Bacteriophages in Human Gastrointestinal Health Applications

Abstract

Bacteriophages are abundant viruses that naturally inhabit the human gastrointestinal tract, interacting closely with bacterial communities. While their therapeutic potential against bacterial infections has been recognized, clinical evidence remains limited. Here, we review recent randomized, double-blind, placebo-controlled human trials evaluating oral bacteriophage administration for gastrointestinal applications, including treatment of bacterial diarrhea and supplementation in individuals with mild gastrointestinal distress. These studies demonstrate that phage therapy is safe and well-tolerated, with minimal impact on overall gut microbiota composition. There is also some evidence of reduced target bacterial populations and symptom improvement during prolonged use. Additionally, combining phages with probiotics shows promise in enhancing gastrointestinal health. These findings suggest bacteriophages may serve as safe adjuncts or supplements for maintaining gut health and preventing infections, warranting further investigation into their mechanisms and long-term effects within the human microbiome.

Keywords

Antibacterial agents / Bacteriophage therapy / Gastrointestinal health / Phage

Author Contributions

N.B.W. wrote the review and created figures and T.L.W. edited and provided revisions.

Ethics Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Funding

N.B.W. is supported by an assistantship funded by ADM Deerland Enzymes and Probiotics.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

[1] Cowan MK. Microbiology: A Systems Approach, 6th ed.; Mc-Graw Hill: New York, NY, USA, 2020.

[2] Keen EC. Felix d’Herelle and our microbial future. Future Microbiol. 2012, 7, 1337-1339. DOI:10.2217/fmb.12.115

[3] Dabrowska K, Switala-Jelen K, Opolski A, Weber-Dabrowska B, Gorski A. Bacteriophage penetration in vertebrates. J. Appl. Microbiol. 2005, 98, 7-13. DOI:10.1111/j.1365-2672.2004.02422.x

[4] Willey JM, Prescott LM, Sandman KM, Wood DH. Prescott’s Microbiology, 12th ed.; McGraw-Hill: New York, NY, USA, 2023.

[5] Comeau AM, Hatfull GF, Krisch HM, Lindell D, Mann NH, Prangishvili D. Exploring the prokaryotic virosphere. Res. Microbiol. 2008, 159, 306-313. DOI:10.1016/j.resmic.2008.05.001

[6] Gorski A, Dabrowska K, Switala-Jelen K, Nowaczyk M, Weber-Dabrowska B, Boratynski J, et al. New insights into the possible role of bacteriophages in host defense and disease. Med. Immunol. 2003, 2, 2. DOI:10.1186/1476-9433-2-2

[7] Abedon ST, Kuhl SJ, Blasdel BG, Kutter EM. Phage treatment of human infections. Bacteriophage 2011, 1, 66-85. DOI:10.4161/bact.1.2.15845

[8] Golkar Z, Bagasra O, Pace DG. Bacteriophage therapy: A potential solution for the antibiotic resistance crisis. J. Infect. Dev. Ctries. 2014, 8, 129-136. DOI:10.3855/jidc.3573

[9] Keen EC. A century of phage research: Bacteriophages and the shaping of modern biology. Bioessays 2015, 37, 6-9. DOI:10.1002/bies.201400152

[10] Summers WC. In the beginning. Bacteriophage 2011, 1, 50-51. DOI:10.4161/bact.1.1.14070

[11] Wittebole X, De Roock S, Opal SM. A historical overview of bacteriophage therapy as an alternative to antibiotics for the treatment of bacterial pathogens. Virulence 2014, 5, 226-235. DOI:10.4161/viru.25991

[12] Chanishvili N. Phage therapy—History from Twort and d’Herelle through Soviet experience to current approaches. Adv. Virus Res. 2012, 83, 3-40. DOI:10.1016/B978-0-12-394438-2.00001-3

[13] Gorski A, Miedzybrodzki R, Borysowski J, Weber-Dabrowska B, Lobocka M, Fortuna W, et al. Bacteriophage therapy for the treatment of infections. Curr. Opin. Investig. Drugs 2009, 10, 766-774.

