Immune-Microbiota Interplay and Colonization Resistance in Infection

Commensal microbial communities inhabit biological niches in the mammalian host, where they impact the host’s physiology through induction of “colonization resistance” against infections by a multitude of molecular mechanisms. These colonization-regulating activities involve microbe-microbe and microbe-host interactions, which induce, through utilization of complex bacterial networks, competition over nutrients, inhibition by antimicrobial peptides, stimulation of the host immune system, and promotion of mucus and intestinal epithelial barrier integrity. Distinct virulent pathogens overcome this colonization resistance and host immunity as part of a hostile takeover of the host niche, leading to clinically overt infection. The following review provides a mechanistic overview of the role of commensal microbes in modulating colonization resistance and pathogenic infections and means by which infectious agents may overcome such inhibition. Last, we outline evidence, unknowns, and challenges in developing strategies to harness this knowledge to treat infections by microbiota transfer, phage therapy, or supplementation by rationally defined bacterial consortia. Commensal microbial communities inhabit biological niches in the mammalian host, where they impact the host’s physiology through induction of “colonization resistance” against infections by a multitude of molecular mechanisms. These colonization-regulating activities involve microbe-microbe and microbe-host interactions, which induce, through utilization of complex bacterial networks, competition over nutrients, inhibition by antimicrobial peptides, stimulation of the host immune system, and promotion of mucus and intestinal epithelial barrier integrity. Distinct virulent pathogens overcome this colonization resistance and host immunity as part of a hostile takeover of the host niche, leading to clinically overt infection. The following review provides a mechanistic overview of the role of commensal microbes in modulating colonization resistance and pathogenic infections and means by which infectious agents may overcome such inhibition. Last, we outline evidence, unknowns, and challenges in developing strategies to harness this knowledge to treat infections by microbiota transfer, phage therapy, or supplementation by rationally defined bacterial consortia. The human body is inherently metagenomic in that it not only consists of its eukaryotic genome but also integrates the genomes (microbiome) of a myriad of microbes colonizing its surfaces (microbiota), including bacteria, archaea, fungi, protozoa, and viruses (Ley et al., 2008Ley R.E. Hamady M. Lozupone C. Turnbaugh P.J. Ramey R.R. Bircher J.S. Schlegel M.L. Tucker T.A. Schrenzel M.D. Knight R. Gordon J.I. Evolution of mammals and their gut microbes.Science. 2008; 320: 1647-1651Crossref PubMed Scopus (1799) Google Scholar). The metazoan host and its microbiome have coevolved, and a rapidly growing body of research shows that commensal microbial communities interact with almost any aspect of host physiology in health and disease. The microbiome in the gut is most extensively studied, as it surpasses other body habitats in microbial biomass by more than an order of magnitude and is separated from the near-sterile host by only a single layer of lining epithelial cells (Sender et al., 2016Sender R. Fuchs S. Milo R. Revised estimates for the number of human and bacteria cells in the body.PLoS Biol. 2016; 14: e1002533Crossref PubMed Google Scholar). The deeper understanding of the microbiome’s diversity and mechanisms at the host-microbiome interface sheds new light on infectious diseases as interactions between species within the context of these complex ecosystems. It is estimated that more than 90% of pathogens infect the human host through its mucosal surfaces (Brandtzaeg, 2010Brandtzaeg P. The mucosal immune system and its integration with the mammary glands.J. Pediatr. 