion of microbial competitors with a potential pathogenic outcome 
 for the host . quite 
 remarkably , an absence of intestinal bacteria is associated with reduction in 
 mucosal cell turnover , vascularity , muscle wall thickness , motility , baseline 
 cytokine production , digestive enzyme activity , and defective cell - mediated 
 immunity . indeed , comparative studies in 
 germ - free and conventional animals have established that the intestinal 
 microflora is essential for the development and function of the mucosal immune 
 system during early life , a process that is now known to be important to 
 overall immunity in adults . for example , it has been well established that the 
 number of intraepithelial and lamina propria t cells is lower in germ - free 
 animals , a feature that is reversed upon the restoration of the normal flora . likewise , levels of secretory iga are 
 low in the intestine of germ - free animals but are markedly increased upon 
 intestinal colonization of the commensal bacterium , bacteroides thetaiotamicron . furthermore , the intimate relationship 
 between the commensal microbiota and the intestinal epithelium are involved in 
 shaping the memory mechanisms of systemic immunity , such as oral tolerance . this was initially recognized by the discovery that the systemic response to a 
 specific pathogen can be abrogated after ingesting the antigen ; this effect 
 continues for several months in conventionally colonized mice , whereas in 
 germ - free mice systemic unresponsiveness persists for only a few days . therefore , the innate immune system 
 discriminates between potential pathogens from the commensal microbiota by 
 inducing tolerance to microbial epitopes . this , in turn , dampens responses to 
 commonly encountered foodstuffs and other environmental antigens . collectively , 
 these examples help to illustrate the important concept that the commensal 
 microbiota profoundly influence the development of the gut mucosal immune 
 system and are essential in preventing exogenous pathogen intrusion . the intestinal microflora also makes 
 important metabolic contributions by producing vitamin k , folate , and short - chain 
 fatty acids ( a major energy source for enterocytes ) , and mediates the breakdown 
 of dietary carcinogens as well [ 2 , 17 ] . perhaps the major metabolic function of the colonic 
 microflora is the fermentation of nondigestible carbohydrates . these 
 nondigestible carbohydrates include large polysaccharides ( i.e. , resistant 
 starches , pectins , cellulose ) , some oligosaccharides that escape digestion , as 
 well as unabsorbed sugars and alcohols . the primary metabolic endpoint of such 
 fermentation is the generation of short - chain fatty acids ( acetate , 
 proprionate , butyrate ) . a fundamental role of short - chain fatty acids on 
 colonic physiology is their trophic effect on the intestinal epithelium . therefore , short - chain fatty acids appear to play an essential role in the 
 control of epithelial cell proliferation and differentiation in the colon . moreover , it has been shown that commensal bacterial can modulate gene 
 expression in the host in order to create a sustainable environment for 
 themselves , while at the same time prevent the growth of other competitive 
 bacteria within the intestinal ecosystem . for the host to thrive and produce more 
 gut residents , the gut microbial ecosystem must be functionally stable over 
 time despite the internal dynamics of the community . constituent bacteria are 
 expected to have a high degree of functional redundancy between species , so 
 that the loss of one lineage does not adversely impact the homeostatic balance 
 of the intestinal microenvironment . while it is unclear how the selective 
 pressures , microbial community dynamics , and the intestinal microenvironment 
 shape the genome and subsequent functions of members of the gut microbiota , 
 there are some exciting new developments in the field . for example , gordon et 
 al . have introduced the provocative concept that the evolution of the gut 
 microbiome also likely plays a significant role in shaping the evolution of 
 humans . this tenet is founded on experiments in 
 which this team of investigators sequenced the genomes of two gut - dwelling 
 bacteroidetes and compared their genomes to the genomes of other bacteria that 
 live both inside and outside of the human body . quite remarkably , they 
 discovered that lateral gene transfer , mobile genetic elements , and gene 
 amplification play an important role in affecting the ability of the 
 bacteroidetes to vary their cell surface , sense their environment , and harvest 
 nutrient resources present in the distal intestine . importantly , these findings lay the 
 conceptual groundwork to suggest that adaptation to the gut ecosystem is a 
 dynamic process that includes acquisition of genes from other microorganisms , 
 and further underscores the significance of considering the evolution humans 
 from the perspective of the evolution of the microbiome [ 19 , 20 ] . the 
 host is protected from potentially harmful enteric microorganisms by the 
 physical and chemical barriers created by the intestinal epithelium that are 
 primarily comprised of absorptive villus enterocytes . the apical surface of the enterocytes 
 are highly differentiated structures consisting of rigid , closely packed 
 microvilli whose membranes contain stalked glycoprotein enzymes [ 22 , 23 ] . in addition , the tips of enterocyte microvilli are 
 coated with a 400500 nm thick 
 meshwork referred to as the filamentous brush border glycocalyx   and is composed of highly glycosylated 
 transmembrane mucins [ 25 , 26 ] . the intestinal epithelial barrier is also composed of 
 enteroendocrine cells , goblet cells , and paneth cells . microfold ( m ) cells are 
 also present in the follicle - associated epithelia where they represent a 
 morphologically distinct epithelial cell type whose primary function 
 is in the transport of macromolecules , particles , and microorganisms 
 from the lumen to underlying lymphoid tissue [ 27 , 28 ] . intercellular junctional complexes that are composed of 
 tight junctions , adherens junctions , and desomosomes maintain the integrity of 
 the epithelial barrier . the most apical components of the junctional complex 
 are the epithelial tight junctions , which are highly regulated and serve to 
 create a semipermeable diffusion barrier between individual cells ( figure 1(a ) ) . 
