Mobile genetic elements: the hidden puppet masters underlying infant gut microbiome assembly?

Abstract

The gut microbiota is important for healthy infant development. Part of the initial colonizing microbial strains originate from the maternal gut, and undergo a selective event, termed the “colonization bottleneck”. While vertical mother-to-infant inheritance and subsequent colonization of bacteria have previously been studied, the role of mobile genetic elements (MGEs) in the infant gut microbiota assembly is unclear. In this perspective article, we discuss how horizontally and vertically transmitted phages and conjugative elements potentially have important roles in infant gut microbiota assembly and colonization through parasitic and mutualistic interactions with their bacterial hosts. While some of these MGEs are likely to be detrimental to their host survival, in other contexts, they may help bacteria colonize new niches, antagonize other bacteria, or protect themselves from other parasitic MGEs in the infant gut. As a result, the horizontal transfer of MGEs likely occurs at high rates in the infant gut, contributing to gene transfer between bacteria and affecting which bacteria can pass the colonization bottleneck. We conclude by highlighting the potential in silico, in vitro, and in vivo methodological approaches that could be employed to study the transmission and colonization dynamics of MGEs and bacteria in the infant gut.

Keywords

Colonization bottleneck / MGEs / infant gut microbiome / horizontal transmission / phage / phage-plasmid / plasmid

References

[1] Charbonneau MR,Blanton LV.Sialylated milk oligosaccharides promote microbiota-dependent growth in models of infant undernutrition.Cell2016;164:859-71 PMCID:PMC4793393

[2] Riva A,Lassandro C.Pediatric obesity is associated with an altered gut microbiota and discordant shifts in Firmicutes populations.Environ Microbiol2017;19:95-105 PMCID:PMC5516186

[3] Kim YG,Seo SU.Neonatal acquisition of Clostridia species protects against colonization by bacterial pathogens.Science2017;356:315-9 PMCID:PMC6082366

[4] Henrick BM,Lakshmikanth T.Bifidobacteria-mediated immune system imprinting early in life.Cell2021;184:3884-98.e11

[5] Yao Y,Ye Y,Chen F.The role of microbiota in infant health: from early life to adulthood.Front Immunol2021;12:708472 PMCID:PMC8529064

[6] Yassour M, Vatanen T, Siljander H, et al; DIABIMMUNE Study Group. Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability. Sci Transl Med 2016;8:343ra81. PMCID:PMC5032909

[7] Mitchell CM,Hogstrom L.Delivery mode affects stability of early infant gut microbiota.Cell Rep Med2020;1:100156 PMCID:PMC7762768

[8] Yang R,Ying Z.Inspecting mother-to-infant microbiota transmission: disturbance of strain inheritance by cesarian section.Front Microbiol2024;15:1292377 PMCID:PMC10937581

[9] Lou YC,Diamond S.Infant gut strain persistence is associated with maternal origin, phylogeny, and traits including surface adhesion and iron acquisition.Cell Rep Med2021;2:100393 PMCID:PMC8484513

[10] Bogaert D,de Koff EM.Mother-to-infant microbiota transmission and infant microbiota development across multiple body sites.Cell Host Microbe2023;31:447-60.e6

[11] Ferretti P,Tett A.Mother-to-infant microbial transmission from different body sites shapes the developing infant gut microbiome.Cell Host Microbe2018;24:133-45.e5 PMCID:PMC6716579

[12] Yassour M,Hogstrom LJ.Strain-level analysis of mother-to-child bacterial transmission during the first few months of life.Cell Host Microbe2018;24:146-54.e4 PMCID:PMC6091882

[13] Chen DW.Rapid evolution and strain turnover in the infant gut microbiome.Genome Res2022;32:1124-36 PMCID:PMC9248880

[14] Scholtens PA,Martin R,Knol J.The early settlers: intestinal microbiology in early life.Annu Rev Food Sci Technol2012;3:425-47

[15] Mäklin T,Pöntinen AK.Strong pathogen competition in neonatal gut colonisation.Nat Commun2022;13:7417 PMCID:PMC9715557