2010; 156: S8-S15Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). A crucial function of mucosal microbiotas in humans is, therefore, to provide resistance to infectious diseases (McKenney and Pamer, 2015McKenney P.T. Pamer E.G. From hype to hope: the gut microbiota in enteric infectious disease.Cell. 2015; 163: 1326-1332Abstract Full Text Full Text PDF PubMed Google Scholar). To fulfill this purpose, four classes of mechanisms of the microbiota can be delineated in relation to infectious pathogens: direct inhibition, barrier maintenance, immune modulation, and bacterial metabolism (McKenney and Pamer, 2015McKenney P.T. Pamer E.G. From hype to hope: the gut microbiota in enteric infectious disease.Cell. 2015; 163: 1326-1332Abstract Full Text Full Text PDF PubMed Google Scholar). Collectively, these mechanisms contribute to “colonization resistance” (Lawley and Walker, 2013Lawley T.D. 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Microbial interference and colonization of the murine gastrointestinal tract by Listeria monocytogenes.Infect. Immun. 1979; 23: 168-174Crossref PubMed Google Scholar). In a homeostatic state, commensal microbiota offer protection to the host against pathogenic agents via a wide array of mechanisms. Commensals such as Faecalibacterium prausnitzii enhance mucus production via stimulation of enterocyte genes involved in mucin production and upregulate tight junction expression in an IL-10-dependent manner. Various pathogenic bacteria erode the mucus barrier to promote invasive infection. Moreover, commensals may stimulate intestinal antimicrobial peptide production and stimulate the host’s immune response. Commensals compete with pathogens over dietary nutrients and, therefore, occupy the ecological niche required by the pathogen to thrive. Pathogens have developed mechanisms to eliminate commensal competitors, e.g., via bacterial secretion systems. Many commensals directly inhibit pathogens via secreted factors such as bacteriocins, SCFAs, or secondary bile acids. In an evolutionary arms race, pathogens develop mechanisms antagonizing these factors, e.g., by degrading enzymes or efflux pumps. Genes enhancing the pathogen’s fitness and virulence may be passed on via horizontal gene transfer, e.g., through nanotubes. Some commensals directly inhibit other bacteria by secreting soluble factors (Suez et al., 2018Suez J. Zmora N. Zilberman-Schapira G. Mor U. Dori-Bachash M. Bashiardes S. Zur M. Regev-Lehavi D. Ben-Zeev Brik R. Federici S. et al.Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT.Cell. 2018; 174: 1406-1423.e16Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar), such as bacteriocins (peptides with antimicrobial activity). Such factors restrain the growth of adjacent bacteria by a plethora of mechanisms such as cell-wall synthesis inhibition, pore formation, and nuclease activity (Kommineni et al., 2015Kommineni S. Bretl D.J. Lam V. Chakraborty R. Hayward M. Simpson P. Cao Y. Bousounis P. Kristich C.J. Salzman N.H. Bacteriocin production augments niche competition by enterococci in the mammalian gastrointestinal tract.Nature. 2015; 526: 719-722Crossref PubMed Scopus (150) Google Scholar). Bacteriocins such as microcin, thuricin, and lantibiotics (a class of polycyclic peptide antibiotics) inhibit pathogens such as E. coli O157:H7 (Schamberger and Diez-Gonzalez, 2002Schamberger G.P. Diez-Gonzalez F. Selection of recently isolated colicinogenic Escherichia coli strains inhibitory to Escherichia coli O157:H7.J. Food Prot. 2002; 65: 1381-1387Crossref PubMed Google Scholar), Salmonella enterica (Sassone-Corsi et al., 2016Sassone-Corsi M. Nuccio S.P. Liu H. Hernandez D. Vu C.T. Takahashi A.A. Edwards R.A. 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Remarkably, small-molecule biosynthetic gene clusters for thiopeptide-class antibiotics are widely distributed in the metagenome of the human microbiota (Donia et al., 2014Donia M.S. Cimermancic P. Schulze C.J. Wieland Brown L.C. Martin J. Mitreva M. Clardy J. Linington R.G. Fischbach M.A. A systematic analysis of biosynthetic gene clusters in the human microbiome reveals a common family of antibiotics.Cell. 2014; 158: 1402-1414Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Other non-proteinaceous secreted molecules that inhibit the proliferation of neighboring bacteria include short-chain fatty acids (SCFAs) (Cherrington et al., 1991Cherrington C.A. Hinton M. Pearson G.R. Chopra I. Short-chain organic acids at ph 5.0 kill Escherichia coli and Salmonella spp. without causing membrane perturbation.J. Appl. Bacteriol. 