Exploring microorganism–host interactions: Emerging organoid models and analytical approaches

Abstract

Microorganisms play a vital role in human health through their interactions with the body. Studies of host–microbe mechanisms and interactions are crucial for advancing health management. Recently, the organoid-based models have provided new platforms in this field. Derived from human tissues, these models offer several advantages over traditional systems and, when combined with advanced analytical techniques, they enable deeper insights into host–microbe interactions. In this review, we summarize the different models and techniques used, with a particular focus on the newly developed organoid models. We discuss how these models can be effectively utilized in microorganism–host interaction studies and address their associated limitations.

Keywords

disease modeling / host–microbe interaction / infectious diseases / organoids / organ-on-a-chip

References

[1] Liang G, Bushman FD. The human virome: assembly, composition and host interactions. Nat Rev Microbiol. 2021; 19: 514–527.

[2] Malard F, Dore J, Gaugler B, Mohty M. Introduction to host microbiome symbiosis in health and disease. Mucosal Immunol. 2021; 14: 547–554.

[3] Rackaityte E, Lynch SV. The human microbiome in the 21st century. Nat Commun. 2020; 11: 5256.

[4] Casadevall A, Pirofski L. Host-pathogen interactions: basic concepts of microbial commensalism, colonization, infection, and disease. Infect Immun. 2000; 68: 6511–6518.

[5] Belanger CR, Dostert M, Blimkie TM, Lee AH-Y, Dhillon BK, Wu BC, et al. Surviving the host: microbial metabolic genes required for growth of Pseudomonas aeruginosa in physiologically-relevant conditions. Front Microbiol. 2022; 13:1055512.

[6] Hirose Y, Yamaguchi M, Sumitomo T, Nakata M, Hanada T, Okuzaki D, et al. Streptococcus pyogenes upregulates arginine catabolism to exert its pathogenesis on the skin surface. Cell Rep. 2021; 34:108924.

[7] LaRock DL, Johnson AF, Wilde S, Sands JS, Monteiro MP, LaRock CN. Group A Streptococcus induces GSDMA-dependent pyroptosis in keratinocytes. Nature. 2022; 605: 527–531.

[8] Peres NTA, Silva LG, Santos RS, Jacob TR, Persinoti GF, Rocha LB, et al. In vitro and ex vivo infection models help assess the molecular aspects of the interaction of Trichophyton rubrum with the host milieu. Med Mycol. 2016; 54: 420–427.

[9] Ma W, Zhang M, Cui Z, Wang X, Niu X, Zhu Y, et al. Aloe-emodin-mediated antimicrobial photodynamic therapy against dermatophytosis caused by Trichophyton rubrum. Microb Biotechnol. 2022; 15: 499–512.

[10] Staudenmaier L, Focken J, Schlatterer K, Kretschmer D, Schittek B. Bacterial membrane vesicles shape Staphylococcus aureus skin colonization and induction of innate immune responses. Exp Dermatol. 2022; 31: 349–361.

[11] Jia Y, Guan Z, Liu C, Huang M, Li J, Feng J, et al. Staphylococcus aureus β-hemolysin causes skin inflammation by acting as an agonist of epidermal growth factor receptor. Microbiol Spectr. 2024; 12:e0222723.

[12] R. A. Microbial Infections of Skin and Nails. In: S B editor Medical microbiology. Galveston (TX): University of Texas Medical Branch at Galveston; 1998.

[13] Mills KB, Maciag JJ, Wang C, Crawford JA, Enroth TJ, Keim KC, et al. Staphylococcus aureus skin colonization is mediated by SasG lectin variation. Cell Rep. 2024; 43:114022.

[14] Ravins M, Jaffe J, Hanski E, Shetzigovski I, Natanson-Yaron S, Moses AE. Characterization of a mouse-passaged, highly encapsulated variant of group A Streptococcus in in vitro and in vivo studies. J Infect Dis. 2000; 182: 1702–1711.