 collectively , these features facilitate the intestinal epithelium to act as a 
 physical barrier to prevent unwanted bacteria from gaining access to the host . the intestinal epithelium also 
 provides a unique surface that is armed with a bounty of specialized cells that 
 produce mucus , antimicrobial peptides , and antimicrobial molecules , which 
 together form the front line of defense against pathogenic microorganisms ( figure 1(a ) ) . the mucus layer is secreted by the goblet cells and this layer overlies 
 the intestinal epithelium to create a physical blockade against offending 
 enteric microbial pathogens . for example , it has been demonstrated that 
 secreted mucus acts as a barrier to yersinia enterocolitica , rhesus rotavirus , and shigella 
 flexneri . the commensal microbiota has also been 
 found to regulate the production of intestinal mucins , which consequently 
 inhibits the adherence of numerous pathogenic bacteria to intestinal epithelial 
 cells [ 3234 ] . paneth cells are 
 another important cell type that are involved in intestinal defense against 
 potential harmful pathogenic bacteria . these cells are present at the base of 
 the crypt of lieberkhn   and have been shown to produce a number 
 of antimicrobial peptides . in addition , the gastrointestinal expression of 
 antimicrobial peptides is evolutionarily conserved , and to date , -defensins ( hd ) , -defensins ( hbd ) , and cathelicidins have been 
 identified in humans . paneth cells also produce a number of 
 antimicrobial molecules , including lysozyme , phospholipase a2 , and 
 angiogenin-4 ( reviewed in ) . therefore , it is inferred by numerous 
 studies that paneth cells are able to control the bacterial ecosystem ( table 
 1 ) . angiogenin-4 is expressed mainly in the 
 small intestine , cecum , and colon and acts on gram - positive bacteria [ 49 , 50 ] . however , most antimicrobial peptides expressed by 
 mammalian epithelial cells are members of peptide families that mediate 
 nonoxidative microbial cell killing by phagocytes . defensins 
 generally possess a broad range of antimicrobial activity ( table 1 ) . in 
 particular , human intestinal defensin-5 has been shown to kill listeria monocytogenes , e. coli , and candida albicans . additional evidence supporting a 
 critical role for defensins in vivo 
 was demonstrated in a study utilizing human defensin-5 transgenic mice ; these 
 mice exhibited marked resistance to oral challenge with virulent salmonella enterica serovar typhimurium ( s. typhimurium ) . the 
 intestinal epithelial cells also express another class of antimicrobial 
 peptide , the cathelicidins ( ll-37/cap18 ) , in which a cathelin domain is linked 
 to a peptide with antimicrobial activity . ll-37 is expressed within the 
 epithelial cells located at the surface and upper crypts of normal human colon . although little or no expression is seen within the deeper colonic crypts or 
 within epithelial cells of the small intestine , studies in mice have determined 
 these molecules to be protective against bacterial pathogens . interestingly , the expression of these 
 factors , unlike the angiogenins , is not induced by the presence of pathogenic 
 bacteria but rather their secretion is triggered by the commensal microbiota 
 and/or their derivatives . a recent addition to this growing list of intestinal 
 antimicrobial includes regiii , which has been shown to be toxic to 
 gram - positive bacteria . regiii is a c - type lectin that binds to the 
 carbohydrate moiety of bacterial cell wall constituent , petidoglycan . recent 
 studies have further shown that the expression of regiii is strongly dependent upon the presence of the 
 gut microflora since in germ - free mice regiii expression is severely repressed   ( table 1 ) . the intestinal epithelium also provides a 
 surface where the host can sense the microbial microenvironment in order to 
 elicit an appropriate defense response by releasing an array of signaling 
 molecules ( i.e. , chemokines and cytokines ) . these molecules then trigger the recruitment of 
 leukocytes to initiate an early inflammatory response . paradoxically , however , 
 although continuously exposed to gram - positive and gram - negative bacteria and 
 their products ( i.e. , lipopolysaccarhide ( lps ) , peptidoglycan , and lipoprotein ) 
 the normal healthy intestinal mucosa maintains a mechanism of 
 hyporesponsiveness to the lumenal microbiota and their products . exaggerated 
 inflammatory responses in the absence of pathogenic bacteria would be otherwise 
 deleterious [ 57 , 58 ] . accordingly , the normal intestinal epithelial host 
 defenses are able to accurately interpret the complex microbial environment in 
 order to discriminate between permanently established commensal microbes and 
 episodic pathogens . at the core of this strategy the 
