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Gut homeostasis in a microbial world: insights from Drosophila melanogaster

Key Points

  • Drosophila melanogaster feeds on microorganisms and lives in microorganism-rich environments. However, the D. melanogaster gut is an environment of relatively low bacterial diversity, with Lactobacillus and Acetobacter spp. being the most commonly associated species.

  • Bacteria associated with D. melanogaster affect larval growth and adult stem cell activity.

  • Antimicrobial peptide production by the immune deficiency (Imd) pathway and reactive oxygen species (ROS) production by the NADPH oxidase Duox provide two complementary inducible defence mechanisms in the gut.

  • Negative regulators of the Imd pathway ensure that there is an adequate level of immune reactivity to both the gut microbiota and infectious bacteria.

  • Stress and repair mechanisms that maintain tissue integrity contribute to gut homeostasis in response to pathogens.

  • Entomopathogens can kill the host by disrupting or avoiding immune and repair mechanisms.

Abstract

Intestinal homeostasis is achieved, in part, by the integration of a complex set of mechanisms that eliminate pathogens and tolerate the indigenous microbiota. Drosophila melanogaster feeds on microorganism-enriched matter and therefore has developed efficient mechanisms to control ingested microorganisms. Regulatory mechanisms ensure an appropriate level of immune reactivity in the gut to accommodate the presence of beneficial and dietary microorganisms, while allowing effective immune responses to clear pathogens. Maintenance of D. melanogaster gut homeostasis also involves regeneration of the intestine to repair damage associated with infection. Entomopathogenic bacteria have developed common strategies to subvert these defence mechanisms and kill their host.

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Figure 1: Immune and repair mechanisms contribute to the resolution of infection.
Figure 2: Regulation of the immune deficiency pathway in the Drosophila melanogaster midgut.
Figure 3: Regulation of reactive oxygen species production in the Drosophila melanogaster midgut.
Figure 4: Epithelial renewal establishes a homeostatic loop required to tolerate infection.

References

  1. Lemaitre, B. & Hoffmann, J. A. The host defense of Drosophila melanogaster. Annu. Rev. Immunol. 25, 697–743 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Ferrandon, D. The complementary facets of epithelial host defenses in the genetic model organism Drosophila melanogaster: from resistance to resilience. Curr. Opin. Immunol. 25, 59–70 (2012).

    Article  PubMed  CAS  Google Scholar 

  3. Charroux, B. & Royet, J. Gut-microbiota interactions in non-mammals: what can we learn from Drosophila? Semin. Immunol. 24, 17–24 (2012).

    Article  PubMed  Google Scholar 

  4. Apidianakis, Y. & Rahme, L. Drosophila melanogaster as a model for human intestinal infection and pathology. Dis. Model. Mech. 4, 21–30 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sang, J. H. The quantitative nutritional requirements of Drosophila melanogaster. J. Exp. Biol. 33, 45–72 (1956).

    Article  CAS  Google Scholar 

  6. Baumberger, J. P. The food of Drosophila melanogaster Meigen. Proc. Natl Acad. Sci. USA 3, 122–126 (1917).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Begon, M. The role of yeast in the nutrition of an insect (Drosophila). J. Biol. Chem. 30, 122–126 (1917).

    Google Scholar 

  8. Starmer, W. T. A comparison of Drosophila habitats according to the physiological attributes of the associated yeast communities. Evolution 35, 38–52 (1981).

    Article  CAS  PubMed  Google Scholar 

  9. Oakeshott, J. G., Vacek, D. C. & Anderson, P. R. Effects of microbial floras on the distributions of five domestic Drosophila species across fruit resources. Oecologia 78, 533–541 (1989).

    Article  CAS  PubMed  Google Scholar 

  10. Starmer, W. T. & Fogleman, J. C. Coadaptation of Drosophila and yeasts in their natural habitat. J. Chem. Ecol. 12, 1037–1055 (1986).