[16] Ormaasen I,Diep DB.Metagenome-mining indicates an association between bacteriocin presence and strain diversity in the infant gut.BMC Genomics2023;24:295 PMCID:PMC10230729

[17] Gregory AC,Zayed AA,Bolduc B.The gut virome database reveals age-dependent patterns of virome diversity in the human gut.Cell Host Microbe2020;28:724-40.e8 PMCID:PMC7443397

[18] Yu MK,Eren AM.Diverse plasmid systems and their ecology across human gut metagenomes revealed by PlasX and MobMess.Nat Microbiol2024;9:830-47 PMCID:PMC10914615

[19] Vatanen T,Ruohtula T.Mobile genetic elements from the maternal microbiome shape infant gut microbial assembly and metabolism.Cell2022;185:4921-36.e15 PMCID:PMC9869402

[20] Shah SA,Thorsen J.Expanding known viral diversity in the healthy infant gut.Nat Microbiol2023;8:986-98 PMCID:PMC10159846

[21] He W,Klincke F,Sørensen SJ.Insights into the ecology of the infant gut plasmidome.Nat Commun2024;15:6924 PMCID:PMC11322291

[22] Hall JPJ,Baltrus DA.Introduction: the secret lives of microbial mobile genetic elements.Philos Trans R Soc Lond B Biol Sci2022;377:20200460 PMCID:PMC8628069

[23] Bittinger K,Li Y.Bacterial colonization reprograms the neonatal gut metabolome.Nat Microbiol2020;5:838-47 PMCID:PMC8052915

[24] Vatanen T,Siegwald L.A distinct clade of Bifidobacterium longum in the gut of Bangladeshi children thrives during weaning.Cell2022;185:4280-97.e12

[25] Liang G,Zhang H.The stepwise assembly of the neonatal virome is modulated by breastfeeding.Nature2020;581:470-4 PMCID:PMC7263352

[26] Bethke JH,Tsoi R,Xiao M.Vertical and horizontal gene transfer tradeoffs direct plasmid fitness.Mol Syst Biol2023;19:e11300 PMCID:PMC9912019

[27] Ewald PW.Transmission modes and evolution of the parasitism-mutualism continuum.Ann N Y Acad Sci1987;503:295-306

[28] Turner PE,Lenski RE.Tradeoff between horizontal and vertical modes of transmission in bacterial plasmids.Evolution1998;52:315-29

[29] Rankin DJ,Brown SP.What traits are carried on mobile genetic elements, and why?.Heredity2011;106:1-10 PMCID:PMC3183850

[30] Niu J,Qian Y.Evolution of the gut microbiome in early childhood: a cross-sectional study of Chinese children.Front Microbiol2020;11:439 PMCID:PMC7169428

[31] Mäntynen S,Oksanen HM,Díaz-Muñoz SL.Black box of phage-bacterium interactions: exploring alternative phage infection strategies.Open Biol2021;11:210188 PMCID:PMC8440029

[32] Davray D,Kulkarni R.Plasmids encode niche-specific traits in Lactobacillaceae.Microb Genom2021;7:mgen000472 PMCID:PMC8190607

[33] LeGault KN,Angermeyer A.Temporal shifts in antibiotic resistance elements govern phage-pathogen conflicts.Science2021;373:eabg2166 PMCID:PMC9064180

[34] Dragoš A,Lozano-Andrade CN,Kovács ÁT.Phages carry interbacterial weapons encoded by biosynthetic gene clusters.Curr Biol2021;31:3479-89.e5

[35] Dineen RL,O’Connell-Motherway M.Transcriptional landscape of the pMP7017 megaplasmid and its impact on the Bifidobacterium breve UCC2003 transcriptome.Microb Biotechnol2024;17:e14405 PMCID:PMC10832533

[36] Martínez Arbas S,Herold M.Roles of bacteriophages, plasmids and CRISPR immunity in microbial community dynamics revealed using time-series integrated meta-omics.Nat Microbiol2021;6:123-35 PMCID:PMC7752763