[14] Guo M, Li M, Zhang C, Zhang X, Wu Y. Dietary Administration of the Bacillus subtilis Enhances Immune Responses and Disease Resistance in Chickens. Front. Microbiol. 2020, 11, 1768. DOI:10.3389/fmicb.2020.01768

[15] Ho K. Bacteriophage therapy for bacterial infections. Rekindling a memory from the pre-antibiotics era. Perspect. Biol. Med. 2001, 44, 1-16. DOI:10.1353/pbm.2001.0006

[16] Miedzybrodzki R, Borysowski J, Weber-Dabrowska B, Fortuna W, Letkiewicz S, Szufnarowski K, et al. Clinical aspects of phage therapy. Adv. Virus Res. 2012, 83, 73-121. DOI:10.1016/B978-0-12-394438-2.00003-7

[17] Breitbart M, Hewson I, Felts B, Mahaffy JM, Nulton J, Salamon P, et al. Metagenomic analyses of an uncultured viral community from human feces. J. Bacteriol. 2003, 185, 6220-6223. DOI:10.1128/JB.185.20.6220-6223.2003

[18] Minot S, Sinha R, Chen J, Li H, Keilbaugh SA, Wu GD, et al. The human gut virome: Inter-individual variation and dynamic response to diet. Genome Res. 2011, 21, 1616-1625. DOI:10.1101/gr.122705.111

[19] Loeb T, Zinder ND. A bacteriophage containing RNA. Proc. Natl. Acad. Sci. USA 1961, 47, 282-289. DOI:10.1073/pnas.47.3.282

[20] Callanan J, Stockdale SR, Shkoporov A, Draper LA, Ross RP, Hill C. RNA Phage Biology in a Metagenomic Era. Viruses 2018, 10, 386. DOI:10.3390/v10070386

[21] Krishnamurthy SR, Janowski AB, Zhao G, Barouch D, Wang D. Hyperexpansion of RNA Bacteriophage Diversity. PLoS Biol. 2016, 14, e1002409. DOI:10.1371/journal.pbio.1002409

[22] Bertozzi Silva J, Storms Z, Sauvageau D. Host receptors for bacteriophage adsorption. FEMS Microbiol. Lett. 2016, 363, fnw002. DOI:10.1093/femsle/fnw002

[23] Degroux S, Effantin G, Linares R, Schoehn G, Breyton C. Deciphering Bacteriophage T5 Host Recognition Mechanism and Infection Trigger. J. Virol. 2023, 97, e0158422. DOI:10.1128/jvi.01584-22

[24] Kortright KE, Chan BK, Turner PE. High-throughput discovery of phage receptors using transposon insertion sequencing of bacteria. Proc. Natl. Acad. Sci. USA 2020, 117, 18670-18679. DOI:10.1073/pnas.2001888117

[25] Zeng X, Wang W, Zhu D, Liu M, Wang M, Jia R, et al. Two receptor-targeting mechanisms of lambda-like siphophage Gifsy-1 of Salmonella Typhimurium. PLoS Pathog. 2025, 21, e1013352. DOI:10.1371/journal.ppat.1013352

[26] Ge X, Wang J. Structural mechanism of bacteriophage lambda tail’s interaction with the bacterial receptor. Nat. Commun. 2024, 15, 4185. DOI:10.1038/s41467-024-48686-3

[27] Bignaud A, Conti DE, Thierry A, Serizay J, Labadie K, Poulain J, et al. Phages with a broad host range are common across ecosystems. Nat. Microbiol. 2025, 10, 2537-2549. DOI:10.1038/s41564-025-02108-2

[28] Göller PC, Elsener T, Lorgé D, Radulovic N, Bernardi V, Naumann A, et al. Multi-species host range of staphylococcal phages isolated from wastewater. Nat. Commun. 2021, 12, 6965. DOI:10.1038/s41467-021-27037-6

[29] Fong K, Wong CWY, Wang S, Delaquis P. How Broad Is Enough: The Host Range of Bacteriophages and Its Impact on the Agri-Food Sector. Ther. Appl. Res. 2021, 2, 83-91. DOI:10.1089/phage.2020.0036

[30] Meader E, Mayer MJ, Gasson MJ, Steverding D, Carding SR, Narbad A. Bacteriophage treatment significantly reduces viable Clostridium difficile and prevents toxin production in an in vitro model system. Anaerobe 2010, 16, 549-554. DOI:10.1016/j.anaerobe.2010.08.006

