inflammatory disease caused by intestinal pathobionts

Available online at www.sciencedirect.com ScienceDirect Inflammatory disease caused by intestinal pathobionts Ellen L Zechner1,2 Environmental and intrinsic factors that alter microbiota structure can trigger aberrant immune responses The resulting states of dysbiosis take many forms characterized by overrepresentation of pro-inflammatory organisms and pathobionts and loss of beneficial commensals further aggravating the inflammatory state The pathogenic potential of the dysbiotic community can be linked to specific organisms in some cases but accumulating evidence suggests that intestinal inflammatory diseases are driven by collective functions of highly variable polymicrobial communities Key challenges are to gain sufficient knowledge of the structure and function of a given disease-causing consortium to understand how inflammation is perpetuated, to identify the protective mechanisms lost in the absence of specific commensals and test interventions to shift a persistent dysbiotic community to a more benign state Addresses Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50/1, A-8010 Graz, Austria BioTechMed-Graz, Austria Corresponding author: Zechner, Ellen L (ellen.zechner@uni-graz.at) Current Opinion in Microbiology 2017, 35:64–69 This review comes from a themed issue on Host–microbe interactions: bacteria Edited by Samuel Miller and Rene´e Tsolis http://dx.doi.org/10.1016/j.mib.2017.01.011 1369-5274/ã 2017 The Author Published by Elsevier Ltd This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) Introduction Enteric bacteria and their vertebrate hosts have coevolved over millions of years [1] Colonization and development of a stable microbiota within the intestinal tract is crucial for host physiology and a fully functional immune system [2,3] The intestinal epithelium is a single layer of cells that facilitates absorption of nutrients and vitamins Remarkably this thin barrier also prevents pathogen invasion and dissemination of commensals Coping with the trillions of microbes present in the gut lumen and continuous threats from newly ingested infectious and non-infectious organisms is a tremendous challenge for the mucosal immune system Achieving a healthy steady state requires mounting an effective frontline defense while enabling the host to accommodate the symbiotic Current Opinion in Microbiology 2017, 35:64–69 community Intestinal epithelial cells (IECs) take an active role in both processes through perception of microbial signals and working in concert with immunocompetent cells from the underlying lamina propria Preservation of homeostasis relies on highly efficient innate and adaptive mucosal immunity and continuous epithelial renewal Historically bacteria have been classified according to their relationship with the host: commensal or pathogen However, as the field of human microbiome research has exploded in the last decade, more differentiated terms are needed to adequately describe the host– microbe commensal relationship (for an excellent discussion see Ref [4]) Homeostasis, and the composition and activities of the symbiotic community can be challenged by host genetics [5] or environmental factors such as diet [6,7] or medication [8] The altered host–microbe relationship can be defined as dysbiosis when the microbial shift has pathophysiological consequences Pathobionts are members of the symbiotic community that expand as a result of the imbalance and exert pathogenic effects on the host Here I discuss how microbial dysbiosis contributes to the development and pathology of inflammatory diseases of the intestine, use recent advances with selected experimental models to illustrate microbial-driven pathologies and focus on the particular role of pathobionts in this dysregulated state Individualists vs community level pathogenic potential Antibiotics alter microbiota composition and functions producing both acute and long-lasting deleterious effects for the host [9] Depletion of microbial density diminishes signaling to the intestinal mucosa, impairs colonization resistance and allows expansion by the antibiotic resistant population A healthy human microbiota harbors a rich and diverse reservoir of resistance genes, which amplify dramatically during treatment [10] Moreover, antibiotic use lowers resistance to intestinal domination by bacteria associated with hospital-acquired infections [11] Overgrowth and dissemination to extraintestinal organs by highly resistant bacteria such as vancomycin-resistant Enterococci and multidrug-resistant Enterobacteriaceae create clinical problems that increasingly defy treatment [12,13] The induced dysbiosis can also result in overgrowth of toxigenic members The organisms causing antibiotic associated diarrhea remain unidentified in many cases, www.sciencedirect.com Inflammatory disease caused by intestinal pathobionts Zechner 65 yet antibiotic associated colitis is a disease model that has enabled single organisms and their specific pathophysiological effects to be causally linked to the development of inflammatory disorders Resident members such as Clostridium difficile or Klebsiella oxytoca flourish under these conditions and