 endogenous microbiota all share however , upon infection of a pathogenic 
 organism , the host immune response is activated by the specific recognition of 
  nonself  molecular structures known as pathogen - associated molecular patterns . the epithelial cells are able to sense the microenvironment within the gut by 
 means of pattern recognition receptors ( prrs ) that include toll - like receptors 
 ( tlrs ) and nucleotide - binding oligimerization domain ( nod ) proteins [ 38 , 6063 ] . tlrs are evolutionary conserved and are characterized by 
 an extracellular leucine rich repeat ( lrr ) domain ( involved in ligand 
 recognition ) , as well as an intracellular toll / interleukin-1 receptor - like 
 domain ( involved in proinflammatory signal transduction ) [ 60 , 6466 ] . in addition , two nod proteins ( nod1 and nod2 ) function as 
 intracellular sensors of bacterial products in the induction of an inflammatory 
 response [ 60 , 6467 ] . these 
 prrs recognize bacterial factors , such as lps , lipoproteins , flagellin , 
 unmethylated - cpg dna , and a large number of other specific components . regulation of the expression and the specific location of tlrs and nods in 
 intestinal epithelial cells fosters efficient immune recognition of the 
 commensal microflora and maintains a delicate balance ; permitting a basal level 
 of signaling events to proceed , while at the same time restraining innate 
 immune responses . for instance in a healthy intestine , epithelial cells express 
 very little or no tlr2 , tlr4 , and cd14 , and as a result minimizes the 
 recognition of commensal lps [ 68 , 69 ] . tlr5 , which recognizes bacterial flagellin , has been 
 reported to be expressed exclusively on the basolateral surfaces of the 
 epithelial cells . moreover tlr3 , tlr7 , tlr8 , and tlr9 are 
 expressed in the intracellular endosomal compartments . these intracellular prrs would not 
 ordinarily encounter luminal commensal bacteria or those attached to the apical 
 surface of intestinal epithelial cells but are well positioned to recognize 
 pathogenic bacteria that actively breach the epithelial barrier . as an 
 additional measure , commensal bacteria have the ability to induce the 
 expression of intestinal alkaline phosphatase , which not only dephosphorylates 
 dietary lipids but also dephosphorylates the lps of commensal flora resulting 
 in reduced toxicity in mammals . nonpathogenic microorganisms may also be 
 able to selectively attenuate the nf - kb pathway as mechanism of intestinal 
 immune tolerance . neish et al . initially reported that colonization of a human 
 model intestinal epithelium with certain strains of nonpathogenic bacteria 
 could dampen the host cell responses to subsequent proinflammatory challenges 
 by blocking the proinflammatory / antiapoptic nf-b pathway . this effect is mediated by the inhibition of ib- ubiquitination , which prevents regulated 
 ib- degradation , nf-b nuclear translocation , and subsequent 
 activation of proinflammatory / antiapoptic genes . ib- ubiquitination is catalyzed by e3-scf ubiquitin ligase , which is regulated via covalent modification of the 
 cullin-1 subunit by the ubiquitin - like protein nedd8 [ 75 , 76 ] . recently , it was determined that the interaction of 
 nonpathogenic bacteria with epithelial cells results in the rapid loss of 
 neddylated cul-1 and consequent repression of the nf-b pathway . collectively , this set of observations 
 underscores the ability of intestinal bacterial communities to influence 
 eukaryotic processes , and perhaps more specifically demonstrates inflammatory 
 tolerance of the mammalian intestinal epithelia . as 
 described above , the intestinal epithelium has evolved a rather formidable 
 fortress to guard against microbial invasion . however , through a process of 
 coevolution , potential harmful enteric microorganisms have evolved counter 
 strategies to hijack the cellular molecules and signaling pathways of the host 
 to become potentially pathogenic . as an initial step in the infection process , 
 certain enteric pathogens target specific epithelial cell structures , including 
 glycoproteins and glycolipids , which serve as receptors for bacterial 
 attachment ; thus , enabling them to exploit the 
 underlying signal transduction pathway . other strategies utilized by invading 
 enteric pathogens , such as s. typhimurium and shigella flexneri have evolved a sophisticated strategythat 
 directs the entry of the enteric pathogen into intestinal epithelial cells . this process requires the expression of a bacterial type iii protein secretion system ( ttss ) , the function of which is to deliver a set of effector proteins into the host cell [ 7981 ] . these effector proteins co - opt host cell signal 