    Article  CAS  PubMed  Google Scholar 

  11. McFall-Ngai, M. et al. Animals in a bacterial world, a new imperative for the life sciences. Proc. Natl Acad. Sci. USA 110, 3229–3236 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Vodovar, N. et al. Drosophila host defense after oral infection by an entomopathogenic Pseudomonas species. Proc. Natl Acad. Sci. USA 102, 11414–11419 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nehme, N. T. et al. A model of bacterial intestinal infections in Drosophila melanogaster. PLoS Pathog. 3, e173 (2007). This paper presents a thorough description of S. marcescens -induced pathogenesis and the coordination of gut and systemic responses.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Buchon, N. et al. Morphological and molecular characterization of adult midgut compartmentalization in Drosophila. Cell Rep. 3, 1725–1738 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Basset, A. et al. The phytopathogenic bacteria Erwinia carotovora infects Drosophila and activates an immune response. Proc. Natl Acad. Sci. USA 97, 3376–3381 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Buchon, N., Broderick, N. A., Chakrabarti, S. & Lemaitre, B. Invasive and indigenous microbiota impact intestinal stem cell activity through multiple pathways in Drosophila. Genes Dev. 23, 2333–2344 (2009). This study demonstrates that both the gut microbiota and pathogens alter epithelial renewal and stem cell activity in the gut of D. melanogaster.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ryu, J.-H. et al. Innate immune homeostasis by the homeobox gene Caudal and commensal-gut mutualism in Drosophila. Science 319, 777–782 (2008). In addition to describing the microbial diversity of the D. melanogaster midgut, this article shows how aberrant activation of the Imd pathway leads to dysbiosis and premature fly death.

    Article  CAS  PubMed  Google Scholar 

  18. Ren, C., Webster, P., Finkel, S. & Tower, J. Increased internal and external bacterial load during Drosophila aging without life-span trade-off. Cell Metab. 6, 144–152 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Cox, C. R. & Gilmore, M. S. Native microbial colonization of Drosophila melanogaster and its use as a model of Enterococcus faecalis pathogenesis. Infect. Immun. 75, 1565–1576 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Corby-Harris, V. et al. Geographical distribution and diversity of bacteria associated with natural populations of Drosophila melanogaster. Appl. Environ. Microbiol. 73, 3470–3479 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chandler, J., Lang, J., Bhatnagar, S. & Eisen, J. Bacterial communities of diverse Drosophila species: ecological context of a host–microbe model system. PLoS Genet. 7, e1002272 (2011). This report provides an analysis of the bacterial communities associated with 14 species in the family Drosophilidae . In addition, using wild and laboratory populations of D. melanogaster , the report describes factors that might influence the microbial composition of the microbiota.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wong, C. N. A., Ng, P. & Douglas, A. E. Low-diversity bacterial community in the gut of the fruitfly Drosophila melanogaster. Environ. Microbiol. 13, 1889–1900 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Broderick, N. A. & Lemaitre, B. Gut-associated microbes of Drosophila melanogaster. Gut Microbes 3, 307–321 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Bakula, M. The persistence of a microbial flora during postembryogenesis of Drosophila melanogaster. J. Invertebr. Pathol. 14, 365–374 (1969).

