microbial activities and intestinal homeostasis a delicate balance between health and disease

REVIEWMicrobial Activities and Intestinal Homeostasis: A DelicateBalance Between Health and Disease

Christina L. Ohland1 and Christian Jobin1,2

1Department of Medicine and 2Department of Infectious Diseases and Pathology, University of Florida, Gainesville, FloridaSUMMARY

This review discusses the equilibrium between host andmicrobial community in the context of health and disease.The focus is on bi-directional pressures between pro-karyotes and eukaryotic cells, as well as inter-bacterialinteractions resulting in alterations to the microbiota.

The concept that the intestinal microbiota modulatesnumerous physiologic processes, including immune devel-opment and function, nutrition and metabolism, and path-ogen exclusion, is relatively well established in the scientificcommunity. The molecular mechanisms driving thesevarious effects and the events leading to the establishmentof a healthymicrobiome are slowly emerging. This reviewbrings into focus important aspects of microbial/host in-teractions in the intestine and discusses key molecularmechanisms controlling health and disease states. Wediscuss the evidence of howmicrobes interact with the hostand one another and their impact on intestinal homeostasis.(Cell Mol Gastroenterol Hepatol 2015;1:2840; http://dx.doi.org/10.1016/j.jcmgh.2014.11.004)

Keywords: Bacterial Communication; Bowel Disease; Host-Microbe Interactions; Inflammatory; Microbiome.

ppearances can be deceiving. Despite what you seeAbbreviations used in this paper: AMP, antimicrobial peptides; CD,Crohns disease; CDI, contact-dependent growth inhibition; GI,gastrointestinal; HGT, horizontal gene transfer; IBD, inflammatorybowel disease; MAMP, microbe-associated molecular pattern; QS,quorum sensing; SCFA, short-chain fatty acids; SFB, segmented fila-mentous bacteria; T6SS, type VI secretion system; UC, ulcerativecolitis.

2015 The Authors. Published by Elsevier Inc. on behalf of the AGAInstitute. This is an open access article under the CC BY-NC-ND

license (http://creativecommons.org/licenses/by-nc-nd/3.0/).2352-345X

http://dx.doi.org/10.1016/j.jcmgh.2014.11.004Ain the mirror, humans are more prokaryotic thaneukaryotic, as the bacteria in and on our bodies outnumberour own cells 10 to 1.1 Microbes are embedded in ourbiological system and are deeply integrated in our daily life,and an emerging field of research has tackled the inter-kingdom communication network present in the walkingmixed cultures we call people.

The gastrointestinal (GI) tract has the highest density andvariety of bacteria in the human body (approximately 100trillion microbes made up of >1000 species) due to the idealgrowth conditions provided by this organ. In the colon, thereare up to 1012 microbes per gram of luminal content whichaccounts for 60%of fecalweight.2,3 A healthy adults intestinalmicrobiome is diverse, relatively stable over time, and domi-nated by two phyla, Bacteroidetes and Firmicutes (w95%).Nevertheless, there is considerable interindividual variabilityat the species level due to genetic, environmental, and nutri-tional factors.4 Diet in particular has been shown to rapidlyshift this community,5 resulting in geographic region-specificmicrobial signatures as seen in rural African children eating afiber-rich diet compared to their European counterparts.6

Although understanding the bacterial species present inthe gastrointestinal tract is important, recentwork has shiftedthe focus to the existence of a core enteric metabolome,which has the potential to change the waywe look at how ourgut functions.7 Because bacterial genes have many over-lapping and redundant functions, the end result of theircombined metabolism and catabolism can ultimately have atremendous impact on the intestinal environment and hostphysiology. As we discuss later, these microbial-derivedproducts are a main component of the host-bacteria andbacteria-bacteria communication network essential to intes-tinal homeostasis.

External pressures, such as infection or antibiotics, causea disequilibrium in the microbial community, a phenomenondesignated as dysbiosis and often associated with pathol-ogies including inflammatory bowel disease (IBD).8,9 Alter-natively, internal pressure resulting from defective hostgenetics, such as innate and adaptive immune genes, resultsin mismanagement of the microbiota, again leading to dys-biosis and pathologic conditions seen in the airway,10 theskin,11 and the gut.12,13 IBD is a chronic, relapsing, andremitting inflammatory disease that can be classified asulcerative colitis (UC) or Crohns disease (CD). Both formscan be thought of as examples of disrupted communicationbetween the intestinal microbiota and the host. The natureof this communication breakdown is not clear but involvesgenetic susceptibility related to the epithelial barrier andinnate immunity, all of which are important components ofhost-bacteria interaction.14

