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Drosophila Antimicrobial Peptides and Lysozymes Regulate Gut Microbiota Composition and Abundance

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Drosophila Antimicrobial Peptides and Lysozymes Regulate Gut Microbiota Composition and Abundance bioRxiv preprint doi: https://doi.org/10.1101/2021.03.19.436153; this version posted March 19, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Drosophila antimicrobial peptides and lysozymes regulate gut 2 microbiota composition and abundance 3 4 A. Marraa, M.A. Hansona, S. Kondob, B. Erkosara #, and B. Lemaitrea # 5 6 a Global Health Institute, School of Life Science, École Polytechnique Fédérale de Lausanne 7 (EPFL), Lausanne, Switzerland. 8 b Invertebrate Genetics Laboratory, Genetic Strains Research Center, National Institute of 9 Genetics, Mishima, Japan 10 11 Running title: Microbiota and Immune effectors 12 13 # Joint last authors. Correspondence to B. Lemaitre ([email protected]), B. Erkosar 14 ([email protected]) 15 16 ORCID IDs: 17 18 Marra: https://orcid.org/0000-0002-3181-634X 19 Hanson: https://orcid.org/0000-0002-6125-3672 20 Erkosar: https://orcid.org/0000-0003-1152-6772 21 Lemaitre: https://orcid.org/0000-0001-7970-1667 22 23 Keywords: Microbiota, innate immunity, aging, gnotobiotic animals, immune effectors, gut 24 25 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.19.436153; this version posted March 19, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 26 Abstract 27 28 The gut microbiota affects the physiology and metabolism of animals and its alteration can lead 29 to diseases such as gut dysplasia or metabolic disorders. Several reports have shown that the 30 immune system plays an important role in shaping both bacterial community composition and 31 abundance in Drosophila, and that immune deficit, especially during aging, negatively affects 32 microbiota richness and diversity. However, there has been little study at the effector level to 33 demonstrate how immune pathways regulate the microbiota. A key set of Drosophila immune 34 effectors are the antimicrobial peptides (AMPs), which confer defense upon systemic infection. 35 AMPs and lysozymes, a group of digestive enzymes with antimicrobial properties, are 36 expressed in the gut and are good candidates for microbiota regulation. Here, we take advantage 37 of the model organism Drosophila melanogaster to investigate the role of AMPs and lysozymes 38 in regulation of gut microbiota structure and diversity. 39 40 Using flies lacking AMPs and newly generated lysozyme mutants, we colonized gnotobiotic 41 flies with a defined set of commensal bacteria and analyzed changes in microbiota composition 42 and abundance in vertical transmission and aging contexts through 16S rRNA gene amplicon 43 sequencing. Our study shows that AMPs and, to a lesser extent, lysozymes are necessary to 44 regulate the total and relative abundance of bacteria in the gut microbiota. We also decouple 45 the direct function of AMPs from the IMD signaling pathway that regulates AMPs but also 46 many other processes, more narrowly defining the role of these effectors in the microbial 47 dysbiosis observed in IMD-deficient flies upon aging. 48 49 Importance 50 This study advances current knowledge in the field of host-microbe interactions by 51 demonstrating that the two families of immune effectors, antimicrobial peptides and lysozymes, 52 actively regulate the gut microbiota composition and abundance. Consequences of the loss of 53 these antimicrobial peptides and lysozymes are exacerbated during aging, and their loss 54 contributes to increased microbiota abundance and shifted composition in old flies. This work 55 shows that immune effectors, typically associated with resistance to pathogenic infections, also 56 help shape the beneficial gut community, consistent with the idea that host-symbiont 57 interactions use the same ‘language’ typically associated with pathogenesis. 58 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.19.436153; this version posted March 19, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 59 Introduction 60 61 The microbiota is the complex array of microbes commonly associated with the digestive tract 62 of animals. This bacterial consortium greatly affects host physiology, for example by promoting 63 immune function or intestinal homeostasis (1–4). Imbalance of the microbiota, called dysbiosis, 64 has been identified as a cause of gut dysplasia and chronic inflammatory diseases, especially 65 during aging (5). 