    Article  CAS  PubMed  Google Scholar 

  25. Shin, S. C. et al. Drosophila microbiome modulates host developmental and metabolic homeostasis via insulin signaling. Science 334, 670–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. Sharon, G. et al. Commensal bacteria play a role in mating preference of Drosophila melanogaster. Proc. Natl Acad. Sci. USA 107, 20051–20056 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Glittenberg, M. et al. Pathogen and host factors are needed to provoke a systemic host response to gastrointestinal infection of Drosophila larvae by Candida albicans. Dis. Model. Mech. 4, 515–525 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Stamps, J. A., Yang, L. H., Morales, V. M. & Boundy-Mills, K. L. Drosophila regulate yeast density and increase yeast community similarity in a natural substrate. PLoS ONE 7, e42238 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rohlfs, M. Clash of kingdoms or why Drosophila larvae positively respond to fungal competitors. Front. Zool. 2, 2 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Storelli, G. et al. Lactobacillus plantarum promotes Drosophila systemic growth by modulating hormonal signals through TOR-dependent nutrient sensing. Cell Metab. 14, 403–414 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Ridley, E. V., Wong, A. C.-N., Westmiller, S. & Douglas, A. E. Impact of the resident microbiota on the nutritional phenotype of Drosophila melanogaster. PLoS ONE 7, e36765 (2012). This work, along with that described in references 25 and 30, shows that gut-associated bacteria affect larval growth. In addition, references 25 and 30 demonstrate that this effect is mediated by insulin signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Amcheslavsky, A., Jiang, J. & Ip, Y. T. Tissue damage-induced intestinal stem cell division in Drosophila. Cell Stem Cell 4, 49–61 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. O'Brien, L. E., Soliman, S. S., Li, X. & Bilder, D. Altered modes of stem cell division drive adaptive intestinal growth. Cell 147, 603–614 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Choi, N.-H., Lucchetta, E. & Ohlstein, B. Nonautonomous regulation of Drosophila midgut stem cell proliferation by the insulin-signaling pathway. Proc. Natl Acad. Sci. USA 108, 18702–18707 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lehane, M. J. Peritrophic matrix structure and function. Annu. Rev. Entomol. 42, 525–550 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Hegedus, D., Erlandson, M., Gillott, C. & Toprak, U. New insights into peritrophic matrix synthesis, architecture, and function. Annu. Rev. Entomol. 54, 285–302 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Vossenkämper, A., Macdonald, T. T. & Marchès, O. Always one step ahead: how pathogenic bacteria use the type III secretion system to manipulate the intestinal mucosal immune system. J. Inflamm. (Lond.) 8, 11 (2011).

    Article  CAS  Google Scholar 

  38. Kuraishi, T., Binggeli, O., Opota, O., Buchon, N. & Lemaitre, B. Genetic evidence for a protective role of the peritrophic matrix against intestinal bacterial infection in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 108, 15966–15971 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Syed, Z. A., Härd, T., Uv, A. & van Dijk-Härd, I. F. A potential role for Drosophila mucins in development and physiology. PLoS ONE 3, e3041 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Buchon, N., Broderick, N. A., Poidevin, M., Pradervand, S. & Lemaitre, B. Drosophila intestinal response to bacterial infection: activation of host defense and stem cell proliferation. Cell Host Microbe 5, 200–211 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Bonnay, F. et al. big bang gene modulates gut immune tolerance in Drosophila. Proc. Natl Acad. Sci. USA 110, 2957–2962 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hegan, P. S., Mermall, V., Tilney, L. G. & Mooseker, M. S. Roles for Drosophila melanogaster myosin IB in maintenance of enterocyte brush-border structure and resistance to the bacterial pathogen Pseudomonas entomophila. Mol. Biol. Cell 18, 4625–4636 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tzou, P. et al. Tissue-specific inducible expression of antimicrobial peptide genes in Drosophila surface epithelia. Immunity 13, 737–748 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Ryu, J.-H. et al. An essential complementary role of NF-κB pathway to microbicidal oxidants in Drosophila gut immunity. EMBO J. 25, 3693–3701 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Liehl, P., Blight, M., Vodovar, N., Boccard, F. & Lemaitre, B. Prevalence of local immune response against oral infection in a Drosophila/Pseudomonas infection model. PLoS Pathog. 2, e56 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Bosco-Drayon, V. et al. Peptidoglycan sensing by the receptor PGRP-LE in the Drosophila gut induces immune responses to infectious bacteria and tolerance to microbiota. Cell Host Microbe 12, 153–165 (2012).

    Article  CAS  PubMed  Google Scholar 

  47. Neyen, C., Poidevin, M., Roussel, A. & Lemaitre, B. Tissue- and ligand-specific sensing of Gram-negative infection in Drosophila by PGRP-LC isoforms and PGRP-LE. J. Immunol. 189, 1886–1897 (2012). References 46 and 47 delineate how a combination of extracellular sensing by PGRP-LC isoforms and intracellular sensing through PGRP-LE provides a sophisticated mechanism to mediate Imd activation along the gut.

    Article  CAS  PubMed  Google Scholar 

  48. Takehana, A. et al. Overexpression of a pattern-recognition receptor, peptidoglycan-recognition protein-LE, activates imd/relish-mediated antibacterial defense and the prophenoloxidase cascade in Drosophila larvae. Proc. Natl Acad. Sci. USA 99, 13705–13710 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Leulier, F. et al. The Drosophila immune system detects bacteria through specific peptidoglycan recognition. Nature Immunol. 4, 478–484 (2003).