This review will discuss the complex cross-talk betweenintestinal cells and the microbiota as well as the antagonisticand mutualistic interactions among enteric bacteria. Thismultifaceted communication network is what shapes theintestinal environment, drives homeostasis, and is thusessential to understanding how to prevent and treat intes-tinal disorders such as IBD.

http://dx.doi.org/10.1016/j.jcmgh.2014.11.004http://dx.doi.org/10.1016/j.jcmgh.2014.11.004http://crossmark.crossref.org/dialog/?doi=10.1016/j.jcmgh.2014.11.004&domain=pdfhttp://creativecommons.org/licenses/by-nc-nd/3.0/http://dx.doi.org/10.1016/j.jcmgh.2014.11.004

January 2015 Microbial Activities and Homeostasis 29Host Effects on the MicrobiotaGastrointestinal Tract Environment

The intestinal microbiota is largely acquired during ourfirst few days of life, although recent studies have shownthat infants may not be bacteria free at birth.15,16 Speciesdiversity and stability increase to an adultlike microbiota bythe age of 3 years as children are exposed to a new milieuthat includes solid food and individuals with differentmicrobiota.1719 The wide topologic and geographic differ-ences that microorganisms encounter along the GI tractdictate their environmental niche for growth and ultimatelyshape the community as a whole (Figure 1).

The acidity of the stomach limits bacterial growth andonly a sparse microbiota (

30 Ohland and Jobin Cellular and Molecular Gastroenterology and Hepatology Vol. 1, No. 1increase along the length of the GI tract to the colon, whichhas 1012 bacteria/g.20

The radial oxygen gradient with the gastrointestinal tract,whereby oxygen diffuses inward from the epithelium into themucous layer, creates a microaerophilic zone in whichfacultative anaerobes such as Proteobacteria thrive in ananaerobic lumen.26 Although nutrient absorption decreasesoxygenation of the mucosal layer by up to 40% due toincreased metabolic demands,27 this is unlikely to substan-tially affect the microbial community, as 4 days of hyperbaricoxygen treatment are needed to alter the microbiota.28

However, survival in an atmosphere with fluctuating oxy-gen does require respiratory flexibility of commensal bacte-ria. Some strict anaerobes, such as Bacteroides fragilis,Clostridium acetobutylicum, Faecalibacterium prausnitzii,have developedmolecular switches and alternate respiratorychains, including extracellular thiols and flavins, that allowthem to tolerate low levels of oxygen over the short term andthereby achieve a selective growth advantage.2931

In disease states, including these accompanied by in-testinal inflammation, diminished vascular perfusion andheightened immune cell metabolic activity result in localizedhypoxia or even anoxia within the intestines.32 It maytherefore be surprising that intestinal dysbiosis in IBD pa-tients is characterized by an enrichment of aerobic bacteriaincluding Enterobacteriaceae, which is also seen in experi-mental models of colitis (eg, Il10/, Tlr5/, TRUC).33,34

This disparity is puzzling but may be explained by thefitness advantage of Enterobacteriaceae, which can use ni-trate generated during inflammation as an alternative ter-minal electron acceptor.35 Therefore, respiration has afundamental influence on the commensal bacteria that areable to thrive in an altered gut milieu.Dietary ComponentsCarbohydrates, proteins, and fats all have specific, pro-

found effects on the composition of the intestinal microbiotaand have been extensively reviewed elsewhere.3639

Notably, Bacteroidetes and Firmicutes such as Clostridialesare able to use host-indigestible polysaccharides and thusdominate in the colon, whereas Proteobacteria and Firmi-cutes such as Lactobacillales are found in the small intestinealong with high levels of monosaccharides and di-saccharides (Figure 1).40 Moreover, dietary vitamins candirectly affect bacterial growth, as some microbes such asRuminococcus bicirculans cannot synthesize their ownessential factors.41 Dietary vitamins can also modulate themicrobiota by promoting the fitness of Bacteroides species(vitamins B12, C, and E) or by decreasing microbial numbers(vitamin A, in particular for segmented filamentousbacteria).4244 However, it is not entirely clear whether thisis a direct effect on the bacteria or occurs indirectly via thehost epithelium or immune system, as with vitamin D.45 Inaddition to host nutrient requirements, Suez et al46 recentlydemonstrated that indigestible artificial sweeteners directlyincrease Bacteroidales and decrease Clostridiales in miceand humans. This elegant study demonstrates that theintricate relationship between our gut microbiota and whatwe consume includes indigestible components and affectswhole body health.