[31] Moye ZD, Woolston J, Abbeele PVD, Duysburgh C, Verstrepen L, Das CR, et al. A Bacteriophage Cocktail Eliminates Salmonella Typhimurium from the Human Colonic Microbiome while Preserving Cytokine Signaling and Preventing Attachment to and Invasion of Human Cells by Salmonella In Vitro. J. Food Prot. 2019, 82, 1336-1349. DOI:10.4315/0362-028X.JFP-18-587

[32] Yu L, Wang S, Guo Z, Liu H, Sun D, Yan G, et al. A guard-killer phage cocktail effectively lyses the host and inhibits the development of phage-resistant strains of Escherichia coli. Appl. Microbiol. Biotechnol. 2018, 102, 971-983. DOI:10.1007/s00253-017-8591-z

[33] Cepko LCS, Garling EE, Dinsdale MJ, Scott WP, Bandy L, Nice T, et al. Myoviridae phage PDX kills enteroaggregative Escherichia coli without human microbiome dysbiosis. J. Med. Microbiol. 2020, 69, 309-323. DOI:10.1099/jmm.0.001162

[34] Federici S, Kredo-Russo S, Valdes-Mas R, Kviatcovsky D, Weinstock E, Matiuhin Y, et al. Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation. Cell 2022, 185, 2879-2898.e24. DOI:10.1016/j.cell.2022.07.003

[35] Gu J, Liu X, Li Y, Han W, Lei L, Yang Y, et al. A method for generation phage cocktail with great therapeutic potential. PLoS ONE 2012, 7, e31698. DOI:10.1371/journal.pone.0031698

[36] Hsu BB, Gibson TE, Yeliseyev V, Liu Q, Lyon L, Bry L, et al. Dynamic Modulation of the Gut Microbiota and Metabolome by Bacteriophages in a Mouse Model. Cell Host Microbe 2019, 25, 803-814.e5. DOI:10.1016/j.chom.2019.05.001

[37] Maura D, Morello E, du Merle L, Bomme P, Le Bouguenec C, Debarbieux L. Intestinal colonization by enteroaggregative Escherichia coli supports long-term bacteriophage replication in mice. Environ. Microbiol. 2012, 14, 1844-1854. DOI:10.1111/j.1462-2920.2011.02644.x

[38] Vahedi A, Soltan Dallal MM, Douraghi M, Nikkhahi F, Rajabi Z, Yousefi M, et al. Isolation and identification of specific bacteriophage against enteropathogenic Escherichia coli (EPEC) and in vitro and in vivo characterization of bacteriophage. FEMS Microbiol. Lett. 2018, 365, fny136. DOI:10.1093/femsle/fny136

[39] Bruttin A, Brussow H. Human volunteers receiving Escherichia coli phage T4 orally: A safety test of phage therapy. Antimicrob. Agents Chemother. 2005, 49, 2874-2878. DOI:10.1128/AAC.49.7.2874-2878.2005

[40] Sarker SA, McCallin S, Barretto C, Berger B, Pittet AC, Sultana S, et al. Oral T4-like phage cocktail application to healthy adult volunteers from Bangladesh. Virology 2012, 434, 222-232. DOI:10.1016/j.virol.2012.09.002

[41] Sarker SA, Sultana S, Reuteler G, Moine D, Descombes P, Charton F, et al. Oral Phage Therapy of Acute Bacterial Diarrhea with Two Coliphage Preparations: A Randomized Trial in Children from Bangladesh. EBioMedicine 2016, 4, 124-137. DOI:10.1016/j.ebiom.2015.12.023

[42] Wright A, Hawkins CH, Anggard EE, Harper DR. A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Clin. Otolaryngol. 2009, 34, 349-357. DOI:10.1111/j.1749-4486.2009.01973.x

[43] Marza JA, Soothill JS, Boydell P, Collyns TA. Multiplication of therapeutically administered bacteriophages in Pseudomonas aeruginosa infected patients. Burns 2006, 32, 644-646. DOI:10.1016/j.burns.2006.02.012

[44] Merabishvili M, Pirnay JP, Verbeken G, Chanishvili N, Tediashvili M, Lashkhi N, et al. Quality-controlled small-scale production of a well-defined bacteriophage cocktail for use in human clinical trials. PLoS ONE 2009, 4, e4944. DOI:10.1371/journal.pone.0004944

