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A Commensal Protozoan Strikes a Balance in the Gut

2016; Cell Press; Volume: 20; Issue: 4 Linguagem: Inglês

10.1016/j.chom.2016.09.016

1934-6069

P’ng Loke, Yvonne Ai Lian Lim,

Parasites and Host Interactions

Gut commensals profoundly affect host immunity and intestinal homeostasis, but the impact of commensal eukaryotic protozoans is poorly understood. In a recent Cell paper, Chudnovskiy et al., 2016Chudnovskiy A. Mortha A. Kana V. Kennard A. Ramirez J.D. Rahman A. Remark R. Mogno I. Ng R. Gnjatic S. et al.Cell. 2016; 167: 444-456Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar identify a commensal protozoan, Tritrichomonas musculis, that can enhance anti-bacterial defenses, but at the cost of increasing intestinal inflammation. Gut commensals profoundly affect host immunity and intestinal homeostasis, but the impact of commensal eukaryotic protozoans is poorly understood. In a recent Cell paper, Chudnovskiy et al., 2016Chudnovskiy A. Mortha A. Kana V. Kennard A. Ramirez J.D. Rahman A. Remark R. Mogno I. Ng R. Gnjatic S. et al.Cell. 2016; 167: 444-456Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar identify a commensal protozoan, Tritrichomonas musculis, that can enhance anti-bacterial defenses, but at the cost of increasing intestinal inflammation. We have co-evolved with the many different organisms living in the gastrointestinal tract, which can have profound effects on the immune system during both steady state and disease conditions. Our current understanding of these mutualistic interactions in the gut is dominated by studies focused on prokaryotic bacterial communities. However, viruses and eukaryotic organisms (e.g., fungi, protozoa, and helminths) are also important constituents of the mammalian gut, which undoubtedly have an impact on the host immune system. The barrier function of the intestine must prevent pathogens from invasion and dissemination, while avoiding unnecessary inflammation that leads to self-harm (Ramanan and Cadwell, 2016Ramanan D. Cadwell K. Cell Host Microbe. 2016; 19: 434-441Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). Maintaining this delicate balance is of mutual benefit for commensal organisms as well as the mammalian host. The impact of commensal eukaryotic protozoans in particular is still poorly understood (Lukeš et al., 2015Lukeš J. Stensvold C.R. Jirků-Pomajbíková K. Wegener Parfrey L. PLoS Pathog. 2015; 11: e1005039Crossref PubMed Scopus (110) Google Scholar). Merad and colleagues (Chudnovskiy et al., 2016Chudnovskiy A. Mortha A. Kana V. Kennard A. Ramirez J.D. Rahman A. Remark R. Mogno I. Ng R. Gnjatic S. et al.Cell. 2016; 167: 444-456Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar) have now identified a commensal protozoa from mice, Tritrichomonas musculis (T.mu), that can enhance anti-bacterial defenses, but at the cost of increasing intestinal inflammation. Specifically, T.mu induces an accumulation of IFN-γ-producing CD4+ TH1 and IL-17-producing CD4+ TH17 cells in the colon that can promote anti-bacterial defenses, without noticeable signs of mucosal injury. Through a series of experiments with mice deficient for different immune components, they identified inflammasome activation and IL-18 production as being essential for conferring this accumulation of TH1 and TH17 cells and providing protective anti-bacterial responses (Figure 1). Inflammasomes are protein complexes that catalytically activate the cytokines IL-1β and IL-18. Previous studies had established a critical role for inflammasome activation and IL-18 signaling in regulating intestinal barrier function and inflammation. Disruption of inflammasome function and IL-18 leads to microbial dysbiosis that sensitizes mice to intestinal inflammation because of disrupted barrier function (Elinav et al., 2011Elinav E. Strowig T. Kau A.L. Henao-Mejia J. Thaiss C.A. Booth C.J. Peaper D.R. Bertin J. Eisenbarth S.C. Gordon J.I. Flavell R.A. Cell. 2011; 145: 745-757Abstract Full Text Full Text PDF PubMed Scopus (1451) Google Scholar). More recently, metabolites associated with bacterial communities were found to regulate inflammasome signaling (Levy et al., 2015Levy M. Thaiss C.A. Zeevi D. Dohnalová L. Zilberman-Schapira G. Mahdi J.A. David E. Savidor A. Korem T. Herzig Y. et al.Cell. 2015; 163: 1428-1443Abstract Full Text Full Text PDF PubMed Scopus (573) Google Scholar). Whether T.mu is also a source of such metabolites or if it modulates the production of bacterial metabolites to shape the intestinal environment is unclear. Notably, Merad and colleagues showed that germ-free mice mono-colonized with T.mu were sufficient to induce TH1 and TH17 cells in the gut, indicating that other components of the gut flora may not be necessary, although whether every aspect of the T.mu colonization phenotype can be recapitulated by mono-colonization remains uncertain. Indirect alterations to the overall ecological communities may be important for some downstream effects of T.mu colonization, such as increased sensitivity to inflammation and intestinal tumors. Acting through the inflammasome and IL-18, T.mu colonization increases host protection against Salmonella Typhimurium infections. However, this benefit to the host comes at the cost of increased sensitization to increased intestinal inflammation and colorectal cancer (Figure 1). With the T cell transfer colitis model, T.mu-colonized mice had more severe disease than uninfected mice. Additionally, there was a significant increase in tumors when Apcmin/+ mice, a model of sporadic colorectal cancer, were colonized with T.mu. This cost-benefit aspect of T.mu colonization illustrates the dilemma of intestinal commensal interactions. A delicate balance has to be struck between resisting pathogens by mounting an effective immune response and tolerating other foreign antigens and modulating inflammation. As an extracellular but unicellular eukaryote, T.mu still triggers a primarily TH1/TH17 response, unlike the multicellular metazoan helminths, which primarily stimulate a TH2 response. It is still not entirely evident why cellularity plays a factor in the type of response that is driven. While T.mu is shown here to err on the side of sensitizing inflammation while conferring protection against bacterial infection, intestinal helminths have been shown to dampen inflammation (Ramanan et al., 2016Ramanan D. Bowcutt R. Lee S.C. Tang M.S. Kurtz Z.D. Ding Y. Honda K. Gause W.C. Blaser M.J. Bonneau R.A. et al.Science. 