Intestinal Immune System and Barrier FunctionThe gut also plays a very active role in shaping the mi-

crobial community to protect the host from the high antigenicpotential of bacterial and unwarranted immune stimulation.The dynamic, responsive epithelial cells provide multipledeterrents, including the formation of a mucous layer bygoblet cells, secretion of antimicrobial peptides (AMP) byPaneth cells, intercellular tight junction complexes, andmicrobe-associated molecular pattern (MAMP) recognitionsystems.4749 Similarly, the underlying immune system isvery adept at tolerating nonharmful bacteria while recog-nizing and responding to invading pathogens and opportu-nistic commensal organisms. Luminal sampling bytolerogenic immune cells in the lamina propria, secretory IgAin the mucous layer, and the complement network operatetogether to maintain intestinal homeostasis.4853 Computer-based mathematical modeling of such a complex interactionsupports the theory that these defense systems, along withhost-derived nutrients, work together to shape the compo-sition of the microbiota and maintain its stability.54 Althoughdirect evidence of whether these systems impact microbialspecies present in the intestine is lacking, host defense is acritical factor in maintaining intestinal homeostasis.

Microbial Influences on the HostEducating the Immune System

Tolerance of the normal gut microbiota is an absolutelyvital element of enteric homeostasis, requiring an extensivenetwork of regulatory immune cells including Tregs andtolerogenic dendritic cells.55,56 The intestinal architecture ofthe uncolonized fetal or germ-free gut is immature, withreduced epithelial turnover, thin muscle wall and mucouslayers, a decreased number of immune cells, and disorga-nized gut-associated lymphoid tissue.5759 Microbial colo-nization of mice enhances the intestinal barrier function viaMAMP signaling and educates the immune system, resultingin maturation of the gut-associated lymphoid tissue into atolerant phenotype to prevent unregulated inflammation(Figure 2).2,60 However, there appears to be a window ofopportunity for this codevelopment, as colonization of adultgerm-free mice with healthy mouse microbiota does notinduce the same protective effects as when germ-free miceare colonized as neonates.61,62

Segmented filamentous bacteria (SFB) are able to traversethe mucous layer and are found attached to the small intes-tinal epithelium of many vertebrates, including humans.63

Although they are only present in low numbers, SFB areessential to the development of Th17 cells through epithelialcytokine production and dendritic cell processing,6466 andthey are required for full immune system maturation inmice.67 This is an important discovery, as aberrant Th17signaling has been documented in IBD, although evidencethat SFB have a similar function in humans is lacking.

Alternatively, Bacteroides fragilis express polysaccharideA, which profoundly influences the development of enteric

Figure 2. Microbial effects on the host. The microbiota induces host immune tolerance to commensal bacteria directly via amicrobe-associated molecular pattern (MAMP) and polysaccharide (PSA) signaling, indirectly through the production of short-chain fatty acids (SCFA) and potentially through expression of epithelial intestinal alkaline phosphatase (IAP), which detoxifiesluminal lipopolysaccharides (LPS). Furthermore, segmented filamentous bacteria (SFB) promote immune development of Th17cells through epithelial cytokine production and antigen presentation by dendritic cells (DC), and the community as a whole isrequired for proper gut-associated lymphoid tissue (GALT) development. SCFA also induce IgA and mucus secretion into thelumen, promote epithelial barrier integrity, and prevent pathogen colonization. The microbiota also participates in the formationof the active, secondary forms of bile acids.

January 2015 Microbial Activities and Homeostasis 31tolerance by converting proinflammatory CD4 T cells intoTregs during colonization68,69 and mediates equilibriumbetween TH1 and TH2 responses.

70 Infants born by cesareandelivery have decreased microbial diversity, includingdelayed colonization by the B fragilis (Bacteroidetesphylum), which is associated with decreased TH1 activa-tion.71 Similarly, strains of Clostridium clusters IV and XIVa(Firmicutes phylum) can promote differentiation, expansion,and colonic homing of Treg cells through bacterial antigensignaling and short-chain fatty acids (SCFA) stimulation ofepithelial transforming growth factor-b1 production.72