[37] Clokie MR,Letarov AV.Phages in nature.Bacteriophage2011;1:31-45 PMCID:PMC3109452

[38] Tisza M, Lloyd R, Hoffman K, et al; TEDDY Study Group. Phage-bacteria dynamics during the first years of life revealed by trans-kingdom marker gene analysis. bioRxiv 2023. PMCID:PMC10557657

[39] Lou YC,Borges AL.Infant gut DNA bacteriophage strain persistence during the first 3 years of life.Cell Host Microbe2024;32:35-47.e6 PMCID:PMC11156429

[40] Maqsood R,Rodriguez C.Discordant transmission of bacteria and viruses from mothers to babies at birth.Microbiome2019;7:156 PMCID:PMC6902606

[41] Garmaeva S, Sinha T, Gulyaeva A, et al; Lifelines NEXT cohort study. Transmission and dynamics of mother-infant gut viruses during pregnancy and early life. Nat Commun 2024;15:1945. PMCID:PMC10908809

[42] Mathieu A,Deng L.Virulent coliphages in 1-year-old children fecal samples are fewer, but more infectious than temperate coliphages.Nat Commun2020;11:378 PMCID:PMC6969025

[43] Redgwell TA,Petit MA. Prophages in the infant gut are largely induced, and may be functionally relevant to their hosts. Available from: https://www.biorxiv.org/content/10.1101/2021.06.25.449885v1. [Last accessed on 8 Nov 2024]

[44] Beller L,Vieira-Silva S.The virota and its transkingdom interactions in the healthy infant gut.Proc Natl Acad Sci U S A2022;119:e2114619119 PMCID:PMC9060457

[45] Zeng S,Li S.A metagenomic catalog of the early-life human gut virome.Nat Commun2024;15:1864 PMCID:PMC10904392

[46] Humphrey S,Quiles-Puchalt N.Bacterial chromosomal mobility via lateral transduction exceeds that of classical mobile genetic elements.Nat Commun2021;12:6509 PMCID:PMC8575950

[47] Ravi A,Gueimonde M.Transmission and persistence of IncF conjugative plasmids in the gut microbiota of full-term infants.FEMS Microbiol Ecol2018;94:fix158

[48] Pärnänen K,Hultman J.Maternal gut and breast milk microbiota affect infant gut antibiotic resistome and mobile genetic elements.Nat Commun2018;9:3891 PMCID:PMC6155145

[49] Fogarty EC,Lolans K.A cryptic plasmid is among the most numerous genetic elements in the human gut.Cell2024;187:1206-22.e16 PMCID:PMC10973873

[50] Beaber JW,Waldor MK.SOS response promotes horizontal dissemination of antibiotic resistance genes.Nature2004;427:72-4

[51] Chen X,Li G.Antibiotic-resistance gene transfer in antibiotic-resistance bacteria under different light irradiation: implications from oxidative stress and gene expression.Water Res2019;149:282-91

[52] Yu Z,Lu J,Guo J.Nonnutritive sweeteners can promote the dissemination of antibiotic resistance through conjugative gene transfer.ISME J2021;15:2117-30 PMCID:PMC8245538

[53] Yu Z,Guo J.Non-caloric artificial sweeteners modulate conjugative transfer of multi-drug resistance plasmid in the gut microbiota.Gut Microbes2023;15:2157698 PMCID:PMC9762752

[54] Hu J,Wang S,Han D.Prophage activation in the intestine: insights into functions and possible applications.Front Microbiol2021;12:785634 PMCID:PMC8710666

[55] Pfeifer E,Touchon M.Bacteria have numerous distinctive groups of phage-plasmids with conserved phage and variable plasmid gene repertoires.Nucleic Acids Res2021;49:2655-73 PMCID:PMC7969092

[56] Pfeifer E,Rocha EPC.Phage-plasmids spread antibiotic resistance genes through infection and lysogenic conversion.mBio2022;13:e0185122 PMCID:PMC9600943

[57] Pfeifer E.Phage-plasmids promote recombination and emergence of phages and plasmids.Nat Commun2024;15:1545 PMCID:PMC10879196