[45] Rhoads DD, Wolcott RD, Kuskowski MA, Wolcott BM, Ward LS, Sulakvelidze A. Bacteriophage therapy of venous leg ulcers in humans: Results of a phase I safety trial. J. Wound Care 2009, 18, 237-243. DOI:10.12968/jowc.2009.18.6.42801

[46] Chegini Z, Khoshbayan A, Vesal S, Moradabadi A, Hashemi A, Shariati A. Bacteriophage therapy for inhibition of multi drug-resistant uropathogenic bacteria: A narrative review. Ann. Clin. Microbiol. Antimicrob. 2021, 20, 30. DOI:10.1186/s12941-021-00433-y

[47] Jennes S, Merabishvili M, Soentjens P, Pang KW, Rose T, Keersebilck E, et al. Use of bacteriophages in the treatment of colistin-only-sensitive Pseudomonas aeruginosa septicaemia in a patient with acute kidney injury—A case report. Crit. Care 2017, 21, 129. DOI:10.1186/s13054-017-1709-y

[48] Leitner L, Sybesma W, Chanishvili N, Goderdzishvili M, Chkhotua A, Ujmajuridze A, et al. Bacteriophages for treating urinary tract infections in patients undergoing transurethral resection of the prostate: A randomized, placebo-controlled, double-blind clinical trial. BMC Urol. 2017, 17, 90. DOI:10.1186/s12894-017-0283-6

[49] Malik S, Nehra K, Rana JS. Bacteriophage cocktail and phage antibiotic synergism as promising alternatives to conventional antibiotics for the control of multi-drug-resistant uropathogenic Escherichia coli. Virus Res. 2021, 302, 198496. DOI:10.1016/j.virusres.2021.198496

[50] Gorski A, Jonczyk-Matysiak E, Lusiak-Szelachowska M, Miedzybrodzki R, Weber-Dabrowska B, Borysowski J. The Potential of Phage Therapy in Sepsis. Front. Immunol. 2017, 8, 1783. DOI:10.3389/fimmu.2017.01783

[51] Pirnay J-P, Djebara S, Steurs G, Griselain J, Cochez C, De Soir S, et al. Personalized bacteriophage therapy outcomes for 100 consecutive cases: A multicentre, multinational, retrospective observational study. Nat. Microbiol. 2024, 9, 1434-1453. DOI:10.1038/s41564-024-01705-x

[52] Mahmud MR, Tamanna SK, Akter S, Mazumder L, Akter S, Hasan MR, et al. Role of bacteriophages in shaping gut microbial community. Gut Microbes 2024, 16, 2390720. DOI:10.1080/19490976.2024.2390720

[53] Hu J, Ye H, Wang S, Wang J, Han D. Prophage Activation in the Intestine: Insights into Functions and Possible Applications. Front. Microbiol. 2021, 12, 785634. DOI:10.3389/fmicb.2021.785634

[54] Kim MS, Park EJ, Roh SW, Bae JW. Diversity and abundance of single-stranded DNA viruses in human feces. Appl. Environ. Microbiol. 2011, 77, 8062-8070. DOI:10.1128/AEM.06331-11

[55] Lourenco M, Chaffringeon L, Lamy-Besnier Q, Pedron T, Campagne P, Eberl C, et al. The Spatial Heterogeneity of the Gut Limits Predation and Fosters Coexistence of Bacteria and Bacteriophages. Cell Host Microbe 2020, 28, 390-401.e5. DOI:10.1016/j.chom.2020.06.002

[56] Manrique P, Bolduc B, Walk ST, van der Oost J, de Vos WM, Young MJ. Healthy human gut phageome. Proc. Natl. Acad. Sci. USA 2016, 113, 10400-10405. DOI:10.1073/pnas.1601060113

[57] Mathieu A, Dion M, Deng L, Tremblay D, Moncaut E, Shah SA, et al. Virulent coliphages in 1-year-old children fecal samples are fewer, but more infectious than temperate coliphages. Nat. Commun. 2020, 11, 378. DOI:10.1038/s41467-019-14042-z

[58] Shkoporov AN, Clooney AG, Sutton TDS, Ryan FJ, Daly KM, Nolan JA, et al. The Human Gut Virome Is Highly Diverse, Stable, and Individual Specific. Cell Host Microbe 2019, 26, 527-541.e5. DOI:10.1016/j.chom.2019.09.009