Thus, the far-reaching influences of the microbiota indi-cate the vital role of bacterial immunomodulation in main-taining whole-body health.Maintaining HomeostasisOnce an appropriately tolerant milieu is established,

maintenance of healthy host-microbial communication isparamount for the host, as dysbiosis jeopardizes protectivemicrobial functions. A recent article by Zelante et al73 estab-lishes a role for microbial catabolism in balancing T-cell acti-vation of the mucosal immune system. When converted fromsugar to tryptophan as the primary energy source, the popu-lation of Lactobacilli expand and increase the production ofindole-3-aldehyde. This metabolite induces interleukin-22expression through activation of aryl hydrocarbon receptors,conferring both tolerance of the healthy microbiota and resis-tance to the opportunistic fungal pathogen Candida albicans.73

32 Ohland and Jobin Cellular and Molecular Gastroenterology and Hepatology Vol. 1, No. 1Beyond regulation of the host immune system, themicrobiota influences many other normal functions of ahealthy intestinal tract (Figure 2). For example, the micro-biota convert bile acids into secondary forms in the lumen bydehydroxylation, dehydrogenation, and deconjugation.74,75

Studies in germ-free mice demonstrate that bacterialsignaling via G protein-coupled and nuclear receptors(G protein-coupled bile acid receptor [TGR5] and farnesoid Xreceptor [FXR], respectively) not only controls levels of sec-ondary bile acids but also can modulate synthesis in theliver.76 Moreover, expression of intestinal alkaline phospha-tase, an epithelial-bound enzyme that detoxifies luminallipopolysaccharide to alleviate inflammation and promotetolerance,77 is affected by diet and antibiotics. It is tempting tospeculate that suchmodulation could occur via changes in themicrobiota.77,78 Maintaining symbiosis with our bacteria istherefore key to preserving intestinal health andhomeostasis.The Extensive Effects of Fatty AcidsFermentation, one of the key metabolic pathways

employed by the enteric microbiota, produces SCFA,including acetate, propionate, and butyrate.79 SCFA havebeen shown to promote homeostatic mechanisms and pro-tect against inflammation in multiple models.80 This topicFigure 3. Bacteria use a complex communication networcombative (AC) and cooperative (DF) methods. (A) Antimicrobinhibit growth of surrounding microbes. (B) Contact-dependent g(CdiA) into the cytoplasm of target cells after contact. (C) Theattacking bacteria. Bacteria cooperate by increasing survivaltransfer (HGT) and (E) the formation of a protective biofilm. (F)group behavior, and has been implicated in T6SS expression, pthese mechanisms have not been observed in the healthy humaare T6SS toxin; and yellow stars are QS signaling molecules.has been thoroughly reviewed elsewhere.60,75,8183 Briefly,SCFA stimulate protective mucus and IgA production, pro-mote tolerance via Treg induction, inhibit the inflammatorymediator nuclear factor kB, enhance epithelial barrierintegrity and repair, and promote competitive exclusion ofpathogens (Figure 2). However, butyrate has also beenshown to be both protective and deleterious in differentmodels of colorectal cancer, highlighting the complexity ofSCFA biology with a disease-specific effect.80,84 Thus, evenpredominantly beneficial molecules or microbes canpotentially have negative effects in complex environmentssuch as the GI tract.Microbe-Microbe InteractionsIn addition to their host-mediated effect on microbial

assembly, composition, and activities, microbial niches arealso under intense pressure from other surrounding bacte-ria. Bacteria use sophisticated intercommunication systemsto help maintain their niches; consequently, this microbialnetwork is essential to host homeostasis. These microbialrelationships can be antagonistic or mutualistic, dependingon the nature of the species (Figure 3). Commensal bacteriacombat other microbes using AMP production and targetedattacks by means of specialized secretion systems, and theyk to thrive in an environment. Bacteria interact throughial peptides (AMP) typically released after cell lysis either kill orrowth inhibition (CDI) systems deliver the toxic C-terminal endtype 6 secretion system (T6SS) forcefully injects toxins intoof similar microbes in their vicinity with (D) horizontal geneQuorum sensing (QS) allows bacteria to talk and coordinateroduction of AMP, and biofilm formation. However, several ofn intestinal tract. Red squares represent AMP; blue triangles

January 2015 Microbial Activities and Homeostasis 33compete for nutrients. Owing to their ruthless requirementsfor survival, bacteria have also developed cooperativemechanisms such as horizontal gene transfer, biofilm for-mation, and quorum sensing to ensure the fitness of theirown community as a whole.CombattingBacteria express highly potent bacteriocins, microcins,

and colicins that fend off other species or pathogensinvading their niche without causing collateral damage toeukaryotic cells.85 Bacteriocins are pore-forming AMP pro-duced by Gram-positive bacteria; they directly relate tothe in vivo fitness and competitiveness of Lactobacillussalivarius and Streptococcus pneumoniae in the gut andnasopharynx, respectively.86,87 Microcins (