their ability to produce protein or small molecule enterotoxins, once high microbial densities are reached [14], is responsible for some but not all forms of antibiotic associated colitis [15,16] Although these organisms appear to exert their pathogenic properties individually, a complex interplay between pathobiont, microbial community, and host response actually determines disease outcome [17] Other inflammatory diseases are instigated not by single organisms but by the collective activities of a multispecies community Interactions between community members create synergies and determine the pathogenic potential of the consortium, such as the capacity to overgrow, produce noxious substances, sustain inflammation and support pathogens [18] Hajishengallis and Lamont [4] suggested the term nososymbiocity [nosos (Greek for disease) arising from host–microbe symbiosis] to describe the capacity of an indigenous community to cause disease in a context-dependent manner The potential for a dysbiotic microbiota to induce an immune response that is uncontrolled and destructive is a key component in inflammatory mucosal diseases Crohn’s disease (CD) and ulcerative colitis (UC) are two intestinal inflammatory conditions collectively called inflammatory bowel disease (IBD) that are caused by multiple factors involving host genetics, the environment, and microbes Hallmark shifts in microbial abundances in CD are expansion of pathobiont microbes from Bacteroidetes and Enterobacteria and a concomitant depletion of symbiont microbes including Firmicutes, Bifidobacteria and Clostridia [19] Nonetheless evidence implicating a single pathobiont has not emerged from studies of different IBD cohorts Perturbation of the host–microbe commensal relationship is widely accepted as a leading factor driving the inflammatory tissue injury Yet the microbial component of IBD has been more difficult to define primarily because the bacterial role in pathogenesis occurs indirectly, via stimulation of the immune system The emerging view based on numerous studies is that collective interactions of the community drive disease through dysregulation of mucosal immunity and disruption of the mucosal barrier The resulting loss of tolerance to antigens present in the commensal microbiota induces chronic intestinal inflammation and disease Knowledge of how immunopathological communities become established has advanced dramatically (Figure 1) Functional mechanistic insights into how the host response shapes the microbial community and the consequences of these fluctuations are also beginning to emerge The challenge remains to delineate the www.sciencedirect.com respective roles of community members to understand causalities between gut microbes and immunity Host genetic deficiencies and colonic microbial ecology Large-scale genome-wide association studies reveal IBD as complex multigenic disorders [20] The genetic variants that confer risk to IBD indicate the importance of genes involved in recognition and intracellular killing of bacteria including autophagy genes involved in bacterial clearance [21] Although genetic polymorphisms associated with IBD predispose the host, it is increasingly appreciated that both genetic background and inflammation itself impacts the microbiota The resulting shift in microbial structure and function is required for induction and perpetuation of chronic inflammation As an illustration of this, both loss and hyperactivity of inflammasomes – complexes that act as steady-state sensors of pathogenassociated molecular patterns and regulators of the colonic microbiota – are linked to dysbiosis, pathobiont expansion and disease [22–24] Lack of the inflammasomes NLRP6 and NLRP3, for example, results in dysbiosis marked by expansion of several specific taxa not found in wild type littermates [23,24] The altered gut microbiota generated by inflammasome deficiency triggered an enhanced inflammatory response in the intestine and predisposed the host to IBD Importantly, the colitogenic phenotypes were communicable to wild type mice through co-housing Moreover, genetically susceptible mice treated with antibiotics to reduce the microbiota or those born via caesarian section then raised germfree developed little or no colitis Thus, genetic alterations play a role, yet it is the associated changes in microbial composition and pathogenic potential that are believed to regulate not only the rate of progression of IBD, but also colorectal cancer and multiple metabolic syndrome-associated abnormalities [25,26] This interpretation raises the question of whether genetics predispose individuals to a less effective microbiota Role of the microbiota in the inflammatory cascade Identifying the causal molecular mechanisms that enable pathobionts to contribute to disease development has been challenging but important insights are emerging In the healthy intestine, there is normally a low oxygen level and a large obligate anaerobe population Fermentation of complex polysaccharides supports anaerobic growth of the resident community However, conditions and diseases leading to intestinal inflammation disrupt the microbiota composition severely [27,28] Inflammatory conditions are mainly