[15] Mook-Kanamori B, Geldhoff M, Troost D, van der Poll T, van de Beek D. Characterization of a pneumococcal meningitis mouse model. BMC Infect Dis. 2012; 12: 71.

[16] Barichello T, Fagundes GD, Generoso JS, Paula Moreira A, Costa CS, Zanatta JR, et al. Brain–blood barrier breakdown and pro-inflammatory mediators in neonate rats submitted meningitis by Streptococcus pneumoniae. Brain Res. 2012; 1471: 162–168.

[17] Østergaard C, Brandt C, Konradsen HB, Samuelsson S. Differences in survival, brain damage, and cerebrospinal fluid cytokine kinetics due to meningitis caused by 3 different Streptococcus pneumoniae serotypes: evaluation in humans and in 2 experimental models. J Infect Dis. 2004; 190: 1212–1220.

[18] Endres LM, Jungblut M, Divyapicigil M, Sauer M, Stigloher C, Christodoulides M, et al. Development of a multicellular in vitro model of the meningeal blood-CSF barrier to study Neisseria meningitidis infection. Fluids Barriers CNS. 2022; 19: 81.

[19] Pinho-Ribeiro FA, Deng L, Neel DV, Erdogan O, Basu H, Yang D, et al. Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion. Nature. 2023; 615: 472–481.

[20] Cheng Z, Zheng Y, Yang W, Sun H, Zhou F, Huang C, et al. Pathogenic bacteria exploit transferrin receptor transcytosis to penetrate the blood–brain barrier. Proc Natl Acad Sci USA. 2023; 120:e2307899120.

[21] Mukherjee K, Hain T, Fischer R, Chakraborty T, Vilcinskas A. Brain infection and activation of neuronal repair mechanisms by the human pathogen Listeria monocytogenes in the lepidopteran model host Galleria mellonella. Virulence. 2013; 4: 324–332.

[22] van de Beek D, Brouwer MC, Koedel U, Wall EC. Community-acquired bacterial meningitis. Lancet. 2021; 398: 1171–1183.

[23] Bucior I, Pielage JF, Engel JN. Pseudomonas aeruginosa pili and flagella mediate distinct binding and signaling events at the apical and basolateral surface of airway epithelium. PLoS Pathog. 2012; 8:e1002616.

[24] Neuhaus M, Munder A, Schipke J, Schmiedl A. Lung infection caused by Pseudomonas aeruginosa in a CD26/DPP4 deficient F344 rat model. Inflamm Res. 2019; 68: 529–544.

[25] Dar HH, Tyurina YY, Mikulska-Ruminska K, Shrivastava I, Ting HC, Tyurin VA, et al. Pseudomonas aeruginosa utilizes host polyunsaturated phosphatidylethanolamines to trigger theft-ferroptosis in bronchial epithelium. J Clin Invest. 2018; 128: 4639–4653.

[26] Kim B, Park JS, Choi HY, Yoon SS, Kim WG. Terrein is an inhibitor of quorum sensing and c-di-GMP in Pseudomonas aeruginosa: a connection between quorum sensing and c-di-GMP. Sci Rep. 2018; 8: 8617.

[27] Valente E, Assis MC, Alvim IMP, Pereira GMB, Plotkowski MC. Pseudomonas aeruginosa induces apoptosis in human endothelial cells. Microb Pathog. 2000; 29: 345–356.

[28] Hammerschmidt S, Wolff S, Hocke A, Rosseau S, Müller E, Rohde M. Illustration of pneumococcal polysaccharide capsule during adherence and invasion of epithelial cells. Infect Immun. 2005; 73: 4653–4667.

[29] McCool TL, Weiser JN. Limited role of antibody in clearance of Streptococcus pneumoniae in a murine model of colonization. Infect Immun. 2004; 72: 5807–5813.

[30] Kietzman CC, Gao G, Mann B, Myers L, Tuomanen EI. Dynamic capsule restructuring by the main pneumococcal autolysin LytA in response to the epithelium. Nat Commun. 2016; 7:10859.