[59] Brussow H. What is needed for phage therapy to become a reality in Western medicine? Virology 2012, 434, 138-142. DOI:10.1016/j.virol.2012.09.015

[60] Chan BK, Abedon ST, Loc-Carrillo C. Phage cocktails and the future of phage therapy. Future Microbiol. 2013, 8, 769-783. DOI:10.2217/fmb.13.47

[61] Menor-Flores M, Vega-Rodriguez MA, Molina F. Computational design of phage cocktails based on phage-bacteria infection networks. Comput. Biol. Med. 2022, 142, 105186. DOI:10.1016/j.compbiomed.2021.105186

[62] Pelfrene E, Willebrand E, Cavaleiro Sanches A, Sebris Z, Cavaleri M. Bacteriophage therapy: A regulatory perspective. J. Antimicrob. Chemother. 2016, 71, 2071-2074. DOI:10.1093/jac/dkw083

[63] Bochkareva SS, Karaulov AV, Aleshkin AV, Novikova LI, Kiseleva IA, Rubal’skii EO, et al. Analysis of the Pharmacokinetics of Suppository Forms of Bacteriophages. Bull. Exp. Biol. Med. 2020, 168, 748-752. DOI:10.1007/s10517-020-04794-w

[64] Corbellino M, Kieffer N, Kutateladze M, Balarjishvili N, Leshkasheli L, Askilashvili L, et al. Eradication of a Multidrug-Resistant, Carbapenemase-Producing Klebsiella pneumoniae Isolate Following Oral and Intra-rectal Therapy with a Custom Made, Lytic Bacteriophage Preparation. Clin. Infect. Dis. 2020, 70, 1998-2001. DOI:10.1093/cid/ciz782

[65] Miedzybrodzki R, Kasprzak H, Letkiewicz S, Rogoz P, Zaczek M, Thomas J, et al. Pharmacokinetic and Pharmacodynamic Obstacles for Phage Therapy From the Perspective of Clinical Practice. Clin. Infect. Dis. 2023, 77, S395-S400. DOI:10.1093/cid/ciad516

[66] Schooley RT, Biswas B, Gill JJ, Hernandez-Morales A, Lancaster J, Lessor L, et al. Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection. Antimicrob. Agents Chemother. 2017, 61, 10-1128. DOI:10.1128/AAC.00954-17

[67] Febvre HP, Rao S, Gindin M, Goodwin NDM, Finer E, Vivanco JS, et al. PHAGE Study: Effects of Supplemental Bacteriophage Intake on Inflammation and Gut Microbiota in Healthy Adults. Nutrients 2019, 11, 666. DOI:10.3390/nu11030666

[68] Gindin M, Febvre HP, Rao S, Wallace TC, Weir TL. Bacteriophage for Gastrointestinal Health (PHAGE) Study: Evaluating the Safety and Tolerability of Supplemental Bacteriophage Consumption. J. Am. Coll. Nutr. 2019, 38, 68-75. DOI:10.1080/07315724.2018.1483783

[69] McCallin S, Alam Sarker S, Barretto C, Sultana S, Berger B, Huq S, et al. Safety analysis of a Russian phage cocktail: From metagenomic analysis to oral application in healthy human subjects. Virology 2013, 443, 187-196. DOI:10.1016/j.virol.2013.05.022

[70] Pargin E, Roach MJ, Skye A, Papudeshi B, Inglis LK, Mallawaarachchi V, et al. The human gut virome: Composition, colonization, interactions, and impacts on human health. Front. Microbiol. 2023, 14, 963173. DOI:10.3389/fmicb.2023.963173

[71] Townsend EM, Kelly L, Muscatt G, Box JD, Hargraves N, Lilley D, et al. The Human Gut Phageome: Origins and Roles in the Human Gut Microbiome. Front. Cell Infect. Microbiol. 2021, 11, 643214. DOI:10.3389/fcimb.2021.643214

[72] Boggione DMG, Batalha LS, Gontijo MTP, Lopez MES, Teixeira AVNC, Santos IJB, et al. Evaluation of microencapsulation of the UFV-AREG1 bacteriophage in alginate-Ca microcapsules using microfluidic devices. Colloids Surf. B Biointerfaces 2017, 158, 182-189. DOI:10.1016/j.colsurfb.2017.06.045