    Article  CAS  Google Scholar 

  50. Kaneko, T. et al. Monomeric and polymeric gram-negative peptidoglycan but not purified LPS stimulate the Drosophila IMD pathway. Immunity 20, 637–649 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Zaidmanremy, A. et al. The Drosophila amidase PGRP-LB modulates the immune response to bacterial infection. Immunity 24, 463–473 (2006).

    Article  CAS  Google Scholar 

  52. Lhocine, N. et al. PIMS modulates immune tolerance by negatively regulating Drosophila innate immune signaling. Cell Host Microbe 4, 147–158 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Johnson, J. W., Fisher, J. F. & Mobashery, S. Bacterial cell-wall recycling. Ann. NY Acad. Sci. 1277, 54–75 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Buchon, N., Broderick, N. A., Kuraishi, T. & Lemaitre, B. Drosophila EGFR pathway coordinates stem cell proliferation and gut remodeling following infection. BMC Biol. 8, 152 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mellroth, P. & Steiner, H. PGRP-SB1: an N-acetylmuramoyl L-alanine amidase with antibacterial activity. Biochem. Biophys. Res. Commun. 350, 994–999 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Bischoff, V. et al. Downregulation of the Drosophila immune response by peptidoglycan-recognition proteins SC1 and SC2. PLoS Pathog. 2, e14 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Zaidmanremy, A. et al. Drosophila immunity: analysis of PGRP-SB1 expression, enzymatic activity and function. PLoS ONE 6, e17231 (2011).

    Article  CAS  Google Scholar 

  58. Paredes, J. C., Welchman, D. P., Poidevin, M. & Lemaitre, B. Negative regulation by amidase PGRPs shapes the Drosophila antibacterial response and protects the fly from innocuous infection. Immunity 35, 770–779 (2011). References 51, 52 and 58 demonstrate the importance of inducible negative regulators to adjust the amplitude of the immune response to both gut microbiota and pathogens.

    Article  CAS  PubMed  Google Scholar 

  59. Kleino, A. et al. Pirk is a negative regulator of the Drosophila Imd pathway. J. Immunol. 180, 5413–5422 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Aggarwal, K. et al. Rudra interrupts receptor signaling complexes to negatively regulate the IMD pathway. PLoS Pathog. 4, e1000120 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Maillet, F., Bischoff, V., Vignal, C., Hoffmann, J. & Royet, J. The Drosophila peptidoglycan recognition protein PGRP-LF blocks PGRP-LC and IMD/JNK pathway activation. Cell Host Microbe 3, 293–303 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Basbous, N. et al. The Drosophila peptidoglycan-recognition protein LF interacts with peptidoglycan-recognition protein LC to downregulate the Imd pathway. EMBO Rep. 12, 327–333 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lee, K.-Z. & Ferrandon, D. Negative regulation of immune responses on the fly. EMBO J. 30, 988–990 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Aggarwal, K. & Silverman, N. Positive and negative regulation of the Drosophila immune response. BMB Rep. 41, 267–277 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Ha, E.-M., Oh, C.-T., Bae, Y. S. & Lee, W.-J. A direct role for dual oxidase in Drosophila gut immunity. Science 310, 847–850 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Bae, Y. S., Choi, M. K. & Lee, W.-J. Dual oxidase in mucosal immunity and host–microbe homeostasis. Trends Immunol. 31, 278–287 (2010).