[31] Kaufhold I, Osbahr S, Shima K, Marwitz S, Rohmann K, Drömann D, et al. Nontypeable haemophilus influenzae (NTHi) directly interfere with the regulation of E-cadherin in lung epithelial cells. Microb Infect. 2017; 19: 560–566.

[32] Juneau RA, Pang B, Armbruster CE, Murrah KA, Perez AC, Swords WE. Peroxiredoxin-glutaredoxin and catalase promote resistance of nontypeable Haemophilus influenzae 86-028NP to oxidants and survival within neutrophil extracellular traps. Infect Immun. 2015; 83: 239–246.

[33] Baddal B. Characterization of biofilm formation and induction of apoptotic DNA fragmentation by nontypeable Haemophilus influenzae on polarized human airway epithelial cells. Microb Pathog. 2020; 141:103985.

[34] Murphy TF, Kirkham C, Gallo MC, Yang Y, Wilding GE, Pettigrew MM. Immunoglobulin A protease variants facilitate intracellular survival in epithelial cells by nontypeable Haemophilus influenzae that persist in the human respiratory tract in chronic obstructive pulmonary disease. J Infect Dis. 2017; 216: 1295–1302.

[35] Kviatcovsky D, Rivadeneyra L, Balboa L, Yokobori N, López B, Ritacco V, et al. Mycobacterium tuberculosis multidrug-resistant strain M induces low IL-8 and inhibits TNF-α secretion by bronchial epithelial cells altering neutrophil effector functions. Mediators Inflamm. 2017; 2017:2810606.

[36] Sugawara I, Sun L, Mizuno S, Taniyama T. Protective efficacy of recombinant BCG Tokyo (Ag85A) in rhesus monkeys (Macaca mulatta) infected intratracheally with H37Rv Mycobacterium tuberculosis. Tuberculosis. 2009; 89: 62–67.

[37] Chatterjee S, Dwivedi VP, Singh Y, Siddiqui I, Sharma P, Van Kaer L, et al. Early secreted antigen ESAT-6 of Mycobacterium tuberculosis promotes protective T helper 17 cell responses in a toll-like receptor-2-dependent manner. PLoS Pathog. 2011; 7:e1002378.

[38] Weidenmaier C, Kokai-Kun JF, Kristian SA, Chanturiya T, Kalbacher H, Gross M, et al. Role of teichoic acids in Staphylococcus aureus nasal colonization, a major risk factor in nosocomial infections. Nature Med. 2004; 10: 243–245.

[39] Liu Q, Du X, Hong X, Li T, Zheng B, He L, et al. Targeting surface protein SasX by active and passive vaccination to reduce Staphylococcus aureus colonization and infection. Infect Immun. 2015; 83: 2168–2174.

[40] Gryllos I, Cywes C, Shearer MH, Cary M, Kennedy RC, Wessels MR. Regulation of capsule gene expression by group A Streptococcus during pharyngeal colonization and invasive infection. Mol Microbiol. 2001; 42: 61–74.

[41] Slevogt H, Seybold J, Tiwari KN, Hocke AC, Jonatat C, Dietel S, et al. Moraxella catarrhalis is internalized in respiratory epithelial cells by a trigger-like mechanism and initiates a TLR2- and partly NOD1-dependent inflammatory immune response. Cell Microbiol. 2007; 9: 694–707.

[42] Li L, Mac Aogáin M, Xu T, Jaggi TK, Chan LLY, Qu J, et al. Neisseria species as pathobionts in bronchiectasis. Cell Host Microbe. 2022; 30: 1311–1327.e8.

[43] Kottom TJ, Köhler JR, Thomas Jr. CF, Fink GR, Limper AH. Lung epithelial cells and extracellular matrix components induce expression of Pneumocystis carinii STE20, a gene complementing the mating and pseudohyphal growth defects of ste20 mutant yeast. Infect Immun. 2003; 71: 6463–6471.