34 Ohland and Jobin Cellular and Molecular Gastroenterology and Hepatology Vol. 1, No. 1catabolized by the microbiota but is not normally found inthe feces, as it is quickly consumed by other bacteria. Afterantibiotic treatment, there is a large spike in sialic acidavailability, which returns to baseline 3 days after treatmentas the microbiota is reestablished. These pathogens exploitthe vacant nutrient niche to establish themselves in theintestinal tract and initiate inflammation.122

Theoretically, a pathobiont could also take advantage ofincreased sugar access to expand and cause pathology,similar to how Bilophila wadsworthia blooms when suppliedwith the bile acid taurocholic acid for sulfite reduction.123

Inflammatory responses can further optimize the milieufor invading species by providing an alternative method ofrespiration, potentiating horizontal gene transfer of viru-lence factors such as colicins and allowing the pathogen tooutcompete commensal bacteria.35,99,124,125

Beyond fighting for sugars as their main carbon source,intestinal microbes also exhibit fierce competition for nitro-gen, phosphorus, trace elements, vitamins, and other essen-tial cofactors.126,127 For instance, bacteria encode a widevariety of transporters for vitamin B12, which indicates thenecessity of these factors for survival.43 Moreover, theavailability of iron, zinc, and selenium have each been shownto modulate the microbiota in vivo, theoretically by allowingthe expansion of bacteria that aremore efficient at competingfor those trace elements.128131 In fact, Salmonella Typhi-murium infection causes up-regulation of intestinal epi-thelialderived lipocalin-2, an AMP that interferes withbacterial iron uptake. Sensitive bacteria are thus out-competed by the pathogen because Salmonella Typhimuriumis resistant to lipocalin-2 action.132 Interestingly, the pro-biotic E coli Nissle 1917 can reduce the Salmonella Typhi-murium burden after chronic infection has been established,as it has multiple lipocalin-2resistant iron uptake systemsand can outcompete the pathogen for iron.133

The ability of bacteria to metabolize host carbohydratesand bile acids was recently shown to be critical duringmouse intestinal colonization, independent of the source ofthe microbes.134 Thus, nutrient competition is a key featureof the microbial community dynamic and may play a role inintestinal pathologies that exhibit nutrient deficiencies. Forexample, IBD is associated with deficiencies in manymicronutrient levels, including zinc, vitamin A, and iron,which could potentially influence the underlying dysbiosisand microbial activities.135,136Cooperating and CommunicatingDespite the cutthroat enteric battlefield, commensal

bacteria also share byproducts rather than competing withtheir neighbors for the same food source. Intricate resourcenetworks have evolved within the microbiota employingthis waste not, want not attitude, and they form the mostbasic method of bacterial communication via detection ofneighboring microbes substrates. These networks arebeyond the scope of this article, but they have been exten-sively reviewed elsewhere.40,137

Another method by which bacterial cooperation occurs ishorizontal gene transfer (HGT). Specifically, HGT of thesecretome is overrepresented in the intestinal microbiota, asthese molecules promote cooperation and social behaviorthrough the production of public goods.138,139 One well-established example where HGT promotes cooperation is inthe production of siderophores; iron chelators secreted toscavenge this essential element.140 Iron bound by side-rophores can be taken up by any bacterium in the vicinity,whether or not it expended the energy to create the chelator.Thus, cheaters arise in these communities,whodonot expresspublic goods but benefit from those who do, which hinderscooperation.141 In limiting conditions, HGT increases therelatedness of cheaters and thus enhancesmicrobiota stabilityby preventing the fitness advantage of cheating.142,143

Secretion of an extracellular matrix, or biofilm, bindsbacteria together and protects the bacteria from outsideattacks, such as antibiotics or host immunity, while alsosmothering competing microbes.144146 Biofilms aid in thefitness of a bacterial population as a whole by decreasingthe diffusion of public goods through the viscous mediumand thus preventing others from acquiring them.147 Thisfunction is important as biofilms are especially vulnerable tocheaters, where any reduction in biofilm activity results in athinning of the biofilm matrix and increased susceptibility toantimicrobials.148 These structures are not regularly foundin the bowels of healthy humans, but are thick, dense, andadherent in untreated IBD patients.149 This could be relatedto the dysbiosis that occurs with IBD and may also explainwhy many patients are refractory to antibiotic treatmentdespite the apparent microbial involvement in disease.