66 The fruit fly Drosophila melanogaster is a powerful model to decipher host-microbe 67 interactions (6–8). Its genetic tractability, the possibility to generate gnotobiotic animals and 68 the simplicity of its natural microbiota have made Drosophila melanogaster a convenient model 69 to gain insight into host-microbiota relationships (7, 9, 10). Drosophila harbors a simple gut 70 microbiota composed of only a few dominant species, mainly belonging to Acetobacteraceae 71 and Lactobacillaceae, which influence multiple aspects of fly physiology, such as growth (11, 72 12), behavior (13), lifespan (14) and infection resistance (15, 16). In turn, the microbiota can 73 be shaped by various host and environmental factors such as food composition, or age of the 74 flies (17–21). 75 Innate immunity is a key regulator of microbial abundance in Drosophila (22–25). Upon acute 76 bacterial infection, Drosophila immune responsive tissues (the fat body and hemocytes in 77 systemic infection, and epithelium in local infection) sense microbe-associated molecular 78 patterns (MAMPs) to activate signaling pathways. In Drosophila, two immune pathways, the 79 Immune deficiency (IMD) and Toll pathways, regulate the expression of genes encoding 80 immune effectors that fight invading microbes (22, 26, 27). Studies in Drosophila have revealed 81 a key role of the IMD pathway in the gut to fight pathogens and keep symbiotic bacteria in 82 check (28–30). It is however unclear how the IMD pathway can effectively combat pathogens 83 but tolerate symbiotic microbiota members in the digestive tract. In fact, the microbiota induces 84 a low level of activation of the IMD pathway (28). Several reports have demonstrated that 85 immune tolerance towards the indigenous microbiota is sustained by several negative feedback 86 loops that prevent hyperactivation of the IMD pathway by peptidoglycan (the bacterial elicitor 87 recognized by IMD pathway) released from commensal bacteria (31–33). 88 Compartmentalization of the immune response to restricted areas can also favor microbiota 89 growth and control (34, 35). However, IMD pathway activation is necessary to regulate both 90 microbiota composition and proliferation, and dysregulation of this pathway leads to abnormal 91 bacterial growth and premature death of the host (28, 32, 33, 36). Notably, mutations affecting bioRxiv preprint doi: https://doi.org/10.1101/2021.03.19.436153; this version posted March 19, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 92 the IMD transcription factor Relish lead to a higher gut microbiota load and a shifted bacterial 93 composition compared to wild-type flies (28, 37). Moreover, aged Relish mutant flies display 94 dysbiosis associated with a loss of gut epithelium integrity and premature death of the animals 95 (21, 38). Collectively, these studies point to an important role of the IMD pathway in control 96 of the microbiota, notably during aging. However, the IMD pathway regulates hundreds of 97 immune effectors, and affects numerous physiological processes such as enterocyte 98 delamination and digestion (39–43). As previous studies have used mutations that suppress the 99 whole pathway (e.g Relish), the precise role of individual immune effectors downstream of the 100 IMD pathway in shaping the gut microbial community has remained elusive. 101 Antimicrobial peptides (AMPs) are molecules that contribute to innate defenses by targeting 102 the negatively charged membranes of microbes (27). These peptides are produced in large 103 quantities by the fat body during systemic infection, but also in local epithelia such as the gut. 104 Seven classic families of inducible AMPs with several isoforms have been identified in D. 105 melanogaster (27, 44). Use of CRISPR/CAS9 has recently enabled the generation of individual 106 and combined AMP mutants, allowing direct investigation of their role in host defense (45) . 107 Hanson et al. showed that Drosophila AMPs are essential for resisting infection by Gram- 108 negative bacteria that trigger the IMD pathway, but appear to be less involved in defense against 109 Gram-positive bacterial infection (45). 110 Another key group of effector proteins that are potential regulators of Gram-positive bacteria 111 in the gut are the lysozymes (46, 47). Lysozymes specifically cleave peptidoglycan exposed on 112 the cell wall of Gram-positive bacteria (48). The Drosophila genome encodes at least 17 113 putative lysozymes, whose functions have never been formally addressed. Among them, six 114 lysozyme genes (LysB, D, E, P, S, and X) are clustered in the genome at cytogenetic map 115 position 61F. This group of lysozyme genes, notably LysB, LysD, LysE, and LysP, is strongly 116 expressed in the digestive tract (46), and may contribute to digestive activities of the gut by 117 degrading peptidoglycan from dietary bacteria. Furthermore, lysozyme genes are expressed in 118 the gut upon microbiota colonization in Drosophila, and these proteins have been proposed to 119 modulate immune signaling (28, 31, 49). Lysozymes may contribute to gut immunity either as 120 direct antimicrobials, or by cleaving peptidoglycan and modulating activation of the IMD 121 pathway (31).
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