[73] Soto MJ, Retamales J, Palza H, Bastías R. Encapsulation of specific Salmonella Enteritidis phage f3αSE on alginate-spheres as a method for protection and dosification. Electron. J. Biotechnol. 2018, 31, 57-60. DOI:10.1016/j.ejbt.2017.11.006

[74] Stanford K, McAllister TA, Niu YD, Stephens TP, Mazzocco A, Waddell TE, et al. Oral delivery systems for encapsulated bacteriophages targeted at Escherichia coliO157:H7 in feedlot cattle. J. Food Prot. 2010, 73, 1304-1312. DOI:10.4315/0362-028x-73.7.1304

[75] Jo SJ, Lee YM, Cho K, Park SY, Kwon H, Giri SS, et al. Standardization of the Agar Plate Method for Bacteriophage Production. Antibiotics 2024, 14, 2. DOI:10.3390/antibiotics14010002

[76] Ács N, Gambino M, Brøndsted L. Bacteriophage Enumeration and Detection Methods. Front. Microbiol. 2020, 11, 594868. DOI:10.3389/fmicb.2020.594868

[77] Fridholm H, Everitt E. Rapid and reproducible infectivity end-point titration of virulent phage in a microplate system. J. Virol. Methods 2005, 128, 67-71. DOI:10.1016/j.jviromet.2005.04.004

[78] Javaudin F, Latour C, Debarbieux L, Lamy-Besnier Q. Intestinal Bacteriophage Therapy: Looking for Optimal Efficacy. Clin. Microbiol. Rev. 2021, 34, e0013621. DOI:10.1128/CMR.00136-21

[79] Danis-Wlodarczyk K, Dabrowska K, Abedon ST. Phage Therapy: The Pharmacology of Antibacterial Viruses. Curr. Issues Mol. Biol. 2021, 40, 81-164. DOI:10.21775/cimb.040.081

[80] Barr JJ, Auro R, Furlan M, Whiteson KL, Erb ML, Pogliano J, et al. Bacteriophage adhering to mucus provide a non-host-derived immunity. Proc. Natl. Acad. Sci. USA 2013, 110, 10771-10776. DOI:10.1073/pnas.1305923110

[81] Barr JJ, Auro R, Sam-Soon N, Kassegne S, Peters G, Bonilla N, et al. Subdiffusive motion of bacteriophage in mucosal surfaces increases the frequency of bacterial encounters. Proc. Natl. Acad. Sci. USA 2015, 112, 13675-13680. DOI:10.1073/pnas.1508355112

[82] Bichet MC, Chin WH, Richards W, Lin Y-W, Avellaneda-Franco L, Hernandez CA, et al. Bacteriophage uptake by mammalian cell layers represents a potential sink that may impact phage therapy. iScience 2021, 24, 102287. DOI:10.1016/j.isci.2021.102287

[83] Douadi C, Theodorou I, Lamy-Besnier Q, Schiettekatte O, Sbardella Y, Brot L, et al. Differential translocation of bacteriophages across the intestinal barrier in health and Crohn’s disease. Cell Rep. 2024, 45, 116726. DOI:10.1101/2024.09.17.613249

[84] Parracho HM, Burrowes BH, Enright MC, McConville ML, Harper DR. The role of regulated clinical trials in the development of bacteriophage therapeutics. J. Mol. Genet. Med. 2012, 6, 279-286. DOI:10.4172/1747-0862.1000050

[85] Eriksen RS, Mitarai N, Sneppen K. Sustainability of spatially distributed bacteria-phage systems. Sci. Rep. 2020, 10, 3154. DOI:10.1038/s41598-020-59635-7

[86] Armstrong HK, Bording-Jorgensen M, Santer DM, Zhang Z, Valcheva R, Rieger AM, et al. Unfermented β-fructan Fibers Fuel Inflammation in Select Inflammatory Bowel Disease Patients. Gastroenterology 2023, 164, 228-240. DOI:10.1053/j.gastro.2022.09.034

[87] Rytter H, Naimi S, Wu G, Lewis J, Duquesnoy M, Vigué L, et al. In vitro microbiota model recapitulates and predicts individualised sensitivity to dietary emulsifier. Gut 2025, 74, 761-774. DOI:10.1136/gutjnl-2024-333925

[88] Carroll-Portillo A, Lin HC. Bacteriophage and the Innate Immune System: Access and Signaling. Microorganisms 2019, 7, 625. DOI:10.3390/microorganisms7120625