[44] Maurice NM, Bedi B, Yuan Z, Goldberg JB, Koval M, Hart CM, et al. Pseudomonas aeruginosa induced host epithelial cell mitochondrial dysfunction. Sci Rep. 2019; 9:11929.

[45] Losa D, Köhler T, Bellec J, Dudez T, Crespin S, Bacchetta M, et al. Pseudomonas aeruginosa-induced apoptosis in airway epithelial cells is mediated by gap junctional communication in a JNK-dependent manner. J Immunol. 2014; 192: 4804–4812.

[46] Barron SL, Saez J, Owens RM. In vitro models for studying respiratory host-pathogen interactions. Adv Biol. 2021; 5:e2000624.

[47] Grassmé H, Kirschnek S, Riethmueller J, Riehle A, von Kürthy G, Lang F, et al. CD95/CD95 ligand interactions on epithelial cells in host defense to Pseudomonas aeruginosa. Science. 2000; 290: 527–530.

[48] Powles MA, Liberator P, Anderson J, Karkhanis Y, Dropinski JF, Bouffard FA, et al. Efficacy of MK-991 (L-743,872), a semisynthetic pneumocandin, in murine models of Pneumocystis carinii. Antimicrob Agents Chemother. 1998; 42: 1985–1989.

[49] Geißert JK, Bohn E, Mostolizadeh R, Dräger A, Autenrieth IB, Beier S, et al. A computational model of bacterial population dynamics in gastrointestinal Yersinia enterocolitica infections in mice. Biology. 2022; 11: 297.

[50] Ketter PM, Yu J-J, Guentzel MN, May HC, Gupta R, Eppinger M, et al. Acinetobacter baumannii gastrointestinal colonization is facilitated by secretory IgA which is reductively dissociated by bacterial thioredoxin A. mBio. 2018; 9:e01298-18.

[51] Hudault S. Escherichia coli strains colonising the gastrointestinal tract protect germfree mice against Salmonella typhimurium infection. Gut. 2001; 49: 47–55.

[52] Samuels AN, Roggiani M, Smith KA, Zhu J, Goulian M, Kohli RM. Deciphering the role of colicins during colonization of the mammalian gut by commensal E. coli. Microorganisms. 2020; 8: 664.

[53] Vergara AF, Vidal RM, Torres AG, Farfan MJ. Long polar fimbriae participates in the induction of neutrophils transepithelial migration across intestinal cells infected with enterohemorrhagic E. coli O157:H7. Front Cell Infect Microbiol. 2014; 4: 185.

[54] McCloskey MC, Shaheen S, Rabago L, Hulverson MA, Choi R, Barrett LK, et al. Evaluation of in vitro and in vivo antibiotic efficacy against a novel bioluminescent Shigella flexneri. Sci Rep. 2019; 9:13567.

[55] Fernández Álvaro E, Voong Vinh P, de Cozar C, Willé DR, Urones B, Cortés A, et al. The repurposing of Tebipenem pivoxil as alternative therapy for severe gastrointestinal infections caused by extensively drug-resistant Shigella spp. eLife. 2022; 11:e83117.

[56] Chang SJ, Hsu YT, Chen Y, Lin YY, Lara-Tejero M, Galan JE. Typhoid toxin sorting and exocytic transport from Salmonella Typhi-infected cells. eLife. 2022; 11:e78561.

[57] Li P, Jiang W, Yu Q, Liu W, Zhou P, Li J, et al. Ubiquitination and degradation of GBPs by a Shigella effector to suppress host defence. Nature. 2017; 551: 378–383.

[58] Duncan-Lowey JK, Wiscovitch AL, Wood TE, Goldberg MB, Russo BC. Shigella flexneri disruption of cellular tension promotes intercellular spread. Cell Rep. 2020; 33:108409.