 transduction cascades as a clever means of subverting normal host cell 
 processes by triggering a marked rearrangement of the host 
 cytoskeleton . this entry mechanism termed bacterial mediated endocytosis drives 
 bacterial entry and facilitates the pathogen to cross the epithelial barrier as 
 well as to induce a proinflammatory response [ 7981 ] . the 
 latter step in this process can be achieved by direct cytotoxic injury , 
 intracellular migration , disruption of the epithelial tight junctions , or 
 indirectly by inducing neutrophil infiltration . although several bacterial 
 pathogens have been able to modulate epithelial tight junctions to 
 their own advantage , the direct interaction of a bacterial virulence 
 factor on component proteins of the tight junction has been proposed 
 only in a few instances . it is well documented that anumber of enteric pathogens perturb the intestinal epithelial 
 barrier and impact ter or paracellular permeability , most often with 
 an alteration in the arrangement of tight junctional component 
 proteins by mechanisms that are unique for different pathogens . for example , clostridium difficile toxins a and b enhance epithelial 
 cell permeability by disrupting actin microfilaments within the 
 perijunctional ring , and enteropathogenic escherichia coli disrupt the epithelial 
 barrier by the phosphorylation of myosin light chains . with respect to s. typhimurium , in vitro models of infection have 
 revealed an alteration of epithelial permeability and loss of 
 barrier function , which involves rapid changes in both tight junction 
 permeability and transcellular conductance [ 85 , 86 ] . recent studies further indicate that the salmonella effector protein sigd ( also called sopb ) , which is encoded in salmonella pathogenicity island-1 ( spi-1 ) , is able to elicit a reduction in 
 epithelial barrier function , perhaps via activation of pkc . also , the effector proteins sopb , sope , 
 sope2 , and sipa are necessary to disrupt the epithelial barrier and 
 alter the distribution of at least some tight junction proteins [ 88 , 89 ] . such 
 perturbations in the components of the tight junction lead to enhanced 
 bacterial translocation 
 and infiltration of neutrophils across the intestinal barrier . therefore , the 
 ability to regulate the molecular composition of the tight junctions 
 facilitates the pathogenecity of s. 
 typhimurium by fostering its uptake and distribution within the host ( figure 1(b ) ) . s. flexneri has a 
 distinct mode of pathogenesis that involves entry into colonic epithelial 
 cells from the basolateral surface , thereby requiring its 
 relocation from the lumenal to the underlying surface of the 
 epithelium . this translocation event has historically been 
 attributed to the uptake and transport by m cells . however , it has since been established that shigellae are also capable of altering components of the 
 tight junctional complex , allowing the bacteria to traverse the 
 paracellular space to reach the basolateral surface ; an event that 
 also decreases barrier function . once at the basolateral surface , shigellae rapidly invade and 
 disseminate through the epithelium , causing a further decrease in 
 barrier function [ 9294 ] through the action of a ttss system and 
 additional proteins encoded on a large virulence plasmid [ 9497 ] . enteric 
 pathogens cause a variety of diseases in humans but one undeniable symptom is 
 the presentation of gastroenteritis . some bacterial enteric infections are 
 characterized by disruption of the normal movement of electrolytes and water 
 across the epithelium , which is converted from a state of net fluid absorption 
 to one of net fluid secretion . secretory diarrhea , as a result of 
 epithelial chloride secretion , has long been regarded as a host defense 
 mechanism . this is based on the notion that increased fluid and electrolyte 
 movement into the gut lumen helps to inhibit adherence of pathogenic organisms 
 by  flushing  them from the body . however , it could also be argued that the 
 induction of pathogen - induced diarrhea is a way to ensure transmission to new 
 hosts , and thus pathogenic fitness . these ideas are not mutually exclusive 
 and secretory diarrhea may be advantageous to both host and pathogen . pathogenic bacteria cause diarrhea by 
 multiple mechanisms . vibrio cholerae reside in the lumen of the small intestine and produce toxins , which alter ion 
 absorption and/or secretion [ 100 , 101 ] . other bacteria such as shigella and enteroinvasive e. coli invade and 
 destroy the colonic epithelium leading to dysentery . more recently pathogenic e. coli have been shown to increase 
 chloride ion secretion from intestinal epithelia by upregulating the expression 
 of the receptor for the neuropeptide galanin 1 . rotavirus , another important cause of 