1991; 70: 161-165Crossref PubMed Google Scholar), H2O2 (Pircalabioru et al., 2016Pircalabioru G. Aviello G. Kubica M. Zhdanov A. Paclet M.H. 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It was recently discovered that the uptake of commensal Neisseria-derived DNA by pathogenic Neisseria gonorrhea induces the pathogen’s death as a result of misrecognition of the DNA’s methylation pattern (Kim et al., 2019bKim W.J. Higashi D. Goytia M. Rendón M.A. Pilligua-Lucas M. Bronnimann M. McLean J.A. Duncan J. Trees D. Jerse A.E. So M. Commensal Neisseria kill Neisseria gonorrhoeae through a DNA-dependent mechanism.Cell Host Microbe. 2019; 26: 228-239.e8Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar). Another study discovered that, injecting an adjacent bacteria, a defective enzyme, P. aeruginosa, can deplete the neighboring bacteria’s ATP and lead to cell death (Ahmad et al., 2019Ahmad S. Wang B. Walker M.D. Tran H.R. Stogios P.J. Savchenko A. Grant R.A. McArthur A.G. Laub M.T. Whitney J.C. An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp.Nature. 2019; 575: 674-678Crossref PubMed Scopus (1) Google Scholar). Whether these findings have any clinical significance in infections remains to be answered and warrant further inquiry. Bacteria develop resistance to such secreted factors through various mechanisms, similar to pharmaceutical antibiotics. Notable examples are enzymatic bacteriocin degradation, modification of bacteriocins’ target site (i.e., the cell-wall envelope), and efflux pumps (Bastos et al., 2015Bastos M.do.C. Coelho M.L. Santos O.C. Resistance to bacteriocins produced by Gram-positive bacteria.Microbiology. 2015; 161: 683-700Crossref PubMed Scopus (44) Google Scholar). Secretion systems are protein complexes located at the bacterial cell wall that are used to transport effector molecules (i.e., proteins, toxins, drugs) from the cytoplasm to the exterior of the cell. These structures are of major importance for microbial competition, as they can serve the purpose of transporting toxic substances to their environment or even into nearby eukaryotic or prokaryotic cells. Several different types of secretion systems with various functions have been described (Meuskens et al., 2019Meuskens I. Saragliadis A. Leo J.C. Linke D. Type V secretion systems: an overview of passenger domain functions.Front. Microbiol. 2019; 10: 1163Crossref PubMed Scopus (1) Google Scholar, Russell et al., 2014Russell A.B. Peterson S.B. Mougous J.D. Type VI secretion system effectors: poisons with a purpose.Nat. Rev. Microbiol. 2014; 12: 137-148Crossref PubMed Scopus (318) Google Scholar, Sgro et al., 2019Sgro G.G. Oka G.U. Souza D.P. Cenens W. Bayer-Santos E. Matsuyama B.Y. Bueno N.F. Dos Santos T.R. Alvarez-Martinez C.E. Salinas R.K. Farah C.S. Bacteria-killing type IV secretion systems.Front. Microbiol. 2019; 10: 1078Crossref PubMed Scopus (2) Google Scholar). The significant importance of secretion systems (especially type VI secretion systems, or T6SSs) has been implicated for the proliferation of gut commensal species as well as a wide range of invasive pathogens such as K. pneumoniae, P. aeruginosa, P. mirabilis, E. coli, S. enterica, Y. entrocolitica, and Campylobacter species. Vibrio cholera is a Gram-negative pathogen that induces a severe diarrheal illness and is typically transmitted through consumption of contaminated water in endemic areas of poor sanitation. Following transmission to a new host, V. cholera overcomes colonization resistance by antagonizing intestinal commensals using a T6SS (Zhao et al., 2018bZhao W. Caro F. Robins W. Mekalanos J.J. Antagonism toward the intestinal microbiota and its effect on Vibrio cholerae virulence.Science. 