associated with an overall drop in species richness and an alteration in the abundance of several taxa [29,30] Obligate anaerobes from the phyla Bacteroidetes and Firmicutes are lost and facultative anaerobes belonging to the Gammaproteobacteria increase The bloom of Enterobacteriaceae is notably Current Opinion in Microbiology 2017, 35:64–69 66 Host–microbe interactions: bacteria Figure INITIAL SYMBIOSIS DYSBIOSIS NOSOSYMBIOCITY Healthy Healthy Antibiotics Infections Intestinal inflammatory disease Inflammation Intestinal lumen Exacerbations Early determinants Initial colonization Geography Evolutionary history Host genetics Diet Intestinal lumen Pathological Pathological TIME Protective organism Commensal Pathobiont Inflammophiles Pathogen (persistent) Pathogen (transient) Current Opinion in Microbiology Variable microbiota composition and the interplay of pathobionts and dysbiotic community activities determine community pathogenic potential or ‘nososymbiocity’ Composition of an individual’s microbiota determines functional outcomes ranging from resilient homeostasis to predisposition to dysbiosis and inflammation (scale bar, left) Multiple factors influence initial development of the gut microbiota, while diet has long-term impact on community maintenance Exposure to exogenous factors such as antibiotics eliminate commensal organisms and allow expansion of the resistant population including pathobionts Suppression of this population can mediate recovery Alternatively, the altered microbial structure stabilizes with increased pro-inflammatory potential Transient exposure to pathogens may also shift community structure and function with lasting impact despite pathogen clearance Inflammation, triggered extrinsically or from host immune deficiencies, drives loss of obligate anaerobes and their protective functions and favors growth of inflammophiles and pathobionts better equipped to withstand host antimicrobial responses Progressive dysregulation, loss of barrier function, loss of tolerance, hyperimmunoactivity, and depletion of even more beneficial organisms exacerbate immunopathologic potential (scale bar, right) more pronounced in the microbiota associated with the oxygen containing environment of the mucosa, than in fecal samples [31] Chronic inflammation of the colon leads to the production of various inflammatory cytokines, free radicals and other antimicrobials Winter et al [32] used murine models with chemically-induced colitis or animals lacking the antiinflammatory cytokine IL-10 to establish a mechanistic link between elevated inducible nitric oxide synthase in the inflamed intestine, abundant nitric oxide and a competitive advantage for facultative anaerobic commensal Enterobacteriaceae Members of this community are able to utilize the highly oxidized by-products as electron acceptors for anaerobic respiration The local inflammatory response thus creates a unique nutritional environment that is conducive to a bloom of bacterial species able to consume inflammation-derived nutrients, survive oxidative stress and evade released antimicrobials [33] Current Opinion in Microbiology 2017, 35:64–69 Oxygen availability is another important component in the relationship between host and microbiota, which initiates and perpetuates dysbiosis in IBD patients [34] Albenberg et al [35] examined intraluminal oxygen levels in the colon of mice and humans and observed a radial gradient of microbes linked to distribution of oxygen and nutrients provided by host tissue Oxygen produced by the epithelium enriches for aerotolerant bacteria closest to the mucosa, while anaerobic organisms dominate the gut lumen [35] Since chronic inflammation is expected to elevate oxygen levels in the intestine through increased blood flow and immunological responses, oxygen-consuming organisms are selected and obligate anaerobic communities disrupted [34,36] Consistent with this view, comparison of the microbiome in new-onset CD patients showed an altered mucosalassociated bacterial community favoring aerotolerant species [36,37] Antibiotic therapy is another driver of dysbiosis that can alter gut oxygenation [38,39] www.sciencedirect.com Inflammatory disease caused by intestinal pathobionts Zechner 67 Bacteria-derived butyrate is a preferred energy source for IECs, which oxidize this short chain fatty acid to CO2 The epithelium becomes hypoxic as a result Antibiotic depletion of butyrate-producing Clostridia in the mouse alters colonocyte energy metabolism with a concomitant increase in tissue oxygenation [38] The shift in pO2 selects for an altered microbiota and may lead to higher diffusible oxygen in the lumen, conditions that support post-antibiotic expansion of pathogens such as S Typhimurium [39] and very likely pathobionts within the altered gut microbiota In summary these data underscore the importance of the microbial component, gut oxygenation and the inflammatory reaction itself as perpetrators of dysbiosis in IBD patients (Figure 1) The condition enriches for inflammophilic pathobionts, more irritating proteobacteria, such as adherent-invasive E coli [40,41] and perhaps other pathogens better equipped to compete in the inflamed gut This more aggressive