 diarrhea in infants , induces this condition by activating the enteric nervous 
 system [ 104 , 105 ] . a large influx of neutrophils ( pmns ) into 
 the mucosa and lumen from the underlying vasculature is a significant feature 
 of intestinal bacterial infections [ 105 , 106 ] . during infection of epithelial cells by enteric pathogens 
 such as s. typhimurium and s. flexneri such basolateral il-8 release imprints subepithelial matrices 
 with long - lived haptotactic gradients that serve to guide neutrophils through 
 the lamina propria to a subepithelial position . however , basolateral il-8 release is 
 insufficient to induce the migration of neutrophils across the intestinal 
 epithelium , suggesting that the production of other inflammatory mediators , 
 whose release would probably be polarized apically , is important for the 
 execution of this step in the inflammatory pathway [ 107 , 108 ] . in support of this contention , kucharzik et al . recently developed a 
 double transgenic mouse model with the ability to induce human il-8 expression 
 restricted to the intestinal epithelium . the results from this transgenic model showed that 
 although acute induction of il-8 in the intestinal epithelium is sufficient to 
 trigger neutrophil recruitment to the lamina propria , additional signals are 
 required for neutrophil transepithelial migration and mucosal tissue injury . indeed , recent evidence suggests that the eicosanoid , hepoxilin a3 , 
 is secreted apically and is responsible for the final step of neutrophil 
 transepithelial migration into the gut lumen [ 110 , 111 ] . this process is 
 quite complex as distinct signaling pathways mediate s. typhimurium invasion , induction of cxcl8 secretion , and 
 induction of hepoxilin a3 secretion [ 111113 ] . the ability of salmonella serotypes to elicit pmn transmigration in vitro correlates with their 
 ability to cause diffuse enteritis ( defined histologically as transepithelial 
 migration of neutrophils ) , but not typhoid fever in humans . studies exploring the mechanism underlying the release of hxa3 during 
 infection with s. typhimurium revealed the involvement of the s. typhimurium type iii secreted effector protein , sipa . the s. 
 typhimurium effector protein , sipa , promotes a lipid signal transduction cascade 
 that recruits an adp - ribosylation factor 6 guanine nucleotide exchange factor 
 ( such as arno ) to the apical plasma membrane . arno facilitates adp - ribosylation 
 factor 6 activation at the apical membrane , which in turn , stimulates 
 phospholipase d recruitment to and activity at this site . the phospholipase d 
 product , phosphatidic acid , is metabolized by a phosphohydrolase into 
 diacylglycerol , which recruits cytosolic protein kinase c ( pkc)-alpha to 
 the apical membrane . through a process that is less understood , activated 
 pkc - alpha phosphorylates downstream targets that are responsible for the 
 production and apical release of hxa3 , which drives transepithelial 
 neutrophil movement . there 
 are ample lines of evidence to support the emerging concept that a change in 
 the composition of the commensal microbiota alters the intestinal 
 microenvironment making this niche vulnerable to pathogenic insult . in this 
 section we discuss examples to illustrate the remarkable crosstalk between the 
 host , its intestinal microbiota , and potential pathogenic bacteria . it 
 has been well documented that s. 
 typhimurium causes a systemic ( typhoid fever ) infection in mice while in 
 humans this enteric pathogen causes gastroenteritis . however , barthel et al . discovered 
 that pretreatment of c57bl/6 mice with streptomycin , an antibiotic that kills 
 facultative anaerobes , followed by infection with a streptomycin - resistant 
 strain of s. typhimurium produced a robust intestinal inflammatory response . such enteritis is primarily characterized by inflammation 
 in the cecum , and also presents with several of the typical pathological 
 hallmarks of acute salmonella - induced 
 gastroenteritis in humans , including pmn infiltration and epithelial cell 
 erosion . this is an intriguing result since the only difference between the 
 untreated and streptomycin treated mice is the alteration of the commensal 
 flora ; thus , demonstrating that the presence of the microflora plays a 
 protective role against pathogenic invaders . this study also substantiates the 
 long - standing finding of barrow and tucker who found that pretreatment of a 
 chicken 's cecum with three different strains of e. coli significantly reduced infection with salmonella as compared to untreated animals . additionally , hudault et al . ( 2001 ) 
 determined that the presence of a single species of e. coli in the gut could restrict the infection of s . more 
 recently , stecher et al . used the s. 