2018; 359: 210-213Crossref PubMed Scopus (47) Google Scholar). A few papers outlined that T6SSs can serve as interbacterial defense systems and can be upregulated whenever nearby T6SS activity is sensed (Basler and Mekalanos, 2012Basler M. Mekalanos J.J. Type 6 secretion dynamics within and between bacterial cells.Science. 2012; 337: 815Crossref PubMed Scopus (136) Google Scholar, Basler et al., 2013Basler M. Ho B.T. Mekalanos J.J. Tit-for-tat: type VI secretion system counterattack during bacterial cell-cell interactions.Cell. 2013; 152: 884-894Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar, Ross et al., 2019Ross B.D. Verster A.J. Radey M.C. Schmidtke D.T. Pope C.E. Hoffman L.R. Hajjar A.M. Peterson S.B. Borenstein E. Mougous J.D. Human gut bacteria contain acquired interbacterial defence systems.Nature. 2019; 575: 224-228Crossref PubMed Scopus (2) Google Scholar). B. fragilis uses a T6SS to secrete a ubiquitin-like protein with potent inhibitory activity against coresident strains of B. fragilis (Chatzidaki-Livanis et al., 2016Chatzidaki-Livanis M. Geva-Zatorsky N. Comstock L.E. Bacteroides fragilis type VI secretion systems use novel effector and immunity proteins to antagonize human gut Bacteroidales species.Proc. Natl. Acad. Sci. USA. 2016; 113: 3627-3632Crossref PubMed Scopus (81) Google Scholar, Chatzidaki-Livanis et al., 2017Chatzidaki-Livanis M. Coyne M.J. Roelofs K.G. Gentyala R.R. Caldwell J.M. Comstock L.E. Gut symbiont Bacteroides fragilis secretes a eukaryotic-like ubiquitin protein that mediates intraspecies antagonism.MBio. 2017; 8 (e01902-17)Crossref PubMed Scopus (13) Google Scholar). Utilization of advanced microscopy technology (cryomicroscopy) uncovered mechanisms by which effector molecules are loaded and transported across T6SSs (Quentin et al., 2018Quentin D. Ahmad S. Shanthamoorthy P. Mougous J.D. Whitney J.C. Raunser S. Mechanism of loading and translocation of type VI secretion system effector Tse6.Nat. Microbiol. 2018; 3: 1142-1152Crossref PubMed Scopus (22) Google Scholar). In addition, secretion systems may also serve functions beyond bacterial antagonism, such as signaling or defense against phages; however, these functions are beyond the scope of this article (Russell et al., 2014Russell A.B. Peterson S.B. Mougous J.D. Type VI secretion system effectors: poisons with a purpose.Nat. Rev. Microbiol. 2014; 12: 137-148Crossref PubMed Scopus (318) Google Scholar). Horizontal transfer of substances can also occur by nanotubes (Bhattacharya et al., 2019Bhattacharya S. Baidya A.K. Pal R.R. Mamou G. Gatt Y.E. Margalit H. Rosenshine I. Ben-Yehuda S. A ubiquitous platform for bacterial nanotube biogenesis.Cell Rep. 2019; 27: 334-342.e10Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). These ubiquitous organelles are composed of membranous projections and are used by bacteria to transport various cytoplasmic entities, such as plasmids that may contain antibiotic resistance genes, or even to extract nutrients from mammalian host cells (Pal et al., 2019Pal R.R. Baidya A.K. Mamou G. Bhattacharya S. Socol Y. Kobi S. Katsowich N. Ben-Yehuda S. Rosenshine I. Pathogenic E. coli extracts nutrients from infected host cells utilizing injectisome components.Cell. 2019; 177: 683-696.e18Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The intestine continuously absorbs nutrients and prevents enteric pathogens from systemic spread while concurrently allowing for immune processing of foodborne antigenic load. The gastrointestinal tract can, thus, be understood as a “barrier tissue,” as it selectively separates the body from the external environment. The means by which this intestinal barrier function is achieved include strong inter-cellular epithelial cell adhesion by tight-junction proteins and the secretion of mucus, antibodies (i.e., immunoglobulin A [IgA]), and antimicrobial effector molecules by enterocytes and intestinal immune cells (Martens et al., 2018Martens E.C. Neumann M. Desai M.S. Interactions of commensal and pathogenic microorganisms with the intestinal mucosal barrier.Nat. Rev. Microbiol. 