[59] Yang Z, Qin J, Zhao L, Chen T, Huang Q, Jian Y, et al. Host sorbitol and bacterial sorbitol utilization promote Clostridioides difficile infection in inflammatory bowel disease. Gastroenterology. 2023; 164: 1189–1201.e13.

[60] Engevik MA, Danhof HA, Ruan W, Engevik AC, Chang-Graham AL, Engevik KA, et al. Fusobacterium nucleatum secretes outer membrane vesicles and promotes intestinal inflammation. mBio. 2021; 12:e02706-20.

[61] Kemper L, Hensel A. Campylobacter jejuni: targeting host cells, adhesion, invasion, and survival. Appl Microbiol Biotechnol. 2023; 107: 2725–2754.

[62] Anthouard R, DiRita VJ. Small-molecule inhibitors of toxT expression in Vibrio cholerae. mBio. 2013; 4:e00403-13.

[63] Zhao W, Caro F, Robins W, Mekalanos JJ. Antagonism toward the intestinal microbiota and its effect on Vibrio cholerae virulence. Science. 2018; 359: 210–213.

[64] Ansari S, Yamaoka Y. Animal models and Helicobacter pylori infection. J Clin Med. 2022; 11: 3141.

[65] Jiménez-Soto LF, Kutter S, Sewald X, Ertl C, Weiss E, Kapp U, et al. Helicobacter pylori type IV secretion apparatus exploits β1 integrin in a novel RGD-independent manner. PLoS Pathog. 2009; 5:e1000684.

[66] Berin MC, Darfeuille-Michaud A, Egan LJ, Miyamoto Y, Kagnoff MF. Role of EHEC O157:H7 virulence factors in the activation of intestinal epithelial cell NF-κB and MAP kinase pathways and the upregulated expression of interleukin 8. Cell Microbiol. 2002; 4: 635–648.

[67] Anderson CJ, Medina CB, Barron BJ, Karvelyte L, Aaes TL, Lambertz I, et al. Microbes exploit death-induced nutrient release by gut epithelial cells. Nature. 2021; 596: 262–267.

[68] Cuomo P, Papaianni M, Sansone C, Iannelli A, Iannelli D, Medaglia C, et al. An in vitro model to investigate the role of Helicobacter pylori In type 2 diabetes, obesity, Alzheimer's disease and cardiometabolic disease. Int J Mol Sci. 2020; 21: 8369.

[69] Zhang S, Santos RL, Tsolis RM, Stender S, Hardt WD, Bäumler AJ, et al. The Salmonella enterica serotype Typhimurium effector proteins SipA, SopA, SopB, SopD, and SopE2 act in concert to induce diarrhea In calves. Infect Immun. 2002; 70: 3843–3855.

[70] He Z, Gharaibeh RZ, Newsome RC, Pope JL, Dougherty MW, Tomkovich S, et al. Campylobacter jejuni promotes colorectal tumorigenesis through the action of cytolethal distending toxin. Gut. 2019; 68: 289–300.

[71] Ernst CM, Braxton JR, Rodriguez-Osorio CA, Zagieboylo AP, Li L, Pironti A, et al. Adaptive evolution of virulence and persistence in carbapenem-resistant Klebsiella pneumoniae. Nature Med. 2020; 26: 705–711.

[72] Li J, Tang M, Liu Z, Xia F, Min C, Hu Y, et al. Molecular and clinical characterization of hypervirulent Klebsiella pneumoniae isolates from individuals with urinary tract infections. Front Cell Infect Microbiol. 2022; 12:925440.

[73] Andersen MJ, Fong C, La Bella AA, Molina JJ, Molesan A, Champion MM, et al. Inhibiting host-protein deposition on urinary catheters reduces associated urinary tract infections. eLife. 2022; 11:e75798.

[74] Chang Z, An L, He Z, Zhang Y, Li S, Lei M, et al. Allicin suppressed Escherichia coli-induced urinary tract infections by a novel MALT1/NF-κB pathway. Food Funct. 2022; 13: 3495–3511.