 typhimurium colitis model to investigate competition between an enteric 
 pathogen and the host microbiota . this group found that inflammatory responses induced by s. typhimurium led to profound 
 perturbations in the composition of the commensal microbiota as determined by 
 16s rrna . the inflammatory host responses induced by s. typhimurium not only changed the microbiota composition but also 
 suppressed its growth , thereby , overcoming colonization resistance . in contrast , 
 an avirulent salmonella mutant 
 defective in triggering inflammation was unable to overcome colonization 
 resistance . these results raise an interesting point in that perhaps the 
 intestinal inflammation induced by s. 
 typhimurium might be a crucial event in order to overcome colonization 
 resistance . in this respect , triggering the host 's immune defense may shift the 
 balance between the protective microbiota and the pathogen to favor the 
 pathogen . the idea that the intestinal microbiota can be altered by invading 
 pathogens is further supported by lupp et al . who found that host - mediated 
 inflammation in response to an infectious agent induced alterations in the 
 colonic community that not only resulted in the elimination of a subset of 
 indigenous microbiota but also led to the growth of the enterobacteriaceae 
 family . moreover , in children undergoing 
 treatment for diarrhea , fluctuations in the intestinal microflora were observed 
 for both rotaviral and nonrotaviral - induced diarrhea . this phenotype was reversed and the 
 normal microflora was re - established after about three months of the disease 
 episode . other studies have investigated the role of the intestinal microbiota 
 during infectious disease transmission . in particular , lawley et al . describe a 
 model in which persistently infected 129x1/svj mice provide a natural model of 
 transmission . in this model , only a subset of mice termed  supershedders  could 
 shed high levels of bacteria in their feces . whereas immunosuppression of the 
 infected mice did not induce the supershedder phenotype , antibiotic treated mice 
 displayed a high supershedder phenotype . together , these studies suggest that 
 the intestinal microbiota plays a critical role in controlling pathogen 
 infection , disease , and even transmissibility . there 
 are also examples in which members of the commensal microflora are able to 
 cause disease . this is specifically illustrated by enterococcus faecalis , a prominent member of the gi tract 
 microbiota . in a healthy intestine however , in individuals undergoing antibiotic 
 treatment or those who are immunocompromised , e. faecalis is able to colonize new niches of the intestinal 
 microenvironment as a certain subgroup of this species is antibiotic resistant 
 ( figure 1(c ) ) . under such compromised conditions , e. faecalis can infect and spread to other sites of the host such 
 as the bloodstream , urinary tract , and surgical wounds . not surprisingly , the 
 subgroup population harboring the antibiotic resistance genes also has genetic 
 elements conferring infectivity and virulence . furthermore , the genome sequence 
 of e. faecalis strain v583 , the most 
 causative agent of vancomycin resistant enterococcal infection in america ,   was recently reported . recent studies have determined that more than 25% of the e. faecalis genome is most likely 
 derived from mobile or foreign dna , which might have contributed to the rapid 
 acquisition and dissemination of drug resistant strains . another example is illustrated by clostridium difficle , a 
 gram - positive bacterium that can harmlessly inhabit the human intestine . 
 however , certain individuals undergoing antibiotic therapy , as a result of 
 their altered intestinal microflora , presented with c. difficle infection accompanied with severe intestinal colitis 
 ( figure 1(c ) ) . commensal 
 bacteria , such as bacteroides fragilis , 
 may also inhibit other opportunistic members of the intestinal microflora from 
 causing disease . b. 
 fragilis is a gram - negative bacterium that resides in a healthy human 
 intestine . normally , this bacterium expresses a surface carbohydrate capsule 
 known as polysaccharide a ( psa ) , which contributes to many beneficial 
 activities underlying the immune development of the host , including activation 
 of cd4 + t cells , and stimulation of the innate immune responses through tlr2 
 signaling . mazmanian et al . determined that b. 