2018; 16: 457-470Crossref PubMed Scopus (3) Google Scholar). If these barrier functions are compromised, the risk of infection significantly increases (Desai et al., 2016bDesai M.S. Seekatz A.M. Koropatkin N.M. Kamada N. Hickey C.A. Wolter M. Pudlo N.A. Kitamoto S. Terrapon N. Muller A. et al.A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility.Cell. 2016; 167: 1339-1353.e21Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar, Thaiss et al., 2018Thaiss C.A. Levy M. Grosheva I. Zheng D. Soffer E. Blacher E. Braverman S. Tengeler A.C. Barak O. Elazar M. et al.Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection.Science. 2018; 359: 1376-1383Crossref PubMed Scopus (108) Google Scholar). An extensive body of literature supports the gut microbiota’s role in regulating the intestinal barrier function. This section covers some important mechanisms by which microbes either fortify or overcome the intestinal barrier function, a detailed review of microbial-host interactions in the context of the intestinal barrier function is provided elsewhere (Martens et al., 2018Martens E.C. Neumann M. Desai M.S. Interactions of commensal and pathogenic microorganisms with the intestinal mucosal barrier.Nat. Rev. Microbiol. 2018; 16: 457-470Crossref PubMed Scopus (3) Google Scholar). Mucus is a major component of the intestinal barrier, as microbes are stifled from reaching the epithelium by its diameter. Some commensal bacteria, such as B. thetaiotaomicron and Faecalibacterium prausnitzii, are capable of enhancing mucus production by inducing the expression of genes involved in mucin glycosylation and mucus-secreting goblet cell differentiation (Wrzosek et al., 2013Wrzosek L. Miquel S. Noordine M.-L. Bouet S. Joncquel Chevalier-Curt M. Robert V. Philippe C. Bridonneau C. Cherbuy C. Robbe-Masselot C. et al.Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii influence the production of mucus glycans and the development of goblet cells in the colonic epithelium of a gnotobiotic model rodent.BMC Biol. 2013; 11: 61Crossref PubMed Scopus (219) Google Scholar). Butyrate-producing bacterial species strengthen the barrier function by regulating tight-junction protein expression in an interleukin (IL)-10-dependent manner (Kelly et al., 2015Kelly C.J. Zheng L. Campbell E.L. Saeedi B. Scholz C.C. Bayless A.J. Wilson K.E. Glover L.E. Kominsky D.J. Magnuson A. et al.Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function.Cell Host Microbe. 2015; 17: 662-671Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar, Zheng et al., 2017Zheng L. Kelly C.J. Battista K.D. Schaefer R. Lanis J.M. Alexeev E.E. Wang R.X. Onyiah J.C. Kominsky D.J. Colgan S.P. Microbial-derived butyrate promotes epithelial barrier function through IL-10 receptor-dependent repression of claudin-2.J. Immunol. 2017; 199: 2976-2984Crossref PubMed Scopus (0) Google Scholar). However, various pathogenic bacteria and protozoa such as C. perfringenes and Entamoeba histolytica produce enzymes that degrade mucus by targeting glycoproteins or their attached glycans (Martens et al., 2018Martens E.C. Neumann M. Desai M.S. Interactions of commensal and pathogenic microorganisms with the intestinal mucosal barrier.Nat. Rev. Microbiol. 2018; 16: 457-470Crossref PubMed Scopus (3) Google Scholar). During dietary fiber deprivation, some commensal microbes undergo a metabolic shift to utilize mucus glycoproteins as an energy source. This process erodes the mucosal barrier and increases the risk of infection (Desai et al., 2016bDesai M.S. Seekatz A.M. Koropatkin N.M. Kamada N. Hickey C.A. Wolter M. Pudlo N.A. Kitamoto S. Terrapon N. Muller A. et al.A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility.Cell. 2016; 167: 1339-1353.e21Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar). After passing through the mucus layer, bacterial and protozoal pathogens such as E. coli, V. cholerae, C. perfringenes, C. difficile, and Giardia lamblia can alter tight-junction protein expression to increase gut permeability (Martens et al., 2018Marte