    Article  CAS  PubMed  Google Scholar 

  67. Kumar, S., Molina-Cruz, A., Gupta, L., Rodrigues, J. & Barillas-Mury, C. A peroxidase/dual oxidase system modulates midgut epithelial immunity in Anopheles gambiae. Science 327, 1644–1648 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Anh, N. T. T., Nishitani, M., Harada, S., Yamaguchi, M. & Kamei, K. Essential role of Duox in stabilization of Drosophila wing. J. Biol. Chem. 286, 33244–33251 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Juarez, M. T., Patterson, R. A., Sandoval-Guillen, E. & McGinnis, W. Duox, Flotillin-2, and Src42A are required to activate or delimit the spread of the transcriptional response to epidermal wounds in Drosophila. PLoS Genet. 7, e1002424 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Razzell, W., Evans, I. R., Martin, P. & Wood, W. Calcium flashes orchestrate the wound inflammatory response through DUOX activation and hydrogen peroxide release. Curr. Biol. 23, 424–429 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ha, E.-M. et al. Regulation of DUOX by the Gαq-phospholipase Cβ-Ca2+ pathway in Drosophila gut immunity. Dev. Cell 16, 386–397 (2009).

    Article  CAS  PubMed  Google Scholar 

  72. Ha, E.-M. et al. Coordination of multiple dual oxidase-regulatory pathways in responses to commensal and infectious microbes in Drosophila gut. Nature Immunol. 10, 949–957 (2009).

    Article  CAS  Google Scholar 

  73. Chen, J. et al. Participation of the p38 pathway in Drosophila host defense against pathogenic bacteria and fungi. Proc. Natl Acad. Sci. USA 170, 20774–20779 (2010). A study that highlights the role of p38 stress pathways in host survival to intestinal pathogens.

    Article  Google Scholar 

  74. Lee, K.-A. et al. Bacterial-derived uracil as a modulator of mucosal immunity and gut-microbe homeostasis in Drosophila. Cell 153, 797–811 (2013). This article reports that bacterium-derived uracil is the inducer of ROS production by Duox in gut epithelia. The results of this study suggest that the amount of uracil released by bacteria facilitates differentiation between benign and damage-inducing microorganisms in the gut.

    Article  CAS  PubMed  Google Scholar 

  75. Osman, D. et al. Autocrine and paracrine unpaired signalling regulate intestinal stem cell maintenance and division. J. Cell Sci. 125, 5944–5949 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Michaut, L. et al. Determination of the disulfide array of the first inducible antifungal peptide from insects: drosomycin from Drosophila melanogaster. FEBS Lett. 395, 6–10 (1996).

    Article  CAS  PubMed  Google Scholar 

  77. Zhang, Z.-T. & Zhu, S.-Y. Drosomycin, an essential component of antifungal defence in Drosophila. Insect Mol. Biol. 18, 549–556 (2009).

    Article  CAS  PubMed  Google Scholar 

  78. Zaidmanremy, A., Regan, J. C., Brandão, A. S. & Jacinto, A. The Drosophila larva as a tool to study gut-associated macrophages: PI3K regulates a discrete hemocyte population at the proventriculus. Dev. Comp. Immunol. 36, 638–647 (2012).

    Article  CAS  Google Scholar 

  79. Cronin, S. J. F. et al. Genome-wide RNAi screen identifies genes involved in intestinal pathogenic bacterial infection. Science 325, 340–343 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Jiang, H. et al. Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut. Cell 137, 1343–1355 (2009). References 16, 32, 40, 79 and 80 show that gut damage induces the production of secreted ligands that activate the JAK–STAT pathway in progenitors to promote epithelial renewal, thereby establishing a homeostatic repair loop.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Chatterjee, M. & Ip, Y. T. Pathogenic stimulation of intestinal stem cell response in Drosophila. J. Cell. Physiol. 220, 664–671 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Schneider, D. S. & Ayres, J. S. Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases. Nature Rev. Immunol. 8, 889–895 (2008).