[75] Wang Z, Jiang Z, Zhang Y, Wang C, Liu Z, Jia Z, et al. Exosomes derived from bladder epithelial cells infected with uropathogenic Escherichia coli increase the severity of urinary tract infections (UTIs) by impairing macrophage function. PLoS Pathog. 2024; 20:e1011926.

[76] Alteri CJ, Smith SN, Mobley HLT. Fitness of Escherichia coli during urinary tract infection requires gluconeogenesis and the TCA cycle. PLoS Pathog. 2009; 5:e1000448.

[77] Cole SJ, Hall CL, Schniederberend M, Farrow Iii JM, Goodson JR, Pesci EC, et al. Host suppression of quorum sensing during catheter-associated urinary tract infections. Nat Commun. 2018; 9: 4436.

[78] Mctaggart LA, Rigby RC, Elliott TSJ. The pathogenesis of urinary tract infections associated with Escherichia coli, Staphylococcus saprophyticus and S. epidermidis. J Med Microbiol. 1990; 32: 135–141.

[79] Guiton PS, Hannan TJ, Ford B, Caparon MG, Hultgren SJ. Enterococcus faecalis overcomes foreign body-mediated inflammation to establish urinary tract infections. Infect Immun. 2013; 81: 329–339.

[80] Habibi M, Asadi Karam MR, Shokrgozar MA, Oloomi M, Jafari A, Bouzari S. Intranasal immunization with fusion protein MrpH·FimH and MPL adjuvant confers protection against urinary tract infections caused by uropathogenic Escherichia coli and Proteus mirabilis. Mol Immunol. 2015; 64: 285–294.

[81] Sessa R, Di Pietro M, Filardo S, Bressan A, Mastromarino P, Biasucci AV, et al. Lactobacilli–lactoferrin interplay in Chlamydia trachomatis infection. Pathog Dis. 2017; 75:ftx054.

[82] Feinen B, Jerse AE, Gaffen SL, Russell MW. Critical role of Th17 responses in a murine model of Neisseria gonorrhoeae genital infection. Mucosal Immunol. 2010; 3: 312–321.

[83] Xu SX, Leontyev D, Kaul R, Gray-Owen SD. Neisseria gonorrhoeae co-infection exacerbates vaginal HIV shedding without affecting systemic viral loads in human CD34⁺ engrafted mice. PLoS One. 2018; 13:e0191672.

[84] Yang Y, Liu S, Liu J, Ta N. Inhibition of TLR2/TLR4 alleviates the Neisseria gonorrhoeae infection damage in human endometrial epithelial cells via Nrf2 and NF-Kβ signaling. J Reprod Immunol. 2020; 142:103192.

[85] Yu Q, Wang L-C, Di Benigno S, Gray-Owen SD, Stein DC, Song W. Neisseria gonorrhoeae infects the heterogeneous epithelia of the human cervix using distinct mechanisms. PLoS Pathog. 2019; 15:e1008136.

[86] Ravel J, Moreno I, Simón C. Bacterial vaginosis and its association with infertility, endometritis, and pelvic inflammatory disease. Am J Obstet Gynecol. 2021; 224: 251–257.

[87] Edwards VL, Smith SB, McComb EJ, Tamarelle J, Ma B, Humphrys MS, et al. The cervicovaginal microbiota-host interaction modulates Chlamydia trachomatis infection. mBio. 2019; 10:e01548-19.

[88] Haines A, Wesolowski J, Paumet F. Chlamydia trachomatis subverts alpha-actinins to stabilize its inclusion. Microbiol Spectr. 2023; 11:e0261422.

[89] Ende RJ, Derré I. Host and bacterial glycolysis during Chlamydia trachomatis infection. Infect Immun. 2020; 88:e00545-20.

[90] Xue Y, Zheng H, Mai Z, Qin X, Chen W, Huang T, et al. An in vitro model of azithromycin-induced persistent Chlamydia trachomatis infection. FEMS Microbiol Lett. 2017; 364: fnx145.