community may instigate chronic inflammation in susceptible hosts by shedding pro-inflammatory effectors and activating innate immunity, which worsens inflammation and interferes with its resolution Participation of these organisms in the inflammation process exacerbates the destructive spiral characteristic of IBD Microbial pathogenesis in colitis-associated colorectal cancer Colorectal cancer (CRC) has a multifactorial etiology that includes microbiota-mediated effects [42–44] Chronic inflammation impacts gut microbial composition and metabolic activities Moreover it is becoming increasingly clear that the microbiota associated with inflammation has a direct role in tumorigenesis Community-wide effects involving the gain and loss of bacterial populations and general metabolic functions have been shown Zackular et al [45] compared tumor formation in germ-free mice colonized either with microbiota from tumor-bearing mice or conventional animals They found that the gut microbiota associated with inflammation and CRC directly contributed to tumorigenesis and that antibiotic treatment reduced both the number and size of tumors Pro-carcinogenic activities for specific bacteria associated with colorectal adenomas and IBD are also becoming clear Human colonic isolates of Fusobacterium nucleatum accelerated intestinal tumorigenesis when introduced to genetically susceptible mice [46,47] Certain strains of Bacteroides fragilis and E coli promote CRC in murine models through the production of tumorigenic factors Up to 30% of E coli strains of the B2 phylotype harbor a polyketide synthase ( pks) gene cluster for synthesizing the DNA crosslinking metabolite colibactin [48,49] Arthur et al [50] used germ-free IL-10À/À mice with the colon-specific carcinogen azoxymethane as a model for colitis-associated CRC and linked carriage of the pks gene cluster by a commensal E coli strain to higher www.sciencedirect.com incidence of invasive adenocarcinoma Use of boronbased compounds to block colibactin production controlled tumorigenic effects of pks+ E coli in preclinical models [51] Early gut colonization by pks+ E coli contributes to defective intestinal homeostasis consistent with their frequent association with the mucosa of IBD and CRC patients [52] All these data fuel concerns over the increasing prevalence of B2 group E coli strains colonizing infants [53] Enterotoxigenic B fragilis (ETBF) colonize humans of all ages [54], yet ETBF also causes acute diarrhea and is associated with active IBD and CRC The metalloprotease toxin secreted by ETBF cleaves cadherin family proteins leading to disruption of tight junctions and increased barrier permeability Chronic colonization with ETBF in humans [55] may result in persistent subclinical but potentially tumor promoting colitis [56] E-cadherin cleavage, Wnt signaling and secretion of proinflammatory cytokines contribute further to the toxin’s carcinogenic potential [42] Intriguingly, Hecht et al [57] recently observed that symbiotic non-toxigenic B fragilis could limit acquisition of pathogenic ETBF and prevent disease in a murine host The mechanism of interbacterial competition relies on type VI secretion, thus highlighting the importance of antagonistic factors for microbiota composition and stability Better understanding of bacterial competition may support probiotic interventions to restrict pathobionts or even modulate dysbiotic communities that have reached a metastable state Conclusions Although this Commentary has focused on the role of pathobionts and the positive feedback loop that exacerbates the inflammatory state, an important property of dysbiosis that compounds the problem is the loss of protective microorganisms Appreciation of interdependencies linking beneficial bacteria and the immune system is rising, thus mechanistic understanding of the protective role of anti-inflammatory bacteria such as Faecalibacterium prausnitzii, absent in patients with inflammatory disease [58], will be equally important In a promising approach Miquel and coworkers [59] established a stable dual-association of E coli and the extremely oxygen-sensitive F prausnitzii in a gnotobiotic murine model Variations in the gut metabolomes associated with the presence of F prausnitzii during acute colitis identified a specific metabolic signature linked to anti-inflammatory effects Metabolites monitored with this approach can be of host or bacterial origin, thus through studies of this kind we may begin to understand reciprocal functional adaptation occurring between host and microbes Acknowledgements Work in the author’s laboratory is supported by the Austrian Science Fund (FWF) W901 DK Molecular Enzymology and BioTechMed-Graz, flagship Current Opinion in Microbiology 2017, 35:64–69 68 Host–microbe interactions: bacteria project Secretome S Roier is gratefully acknowledged for providing the graphics and helpful discussion 14 Darkoh C, DuPont HL, Norris SJ, Kaplan HB: Toxin synthesis by Clostridium difficile is regulated through quorum signaling MBio 2015, 6:e02569 References and recommended reading 15 Kuehne SA, Cartman ST, Heap JT, Kelly ML, Cockayne A, Minton NP: The role 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