2016; 352: 608-612Crossref PubMed Scopus (259) Google Scholar); hence, perhaps, this may also come at the cost of increasing susceptibility to bacterial infection. Clearly, the role of eukaryotic organisms in striking a balance between promoting tolerance and resisting pathogens is becoming more evident. Trichomonads are flagellated anaerobic protozoa that often have symbiotic interactions with their animal hosts (Maritz et al., 2014Maritz J.M. Land K.M. Carlton J.M. Hirt R.P. Trends Parasitol. 2014; 30: 333-341Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). Of the human parasites, only Trichomonas vaginalis has strong pathogenic potential as a sexually transmitted infectious agent. The closest human ortholog to T.mu appears to be Dientamoeba fragilis, which has been implicated in irritable bowel syndrome, although this remains controversial. Overall, the immunology of this entire group of organisms is very poorly described, and so T.mu may become an important model for trichomonad immunology. The genome of T. vaginalis was sequenced as far back as 2007, but our understanding of the host-pathogen interactions for these organisms is still rudimentary, partly due to the lack of good animal models. Understanding the pathogenic or protective effects of this group of organisms on host mucosal surfaces in particular will be an exciting development. Merad and colleagues started this study by noticing an immune phenotype shaped by the housing environment their mice were exposed to. Variations in the microbiota between animal housing facilities is likely the source of some inconsistencies between different immunological studies reported in the literature, but more recently has become a basis for uncovering new mutualistic interactions that alter intestinal immune responses (Ivanov et al., 2009Ivanov I.I. Atarashi K. Manel N. Brodie E.L. Shima T. Karaoz U. Wei D. Goldfarb K.C. Santee C.A. Lynch S.V. et al.Cell. 2009; 139: 485-498Abstract Full Text Full Text PDF PubMed Scopus (3171) Google Scholar, Ramanan et al., 2014Ramanan D. Tang M.S. Bowcutt R. Loke P. Cadwell K. Immunity. 2014; 41: 311-324Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar). Nonetheless, these discoveries represent just the tip of the iceberg, as there is emerging evidence that mice exposed to a more natural environment develop immune systems more similar to humans (Beura et al., 2016Beura L.K. Hamilton S.E. Bi K. Schenkel J.M. Odumade O.A. Casey K.A. Thompson E.A. Fraser K.A. Rosato P.C. Filali-Mouhim A. et al.Nature. 2016; 532: 512-516Crossref PubMed Scopus (645) Google Scholar). It is evident that there are many more mutualistic organisms to discover from non-laboratory animals that will impact systemic immunity. A combination of elegant reductionist experiments in the laboratory such as by Merad and colleagues, with new approaches toward characterizing the immune system of mice and other mammals in a wild environment along with the diverse organisms they are exposed to, may provide us with more realistic models of the diverse human immune system. Currently, we are challenged to understand how the changing environment is affecting tolerance to intestinal antigens derived from food or commensal organisms, with the rapid rise of food allergies and intestinal inflammatory diseases. Whether an organism in the environment is a pathogen, pathobiont, or commensal could well be determined by the genotype of the mammalian host. Although T.mu can colonize different strains of mice, whether T.mu strikes the same balance of increased inflammation and anti-bacterial defenses on the intestinal immune system of different mouse strains is uncertain. Disruption of the complex gut ecosystem through the loss of certain groups of organisms may result in reduced regulation of intestinal immune responses, making the mammalian host of a specific genotype more sensitive to pathogen infection or pathogenic inflammation. A better understanding of these genetic and environmental interactions may facilitate ongoing efforts to restore tolerance toward intestinal antigens without increasing susceptibility to infection with pathogens. P.L. and Y.A.L.L. are funded by a UM/MoHE High Impact Research (UM.C/625/1/HIR/MOHE/MED/23) grant from University of Malaya (Y.A.L.L. and P.L.), the Kevin and Masha Keating Family Foundation (P.L.), National Institutes of Health (AI093811 and AI094166), and the Broad Medical Research Program. The funders had no role in the preparation of or the decision to publish the manuscript. Host-Protozoan Interactions Protect from Mucosal Infections through Activation of the InflammasomeChudnovskiy et al.CellOctober 06, 2016In BriefExpanding the vertebrate microbiota diversity: a mutualistic protozoan acts as a “protistic antibiotic,” protecting the intestinal mucosa against bacterial infections. Full-Text PDF Open Archive