    Article  CAS  Google Scholar 

  83. Apidianakis, Y., Pitsouli, C., Perrimon, N. & Rahme, L. Synergy between bacterial infection and genetic predisposition in intestinal dysplasia. Proc. Natl Acad. Sci. USA 106, 20883–20888 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Jiang, H., Grenley, M. O., Bravo, M.-J., Blumhagen, R. Z. & Edgar, B. A. EGFR/Ras/MAPK signaling mediates adult midgut epithelial homeostasis and regeneration in Drosophila. Cell Stem Cell 8, 84–95 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Zhou, F., Rasmussen, A., Lee, S. & Agaisse, H. The UPD3 cytokine couples environmental challenge and intestinal stem cell division through modulation of JAK/STAT signaling in the stem cell microenvironment. Dev. Biol. 373, 383–393 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Cordero, J. B., Stefanatos, R. K., Scopelliti, A., Vidal, M. & Sansom, O. J. Inducible progenitor- derived Wingless regulates adult midgut regeneration in Drosophila. EMBO J. 31, 3901–3917 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Biteau, B. & Jasper, H. EGF signaling regulates the proliferation of intestinal stem cells in Drosophila. Development 138, 1045–1055 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ren, F. et al. Hippo signaling regulates Drosophila intestine stem cell proliferation through multiple pathways. Proc. Natl Acad. Sci. USA 107, 21064–21069 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Karpowicz, P., Perez, J. & Perrimon, N. The Hippo tumor suppressor pathway regulates intestinal stem cell regeneration. Development 137, 4135–4145 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Shaw, R. L. et al. The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration. Development 137, 4147–4158 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Staley, B. K. & Irvine, K. D. Warts and Yorkie mediate intestinal regeneration by influencing stem cell proliferation. Curr. Biol. 20, 1580–1587 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Choi, N.-H., Kim, J.-G., Yang, D.-J., Kim, Y.-S. & Yoo, M.-A. Age-related changes in Drosophila midgut are associated with PVF2, a PDGF/VEGF-like growth factor. Aging Cell 7, 318–334 (2008).

    Article  CAS  PubMed  Google Scholar 

  93. Biteau, B., Hochmuth, C. E. & Jasper, H. JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut. Cell Stem Cell 3, 442–455 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Rera, M., Clark, R. I. & Walker, D. W. Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila. Proc. Natl Acad. Sci. USA 109, 21528–21533 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Mulet, M., Gomila, M., Lemaitre, B., Lalucat, J. & García-Valdés, E. Taxonomic characterisation of Pseudomonas strain L48 and formal proposal of Pseudomonas entomophila sp. nov. Syst. Appl. Microbiol. 35, 145–149 (2012).

    Article  CAS  PubMed  Google Scholar 

  96. Chakrabarti, S., Liehl, P., Buchon, N. & Lemaitre, B. Infection-induced host translational blockage inhibits immune responses and epithelial renewal in the Drosophila gut. Cell Host Microbe 12, 60–70 (2012). This study shows that P. entomophila disrupts gut homeostasis by blocking protein translation, thereby inhibiting immune and repair responses.

    Article  CAS  PubMed  Google Scholar 

  97. Gonzalez, M. R., Bischofberger, M., Pernot, L., van der Goot, F.-G. G. & Frêche, B. Bacterial pore-forming toxins: the (w)hole story? Cell. Mol. Life Sci. 65, 493–507 (2008).

    Article  CAS  PubMed  Google Scholar 

  98. Gonzalez, M. R. et al. Pore-forming toxins induce multiple cellular responses promoting survival. Cell. Microbiol. 13, 1026–1043 (2011).

    Article  CAS  PubMed  Google Scholar 

  99. Opota, O. et al. Monalysin, a novel ß-pore-forming toxin from the Drosophila pathogen Pseudomonas entomophila, contributes to host intestinal damage and lethality. PLoS Pathog. 7, e1002259 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kocks, C. et al. Eater, a transmembrane protein mediating phagocytosis of bacterial pathogens in Drosophila. Cell 123, 335–346 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Chung, Y.-S. A. & Kocks, C. Recognition of pathogenic microbes by the Drosophila phagocytic pattern recognition receptor eater. J. Biol. Chem. 286, 26524–26532 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Limmer, S. et al. Pseudomonas aeruginosa RhlR is required to neutralize the cellular immune response in a Drosophila melanogaster oral infection model. Proc. Natl Acad. Sci. USA 108, 17378–17383 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Berkey, C. D., Blow, N. & Watnick, P. I. Genetic analysis of Drosophila melanogaster susceptibility to intestinal Vibrio cholerae infection. Cell. Microbiol. 11, 461–474 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. Purdy, A. E. & Watnick, P. I. Spatially selective colonization of the arthropod intestine through activation of Vibrio cholerae biofilm formation. Proc. Natl Acad. Sci. USA 108, 19737–19742 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Vallet-Gely, I., Lemaitre, B. & Boccard, F. Bacterial strategies to overcome insect defences. Nature Rev. Microbiol. 6, 302–313 (2008).