[58] Piligrimova EG,Kazantsev AN.Putative plasmid prophages of Bacillus cereus sensu lato may hold the key to undiscovered phage diversity.Sci Rep2021;11:7611 PMCID:PMC8026635

[59] Łobocka MB,Plunkett G 3rd.Genome of bacteriophage P1.J Bacteriol2004;186:7032-68 PMCID:PMC523184

[60] Carattoli A.Resistance plasmid families in Enterobacteriaceae.Antimicrob Agents Chemother2009;53:2227-38 PMCID:PMC2687249

[61] Venturini C,Wyrsch ER.Diversity of P1 phage-like elements in multidrug resistant Escherichia coli.Sci Rep2019;9:18861 PMCID:PMC6906374

[62] Ravin NV.N15: the linear phage-plasmid.Plasmid2011;65:102-9

[63] Schmidtke DT,Liachko I,Bhatt AS. Analysis and culturing of the prototypic crAssphage reveals a phage-plasmid lifestyle. Available from: https://www.biorxiv.org/content/10.1101/2024.03.20.585998v2. [Last accessed on 8 Nov 2024]

[64] Siranosian BA,Sherlock G.Acquisition, transmission and strain diversity of human gut-colonizing crAss-like phages.Nat Commun2020;11:280 PMCID:PMC6962324

[65] Porse A,Munck C.Survival and evolution of a large multidrug resistance plasmid in new clinical bacterial hosts.Mol Biol Evol2016;33:2860-73 PMCID:PMC5062321

[66] Shapiro JW,Turner PE.Evolution of parasitism and mutualism between filamentous phage M13 and Escherichia coli.PeerJ2016;4:e2060 PMCID:PMC4888304

[67] Shapiro JW.The impact of transmission mode on the evolution of benefits provided by microbial symbionts.Ecol Evol2014;4:3350-61 PMCID:PMC4228610

[68] Carroll AC.Plasmid persistence: costs, benefits, and the plasmid paradox.Can J Microbiol2018;64:293-304

[69] Moraïs S,Tovar-Herrera O.Plasmid-encoded toxin defence mediates mutualistic microbial interactions.Nat Microbiol2024;9:108-19 PMCID:PMC10769881

[70] Breitbart M,Suttle C.Exploring the vast diversity of marine viruses.Oceanog2007;20:135-9

[71] Dikareva E,Lahtinen E.An extended catalog of integrated prophages in the infant and adult fecal microbiome shows high prevalence of lysogeny.Front Microbiol2023;14:1254535 PMCID:PMC10508911

[72] Reyes A,Hanson N.Viruses in the faecal microbiota of monozygotic twins and their mothers.Nature2010;466:334-8 PMCID:PMC2919852

[73] Monaghan TM,Stockdale SR.Metagenomics reveals impact of geography and acute diarrheal disease on the Central Indian human gut microbiome.Gut Microbes2020;12:1752605 PMCID:PMC7781581

[74] Shaffer M,McGivern BB.DRAM for distilling microbial metabolism to automate the curation of microbiome function.Nucleic Acids Res2020;48:8883-900 PMCID:PMC7498326

[75] Hurwitz BL.Viral metabolic reprogramming in marine ecosystems.Curr Opin Microbiol2016;31:161-8

[76] Desmond C,Fitzgerald G.Sequence analysis of the plasmid genome of the probiotic strain Lactobacillus paracasei NFBC338 which includes the plasmids pCD01 and pCD02.Plasmid2005;54:160-75

[77] Coyne MJ,McGuire AM,Comstock LE.Evidence of extensive DNA transfer between bacteroidales species within the human gut.mBio2014;5:e01305-14 PMCID:PMC4073490

[78] Finks SS.Plasmid-encoded traits vary across environments.mBio2023;14:e0319122 PMCID:PMC9973032

[79] Kommineni S,Lam V.Bacteriocin production augments niche competition by enterococci in the mammalian gastrointestinal tract.Nature2015;526:719-22 PMCID:PMC4978352