[91] Yu Q, Chow EMC, McCaw SE, Hu N, Byrd D, Amet T, et al. Association of Neisseria gonorrhoeae Opa (CEA) with dendritic cells suppresses their ability to elicit an HIV-1-specific T cell memory response. PLoS One. 2013; 8:e56705.

[92] Lu X, Wang Y, Ma Y, Huang D, Lu Y, Liu X, et al. YAP1 induces marrow derived suppressor cell recruitment in Chlamydia trachomatis infection. Immunol Lett. 2022; 242: 8–16.

[93] Li M, Kim JB, Sastry BKS, Chen M. Infective endocarditis. Lancet. 2024; 404: 377–392.

[94] Schwartz FA, Nielsen L, Struve Andersen J, Bock M, Christophersen L, Sunnerhagen T, et al. Dynamics of a Staphylococcus aureus infective endocarditis simulation model. APMIS. 2022; 130: 515–523.

[95] Schwarz C, Töre Y, Hoesker V, Ameling S, Grün K, Völker U, et al. Host-pathogen interactions of clinical S. aureus isolates to induce infective endocarditis. Virulence. 2021; 12: 2073–2087.

[96] Liesenborghs L, Meyers S, Lox M, Criel M, Claes J, Peetermans M, et al. Staphylococcus aureus endocarditis: distinct mechanisms of bacterial adhesion to damaged and inflamed heart valves. Eur Heart J. 2019; 40: 3248–3259.

[97] Cantier M, Sabben C, Adle-Biassette H, Louedec L, Delbosc S, Desilles JP, et al. Neurologic complications of infective endocarditis: a joint model for a septic thromboembolism and inflammatory small vessel disease. Crit Care Med. 2019; 47: e685–e692.

[98] Panizzi P, Krohn-Grimberghe M, Keliher E, Ye YX, Grune J, Frodermann V, et al. Multimodal imaging of bacterial-host interface in mice and piglets with Staphylococcus aureus endocarditis. Sci Transl Med. 2020; 12:eaay2104.

[99] Ulloa ER, Singh KV, Geriak M, Haddad F, Murray BE, Nizet V, et al. Cefazolin and ertapenem salvage therapy rapidly clears persistent methicillin-susceptible Staphylococcus aureus bacteremia. Clin Infect Dis. 2019; 71: 1413–1418.

[100] Xu J, Liu S, Ai Y, Zhang Y, Li S, Li Y. Establishment and transcriptome analysis of single blastomere-derived cell lines from zebrafish. J Genet Genomics. 2024; 51: 957–969.

[101] Ravi K, Manoharan TJM, Wang KC, Pockaj B, Nikkhah M. Engineered 3D ex vivo models to recapitulate the complex stromal and immune interactions within the tumor microenvironment. Biomaterials. 2024; 305:122428.

[102] Koziol-White C, Gebski E, Cao G, Panettieri, Jr. RA. Precision cut lung slices: an integrated ex vivo model for studying lung physiology, pharmacology, disease pathogenesis and drug discovery. Respir Res. 2024; 25: 231.

[103] Palma E, Doornebal EJ, Chokshi S. Precision-cut liver slices: a versatile tool to advance liver research. Hepatol Int. 2019; 13: 51–57.

[104] Taebnia N, Römling U, Lauschke VM. In vitro and ex vivo modeling of enteric bacterial infections. Gut Microbes. 2023; 15:2158034.

[105] Kaur S, Kidambi S, Ortega-Ribera M, Thuy LTT, Nieto N, Cogger VC, et al. In vitro models for the study of liver biology and diseases: advances and limitations. Cell Mol Gastroenterol Hepatol. 2023; 15: 559–571.

[106] Rahman S, Ghiboub M, Donkers JM, van de Steeg E, van Tol EAF, Hakvoort TBM, et al. The progress of intestinal epithelial models from cell lines to gut-on-chip. Int J Mol Sci. 2021; 22:13472.