 fragilis protects the host from helicobacter 
 hepaticus - induced colitis in experimental mice . however , in animals 
 harboring b. fragilis strains that do 
 not express psa , h. hepaticus colonization led to disease and production of proinflammatory cytokines induced 
 by intestinal immune cells [ 128 , 129 ] . thus , in healthy individuals it appears that psa from b. fragilis is necessary to confer some 
 beneficial activity . in spite of this , psa was also found to potentiate the 
 ability of b. fragilis to cause 
 disease in patients who have a compromised mucosal surface , such as 
 postsurgical patients . this function is initiated upon submucosal entry of the 
 bacteria during which psa activates cd4 + t cells leading to abscess formation . recent evidence from a variety of investigative avenues 
 implicates abnormal host - microbial interactions in the pathogenesis of 
 inflammatory bowel disease ( ibd ) . in fact , ibds preferentially occur in the 
 colon and distal ileum ( i.e. , locations that contain the highest concentrations 
 of intestinal bacteria ) . an important role for microbial agents in the 
 pathogenesis of ibd is inferred by numerous recent studies , which conclude the 
 bacterial flora differs between patients with inflammatory bowel disease ( ibd ) 
 and healthy individuals . moreover , accumulating evidence suggests that the 
 composition and function of the microbiota in patients suffering with ibd are abnormal . ninety - nine 
 percent of the gut microbiota in healthy individuals is composed of species 
 within four bacterial divisions : firmicutes , bacteroidetes , proeobacteia , and actinobacteria [ 131 , 132 ] . investigation of the microbial diversity in active ibd is 
 a highly pursued topic of interest and is an area of research still at its 
 infancy . in ibd patients , early returns have suggested that there is a decrease 
 in the number of beneficial bacteria , such as bifidobacterium and lactobacillus spp . , and an increase in pathogenic bacteria , such as a bacteroides and escherichia coli [ 132136 ] . such dysbiosis induces a breakdown in the balance between 
 putative spp . of protective versus harmful bacteria , and may promote 
 inflammation . other studies have shown that there is a decrease in microbial 
 diversity that accompanies the increased numbers of enterobacteriaceae , 
 including e. coli , with decreased numbers of firmicutes , 
 and a particular decrease in clostridium species . as convincing as this data is , there is still a lack of evidence to 
 denote whether a specific pathogen is responsible for onsets or relapses of ibd 
 . regardless , a number of organisms have been 
 implicated in crohn 's disease , with mycobacterium 
 paratuberculosis and e. coli drawing a great deal of attention . patients 
 with ibd have higher numbers of mucosa - associated bacteria than control patients 
 , and the generalized or local dysbiosis 
 observed is due to the presence of low numbers of normal bacteria and high 
 numbers of unusual bacteria with a decrease in biodiversity . the composition of 
 the increased numbers of bacteria attached to the intestinal epithelium of ibd 
 patients are from diverse genera . , in particular , has been identified as a predominate member of the 
 epithelial layer , and in some instances was located intracellularly . while this remains an intriguing observation , the role of bacteroides in ibd is still unclear . furthermore , distinct adherent or invasive e. 
 coli has been identified in the ileal mucus of patients with crohn 's 
 disease , and the involvement of a new potentially pathogenic group of adherent 
 invasive e. coli ( aiec ) has been 
 suggested . for instance , in studies aimed to 
 assess the predominance of e. coli strains associated with the ileal mucosa of crohn 's disease patients , e. coli was recovered from 65% of 
 chronic lesions and from 100% of the biopsies of early lesions . by comparison , e. coli was also abnormally present ( 50100% of the total 
 number of aerobes and anaerobes ) in early and chronic ileal lesions of cd 
 patients [ 140 , 141 ] . these observations were confirmed in a subsequent study in 
 which adherent e. coli was found in 
 38% of patients with active ileal crohn 's disease . this study also revealed that the 
 number of e. coli in situ correlated with the severity of the disease , and that the invasive e. coli was also restricted to the 
 inflamed mucosa . interestingly , the recovered e. coli strains were predominantly novel in phylogeny , displayed pathogen - like 
 behavior in vitro , and expressed virulence factors . it 
 is suspected that the abnormal colonization of the lieal mucosa is largely due 
 to increased expression of ceacam6 , a receptor for adherent - invasive e. coli . however , crohn 's disease patients also exhibit defective 
 microbial killing mechanisms that result in increased exposure to commensal 
 bacteria . for example , crohn 's disease patients have defective antimicrobial 
 peptide production , including -defensin 5 in ileal disease and human -defensin 2 in crohn 's colitis [ 143 , 144 ] . this is accompanied by functional abnormalities in the 
 killing of bacteroides vulgatus , e. coli , and enterococcus 
 faecalis . in addition , nod2 polymorphisms in 