[80] Chassaing B.Antibacterial weapons: targeted destruction in the microbiota.Trends Microbiol2018;26:329-38

[81] Hols P,Gabant P.Mobilization of microbiota commensals and their bacteriocins for therapeutics.Trends Microbiol2019;27:690-702

[82] Peñil-Celis A.Crosstalk between type VI secretion system and mobile genetic elements.Front Mol Biosci2019;6:126 PMCID:PMC6863884

[83] García-Bayona L,Comstock LE.Mobile type VI secretion system loci of the gut Bacteroidales display extensive intra-ecosystem transfer, multi-species spread and geographical clustering.PLoS Genet2021;17:e1009541 PMCID:PMC8102008

[84] Takala TM,Ahonen SL,Saris PEJ.Wild-type Lactococcus lactis producing bacteriocin-like prophage lysins.Front Microbiol2023;14:1219723 PMCID:PMC10377672

[85] Verster AJ,Radey MC.The landscape of type VI secretion across human gut microbiomes reveals its role in community composition.Cell Host Microbe2017;22:411-9.e4 PMCID:PMC5679258

[86] Burns N,Harrison E.Polylysogeny magnifies competitiveness of a bacterial pathogen in vivo.Evol Appl2015;8:346-51 PMCID:PMC4408145

[87] Li X,Thorsen J.Differential responses of the gut microbiome and resistome to antibiotic exposures in infants and adults.Nat Commun2023;14:8526 PMCID:PMC10746713

[88] Takeuchi N,Suzuki H.Prophages and plasmids can display opposite trends in the types of accessory genes they carry.Proc Biol Sci2023;290:20231088 PMCID:PMC10281811

[89] Mirzaei MK.Ménage à trois in the human gut: interactions between host, bacteria and phages.Nat Rev Microbiol2017;15:397-408

[90] Brown TL,Adriaenssens EM.Ecological and functional roles of bacteriophages in contrasting environments: marine, terrestrial and human gut.Curr Opin Microbiol2022;70:102229

[91] Melderen L, Saavedra De Bast M. Bacterial toxin-antitoxin systems: more than selfish entities?.PLoS Genet2009;5:e1000437 PMCID:PMC2654758

[92] Bondy-Denomy J,Westra ER.Prophages mediate defense against phage infection through diverse mechanisms.ISME J2016;10:2854-66 PMCID:PMC5148200

[93] Doron S,Ofir G.Systematic discovery of antiphage defense systems in the microbial pangenome.Science2018;359:eaar4120 PMCID:PMC6387622

[94] Hussain FA,Elsherbini J.Rapid evolutionary turnover of mobile genetic elements drives bacterial resistance to phages.Science2021;374:488-92

[95] LeRoux M,Teodoro GIC.The DarTG toxin-antitoxin system provides phage defence by ADP-ribosylating viral DNA.Nat Microbiol2022;7:1028-40 PMCID:PMC9250638

[96] Hochhauser D,Sorek R.The defense island repertoire of the Escherichia coli pan-genome.PLoS Genet2023;19:e1010694 PMCID:PMC10121019

[97] Shaw LP,MacLean RC.Restriction-modification systems have shaped the evolution and distribution of plasmids across bacteria.Nucleic Acids Res2023;51:6806-18 PMCID:PMC10359461

[98] Oliveira PH,Rocha EP.The interplay of restriction-modification systems with mobile genetic elements and their prokaryotic hosts.Nucleic Acids Res2014;42:10618-31 PMCID:PMC4176335

[99] Picton DM,Morgan RD.The phage defence island of a multidrug resistant plasmid uses both BREX and type IV restriction for complementary protection from viruses.Nucleic Acids Res2021;49:11257-73 PMCID:PMC8565348

[100] Bleriot I,Pacios O.The role of PemIK (PemK/PemI) type II TA system from Klebsiella pneumoniae clinical strains in lytic phage infection.Sci Rep2022;12:4488 PMCID:PMC8927121