[89] Podlacha M, Grabowski L, Kosznik-Kawsnicka K, Zdrojewska K, Stasilojc M, Wegrzyn G, et al. Interactions of Bacteriophages with Animal and Human Organisms-Safety Issues in the Light of Phage Therapy. Int. J. Mol. Sci. 2021, 22, 8937. DOI:10.3390/ijms22168937

[90] Van Belleghem JD, Dabrowska K, Vaneechoutte M, Barr JJ, Bollyky PL. Interactions between Bacteriophage, Bacteria, and the Mammalian Immune System. Viruses 2018, 11, 10. DOI:10.3390/v11010010

[91] Grubb DS, Wrigley SD, Freedman KE, Wei Y, Vazquez AR, Trotter RE, et al. PHAGE-2 Study: Supplemental Bacteriophages Extend Bifidobacterium animalis subsp. lactis BL04 Benefits on Gut Health and Microbiota in Healthy Adults. Nutrients 2020, 12, 2474. DOI:10.3390/nu12082474

[92] Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat. Rev. Gastroenterol. Hepatol. 2014, 11, 506-514. DOI:10.1038/nrgastro.2014.66

[93] Lamy-Besnier Q, Chaffringeon L, Lourenço M, Payne RB, Trinh JT, Schwartz JA, et al. Prophylactic Administration of a Bacteriophage Cocktail Is Safe and Effective in Reducing Salmonella enterica Serovar Typhimurium Burden In Vivo. Microbiol. Spectr. 2021, 9, e00497-21. DOI:10.1128/Spectrum.00497-21

[94] Matsuzaki S, Rashel M, Uchiyama J, Sakurai S, Ujihara T, Kuroda M, et al. Bacteriophage therapy: A revitalized therapy against bacterial infectious diseases. J. Infect. Chemother. 2005, 11, 211-219. DOI:10.1007/s10156-005-0408-9

[95] Egido JE, Costa AR, Aparicio-Maldonado C, Haas P-J, Brouns SJJ. Mechanisms and clinical importance of bacteriophage resistance. FEMS Microbiol. Rev. 2022, 46, fuab048. DOI:10.1093/femsre/fuab048

[96] Dupuis M-È, Villion M, Magadán AH, Moineau S. CRISPR-Cas and restriction-modification systems are compatible and increase phage resistance. Nat. Commun. 2013, 4, 2087. DOI:10.1038/ncomms3087

[97] Dy RL, Richter C, Salmond GPC, Fineran PC. Remarkable Mechanisms in Microbes to Resist Phage Infections. Annu. Rev. Virol. 2014, 1, 307-331. DOI:10.1146/annurev-virology-031413-085500

[98] Liu Y, Dai L, Dong J, Chen C, Zhu J, Rao VB, et al. Covalent Modifications of the Bacteriophage Genome Confer a Degree of Resistance to Bacterial CRISPR Systems. J. Virol. 2020, 94, e01630-20. DOI:10.1128/JVI.01630-20

[99] Bleriot I, Pacios O, Blasco L, Fernández-García L, López M, Ortiz-Cartagena C, et al. Improving phage therapy by evasion of phage resistance mechanisms. JAC-Antimicrob. Resist. 2023, 6, dlae017. DOI:10.1093/jacamr/dlae017

[100] Arcilla MS, van Hattem JM, Haverkate MR, Bootsma MCJ, van Genderen PJJ, Goorhuis A, et al. Import and spread of extended-spectrum beta-lactamase-producing Enterobacteriaceae by international travellers (COMBAT study): A prospective, multicentre cohort study. Lancet Infect. Dis. 2017, 17, 78-85. DOI:10.1016/S1473-3099(16)30319-X

[101] Armand-Lefevre L, Andremont A, Ruppe E. Travel and acquisition of multidrug-resistant Enterobacteriaceae. Med. Mal. Infect. 2018, 48, 431-441. DOI:10.1016/j.medmal.2018.02.005

[102] Rondinaud E, Clermont O, Petitjean M, Ruppe E, Esposito-Farese M, Nazimoudine A, et al. Acquisition of Enterobacterales carrying the colistin resistance gene mcr following travel to the tropics. J. Travel. Med. 2023, 30, taac141. DOI:10.1093/jtm/taac141