 crohn 's disease are associated with selective decrease in -defensin production by paneth cells , as well 
 as in defective clearance of intracellular pathogens by colonic epithelial 
 cells . thus , combined with defective 
 antimicrobial peptide function in crohn 's disease the functional changes 
 described above provide a reasonable rationale for the profound increase in 
 mucosally associated enterobacteriaceae . also , in light of the alteration in 
 the composition of the luminal microbiota , it is perhaps not surprising that 
 crohn 's disease has features that might be the consequence of a microbial process . this is exemplified by the noted infection of peyer 's patches and lymphoid 
 aggregates , and the presence of ulcerations , microabscesses , fissures , fistulas , granulomas , 
 and lymphangitis . as evidence accumulates to suggest that 
 dysbiosis in ibd patients induces a breakdown in the balance between putative 
 spp . of protective versus harmful bacteria , one potential new method of 
 intervention lies in the modulation of the enteric flora . indeed , current 
 studies suggest that probiotics might offer an alternative or adjuvant approach 
 to conventional ibd therapies by altering the intestinal microflora and , in 
 turn , modulating the host immune system . probiotics are defined as living food 
 supplements or components of bacteria that have a beneficial effect on human 
 health . indeed , probiotic activity has been associated with lactobacillus , bifidobacteria , streptococcus , enterococcus , nonpathogenic e. coli , and saccharomyces bourlardii [ 147 , 148 ] . a growing 
 body of literature supports this emerging concept , which suggests that 
 probiotics have therapeutic effects in ulcerative colitis , crohn 's disease and 
 pouchitis [ 147 , 148 ] . the rationale for employing probiotics in the treatment of 
 ibd is underscored by the proposed pathogenic role of the intestinal microflora 
 in this disease . numerous studies support the notion that introduction of 
 probiotics to the gi tract can alter the enteric microflora in ibd patients , 
 which in turn has a profound effect on intestinal defense mechanisms , including 
 ( i ) inhibiting microbial pathogenic growth , ( ii ) increasing epithelial cell tight 
 junctions and permeability , ( iii ) modulating the immune response of the 
 intestinal mucosa , ( iv ) increasing the secretion of antimicrobial products , and 
 ( iv ) eliminating pathogenic antigens [ 149151 ] . thus , such broad mechanistic effects of probiotics may 
 explain the beneficial effects observed . probiotic 
 preparations are primarily based on a variety of lactic acid bacteria 
 ( lactobacilli , bifidobacteria , and streptococci ) , which under healthy 
 conditions are normal and important components of the commensal microbiota . in 
 addition , probiotic mixtures often contain some nonpathogenic bacteria that 
 include e. coli , enterococci , or 
 yeast ( saccharomyces bourlardii ) . first , probiotics must be safe and tested for human use [ 149 , 152 ] . in addition , such strains should be of human origin , 
 resistant to acid and bile , and survive and be metabolically active within the 
 intestinal lumen . probiotics must also be antagonistic against pathogenic 
 bacteria as they produce antimicrobial substances , compete within the gi tract , 
 and promote a reduction in colonic ph . many 
 clinical trials have documented that probiotics can achieve and maintain 
 remission in patients with ulcerative colitis , and also prevent and maintain 
 remission of pouchitis . however , 
 probiotics seem to be ineffective in crohn 's disease . although controlled clinical trials are 
 still required to investigate the unresolved issues related to efficacy , dose , 
 duration of use , single or multistrain formulation , and simultaneous use of 
 probiotics , synbiotics , or antibiotics , the preliminary data for the 
 therapeutic use of probiotics in selective patients with mild to moderate ibd 
 are encouraging .
the mucosal surfaces of the gastrointestinal tract harbor a vast number of commensal microbiota that have coevolved with the host , and in addition display one of the most complex relationships with the host . 
 this relationship affects several important aspects of the biology of the host including the synthesis of nutrients , protection against infection , and the development of the immune system . on the other hand , despite the existence of several lines of mucosal defense mechanisms , pathogenic organisms such as shigella and salmonella have evolved sophisticated virulence strategies for breaching these barriers . 
 the constant challenge from these pathogens and the attempts by the host to counter them set up a dynamic equilibrium of cellular and molecular crosstalk . 
 even slight perturbations in this equilibrium may be detrimental to the host leading to severe bacterial infection or even autoimmune diseases like inflammatory bowel disease . 
 several experimental model systems , including germ - free mice and antibiotic - treated mice , have been used by various researchers to study this complex relationship . 
 although it is only the beginning , it promises to be an exciting era in the study of these host - microbe relationships .