Tying many of these cooperative pathways together isquorum sensing (QS), the primary method by which bacteriacommunicate cell to cell and coordinate group behavior.Bacterial signaling molecules are released into the envi-ronment and initiate gene regulation once they reach athreshold concentration (typically in the picomolar range),thus providing a means of functionally measuring bacteriadensity.150 QS influences many survival mechanismsimportant to intestinal bacteria, including T6SS expres-sion,151 antibiotic production,126 and biofilm forma-tion.150,152 Cheaters exist within the QS world, and thesebacteria benefit from the protective signaling from othermembers of the same species without expending the energyto produce QS.153 Similarly, some Gram-negative bacteriaeavesdrop by only expressing the QS response transcriptionfactor and not the signaling molecule, which could allowcommensal bacteria such as E coli to sense the presence ofinvading pathogens.154 Alternatively, some bacteria,including multiple Proteobacteria species such as Klebsiellapneumoniae and P aeruginosa, and even mammalian cells,quench QS by degrading the signaling molecules to preventcompetitive colonization.155,156

As most studies have examined pathogens, it is notentirely clear whether human commensal bacteria use QS tocommunicate despite intense speculation.157 However, QSsignaling has been identified in the probiotics E coli Nissle1917 and Lactobacillus species and may be involved in theirbeneficial effects.158160 It is likely that bacterial communi-cation is an important component of microbial communityassembly, composition, and activities. Further work is

January 2015 Microbial Activities and Homeostasis 35needed to establish the extent to which the various forms ofmicrobial communication are implicated in homeostasis anddiseases.Conclusions and PerspectiveThe human gut is a dynamic environment where

eukaryotic and a multitude of prokaryotic cells establish acomplex network of communication that ultimately benefitsboth parties. It has become clear that disrupting this pro-ductive network has dire consequences for the host andmay contribute to intestinal pathologies, including IBD andcolorectal cancer, as well as extraintestinal disorders suchas diabetes and cardiovascular and liver diseases.2

Although significant progress has been made in identi-fying host factors implicated in the disruption of the intes-tinal microbiota and associated pathologic consequences, apaucity of information is available about the functionalconsequences of commensal microbial communication. Ge-netic manipulation of genes implicated in these processes(eg, QS and biofilm formation in IBD) might allow dissectionof the roles of bacterial communication during health anddisease. Further advances will require the field of microbe-microbe communication to move from the test tube and intothe animal, as many of the fascinating interactions in vitrohave not been examined in vivo. Thus, a large piece of thehealth puzzle remains missing.

Although the overwhelming majority of genes (99.1%)examined by metagenomic sequencing of the intestinal tractare bacterial in origin,1 the viruses, fungi, and archaeapresent may influence specific host response and intestinalhomeostasis.161,162 For example, susceptibility to entericviral infection is modulated by bacteria through enhancedviral replication.163 Bacteriophages in particular are anintriguing area of research as they can enhance bacterialfitness in vivo and alter its colonization.164,165

Although there is value in definingwhich bacterial speciesare present in the gut, the field is moving toward regardingthe enteric microbial community as an organ, rather than asindividual parts. For example, does a global healthy micro-biota exist, and is it associated with a defined metabolomicfunction? Because microbial metabolism is intrinsicallylinked to the host, a holistic approach will be necessary todissect this complex relationship. Such an approach has beensuccessful in defining the relationship between diet, mi-crobes, and cardiovascular diseases.166 Although tremen-dous progress has been made in the field of microbiomeresearch, especially regarding intestinal microbiome andIBD, key elements of the dialogues are still missing, and thishinders the generation of novel therapeutic modalities.Replacing an altered microbiota has been validated as atherapeutic alternative to recurrent cases of C difficile infec-tion,167 but it is less clear whether IBD would be a logicalcandidate for this treatment.168 In addition, because of therole of host genetics in IBD, it is not clear how stable andfunctional a transplanted microbe would be. Consequently, atargetedmanipulation of microbial activities may represent abetter approach to disease treatment and management.Clearly, more research is needed to identify the microbialactivities implicated in health and disease and to harnesstheir full potential for therapeutic purposes.References1. Qin J, Li R, Raes J, et al. A human gut microbial gene

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microbial activities and intestinal homeostasis a delicate balance between health and disease

Documents

disease states

intestinal homeostasis

crohns disease cdi

inflammatorybowel disease

context of health

gastrointestinal gi

host andmicrobial community

ncndlicense http