    Article  CAS  Google Scholar 

  106. Stensmyr, M. C. et al. A conserved dedicated olfactory circuit for detecting harmful microbes in Drosophila. Cell 151, 1345–1357 (2012).

    Article  CAS  PubMed  Google Scholar 

  107. Shivers, R. P., Kooistra, T., Chu, S. W., Pagano, D. J. & Kim, D. Tissue-specific activities of an immune signaling module regulate physiological responses to pathogenic and nutritional bacteria in C. elegans. Cell Host Microbe 6, 321–330 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. van Frankenhuyzen, K. Insecticidal activity of Bacillus thuringiensis crystal proteins. J. Invertebr. Pathol. 101, 1–16 (2009).

    Article  CAS  PubMed  Google Scholar 

  109. Muniz, L. R., Knosp, C. & Yeretssian, G. Intestinal antimicrobial peptides during homeostasis, infection, and disease. Front. Immunol. 3, 310 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Liu, X., Lu, R., Wu, S. & Sun, J. Salmonella regulation of intestinal stem cells through the Wnt/β-catenin pathway. FEBS Lett. 584, 911–916 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Abreu, M. T. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nature Rev. Immunol. 10, 131–144 (2010).

    Article  CAS  Google Scholar 

  112. Demerec, M. Biology of Drosophila (Cold Spring Harbor Lab. Press, 1994).

    Google Scholar 

  113. Micchelli, C. A. & Perrimon, N. Evidence that stem cells reside in the adult Drosophila midgut epithelium. Nature 439, 475–479 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Ohlstein, B. & Spradling, A. The adult Drosophila posterior midgut is maintained by pluripotent stem cells. Nature 439, 470–474 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Ohlstein, B. & Spradling, A. Multipotent Drosophila intestinal stem cells specify daughter cell fates by differential Notch signaling. Science 315, 988–992 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Khush, R. S. & Lemaitre, B. Genes that fight infection: what the Drosophila genome says about animal immunity. Trends Genet. 16, 442–449 (2000).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Bettencourt-Scheller Foundation, a European Research Council Advanced Grant, the Swiss National Fund (grant 3100A0-12079/1) and a Human Frontier Science Program Long-term Postdoctoral Fellowship (to N.A.B.).

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Correspondence to Nicolas Buchon, Nichole A. Broderick or Bruno Lemaitre.

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Glossary

Axenic

Pertaining to animals: raised under sterile conditions.

Mitotic index

The proportion of proliferating cells in a tissue.

Ectoderm

The outermost germ cell layer in the metazoan embryo.

Endoderm

The innermost germ cell layer in the metazoan embryo.

Haemolymph

The circulatory fluid of arthropods.

Type III secretion systems

Specialized syringe-like bacterial structures that inject effectors into host cells.

Brush border

The microvillus-covered surface of the epithelium.

Pattern recognition receptors

Host receptors (such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs)) that can sense pathogen-associated molecular patterns and initiate signalling cascades which lead to an innate immune response. These receptors can be membrane bound (such as TLRs) or soluble and cytoplasmic (such as NLRs).

Peptidoglycan recognition protein

(PGRPs). Pattern recognition receptors that bind peptidoglycan from the cell wall of bacteria. Recognition PGRPs bind peptidoglycan and activate the immune response. Catalytic PGRPs degrade peptidoglycan and thereby act either as negative regulators of the immune response or as immune effectors.

Sclerotization

The process of cuticle hardening in insects.

Cardia

A valve-like structure that separates the fore- and midgut in insects.

Dysbiosis

The condition that results from an imbalance in the microbiota.

Fat body

An insect organ with immune and metabolic functions similar to those of the mammalian liver and adipose tissue.

Haemocoel

The haemolymph-containing body cavity of insects.

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Buchon, N., Broderick, N. & Lemaitre, B. Gut homeostasis in a microbial world: insights from Drosophila melanogaster. Nat Rev Microbiol 11, 615–626 (2013). https://doi.org/10.1038/nrmicro3074

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