[101] Pinilla-Redondo R,Mayo-Muñoz D.CRISPR-Cas systems are widespread accessory elements across bacterial and archaeal plasmids.Nucleic Acids Res2022;50:4315-28 PMCID:PMC9071438

[102] Botelho J.Defense systems are pervasive across chromosomally integrated mobile genetic elements and are inversely correlated to virulence and antimicrobial resistance.Nucleic Acids Res2023;51:4385-97 PMCID:PMC10201445

[103] Novick RP.Plasmid incompatibility.Microbiol Rev1987;51:381-95

[104] Hale L,Haines A.An efficient stress-free strategy to displace stable bacterial plasmids.Biotechniques2010;48:223-8

[105] Kamruzzaman M,Thomas CM,Iredell JR.Plasmid interference for curing antibiotic resistance plasmids in vivo.PLoS One2017;12:e0172913 PMCID:PMC5330492

[106] Hedges RW,Barth PT.Compatibility properties of P1 and PhiAMP prophages.Mol Gen Genet1975;141:263-7

[107] Kliem M.The superimmunity gene sim of bacteriophage P1 causes superinfection exclusion.Virology1989;171:350-5

[108] Martin S,Lan Y,Clark MD.Nanopore adaptive sampling: a tool for enrichment of low abundance species in metagenomic samples.Genome Biol2022;23:11 PMCID:PMC8785595

[109] Camargo AP,Schulz F.Identification of mobile genetic elements with geNomad.Nat Biotechnol2024;42:1303-12 PMCID:PMC11324519

[110] Guo J,Zayed AA.VirSorter2: a multi-classifier, expert-guided approach to detect diverse DNA and RNA viruses.Microbiome2021;9:37 PMCID:PMC7852108

[111] Ren J,Lu YY,Sun F.VirFinder: a novel k-mer based tool for identifying viral sequences from assembled metagenomic data.Microbiome2017;5:69 PMCID:PMC5501583

[112] Kent AG,Shi Q,Brito IL.Widespread transfer of mobile antibiotic resistance genes within individual gut microbiomes revealed through bacterial Hi-C.Nat Commun2020;11:4379 PMCID:PMC7463002

[113] Marbouty M,Millot GA.MetaHiC phage-bacteria infection network reveals active cycling phages of the healthy human gut.Elife2021;10:e60608 PMCID:PMC7963479

[114] Lawrence D,Schriefer LA.Single-cell genomics for resolution of conserved bacterial genes and mobile genetic elements of the human intestinal microbiota using flow cytometry.Gut Microbes2022;14:2029673 PMCID:PMC8824198

[115] Browne HP,Anonye BO.Culturing of ‘unculturable’ human microbiota reveals novel taxa and extensive sporulation.Nature2016;533:543-6 PMCID:PMC4890681

[116] Fitzgerald CB,Upadrasta A,Ross RP.Probing the “dark matter” of the human gut phageome: culture assisted metagenomics enables rapid discovery and host-linking for novel bacteriophages.Front Cell Infect Microbiol2021;11:616918 PMCID:PMC8005731

[117] Jin Z,Maurice CF.The mini colon model: a benchtop multi-bioreactor system to investigate the gut microbiome.Gut Microbes2022;14:2096993 PMCID:PMC9291644

[118] Ares-Arroyo M, Coluzzi C, de Sousa JAM, Rocha EPC. Hijackers, hitchhikers, or co-drivers? The mysteries of microbial mobilizable genetic elements. EcoEvoRxiv 2024.

[119] Ibarra-Chávez R,Chen J,Haag AF.Phage-inducible chromosomal islands promote genetic variability by blocking phage reproduction and protecting transductants from phage lysis.PLoS Genet2022;18:e1010146 PMCID:PMC8989297

[120] Rousset F,Miele S.Phages and their satellites encode hotspots of antiviral systems.Cell Host Microbe2022;30:740-53.e5 PMCID:PMC9122126

[121] Fillol-Salom A,Ojiogu AD.Bacteriophages benefit from mobilizing pathogenicity islands encoding immune systems against competitors.Cell2022;185:3248-62.e20