[107] Rossi G, Manfrin A, Lutolf MP. Progress and potential in organoid research. Nat Rev Genet. 2018; 19: 671–687.

[108] Lancaster MA, Knoblich JA. Organogenesis in a dish: modeling development and disease using organoid technologies. Science. 2014; 345:1247125.

[109] Garreta E, Kamm RD, Chuva de Sousa Lopes SM, Lancaster MA, Weiss R, Trepat X, et al. Rethinking organoid technology through bioengineering. Nat Mater. 2021; 20: 145–155.

[110] Hofer M, Lutolf MP. Engineering organoids. Nat Rev Mater. 2021; 6: 402–420.

[111] Yan HHN, Chan AS, Lai FPL, Leung SY. Organoid cultures for cancer modeling. Cell Stem Cell. 2023; 30: 917–937.

[112] Blutt SE, Estes MK. Organoid models for infectious disease. Annu Rev Med. 2022; 73: 167–182.

[113] Dutta D, Heo I, Clevers H. Disease modeling in stem cell-derived 3D organoid systems. Trends Mol Med. 2017; 23: 393–410.

[114] Piraino F, Costa M, Meyer M, Cornish G, Ceroni C, Garnier V, et al. Organoid models: the future companions of personalized drug development. Biofabrication. 2024; 16:032009.

[115] Wang X, Wang S, Guo B, Su Y, Tan Z, Chang M, et al. Human primary epidermal organoids enable modeling of dermatophyte infections. Cell Death Dis. 2021; 12: 35.

[116] Chiu MC, Li C, Liu X, Song W, Wan Z, Yu Y, et al. Human nasal organoids model SARS-CoV-2 upper respiratory infection and recapitulate the differential infectivity of emerging variants. mBio. 2022; 13:e01944-22.

[117] Sano E, Suzuki T, Hashimoto R, Itoh Y, Sakamoto A, Sakai Y, et al. Cell response analysis in SARS-CoV-2 infected bronchial organoids. Communications Biology. 2022; 5: 516.

[118] Chiu MC, Li C, Liu X, Yu Y, Huang J, Wan Z, et al. A bipotential organoid model of respiratory epithelium recapitulates high infectivity of SARS-CoV-2 Omicron variant. Cell Discov. 2022; 8: 57.

[119] Jung S, You HJ, Kim M-J, Ko G, Lee S, Kang K-S. Wnt-activating human skin organoid model of atopic dermatitis induced by Staphylococcus aureus and its protective effects by Cutibacterium acnes. iScience. 2022; 25:105150.

[120] Prince OA, Krunkosky TM, Sheppard ES, Krause DC. Modelling persistent Mycoplasma pneumoniae infection of human airway epithelium. Cell Microbiol. 2018; 20:e12810.

[121] Leon-Icaza SA, Bagayoko S, Vergé R, Iakobachvili N, Ferrand C, Aydogan T, et al. Druggable redox pathways against Mycobacterium abscessus in cystic fibrosis patient-derived airway organoids. PLoS Pathog. 2023; 19:e1011559.

[122] Walker WT, Jackson CL, Allan RN, Collins SA, Kelso MJ, Rineh A, et al. Primary ciliary dyskinesia ciliated airway cells show increased susceptibility to Haemophilus influenzae biofilm formation. Eur Respir J. 2017; 50:1700612.

[123] Wu H, Xie S, Miao J, Li Y, Wang Z, Wang M, et al. Lactobacillus reuteri maintains intestinal epithelial regeneration and repairs damaged intestinal mucosa. Gut Microbes. 2020; 11: 997–1014.

[124] Horsley H, Dharmasena D, Malone-Lee J, Rohn JL. A urine-dependent human urothelial organoid offers a potential alternative to rodent models of infection. Sci Rep. 2018; 8: 1238.

[125] Bagayoko S, Leon-Icaza SA, Pinilla M, Hessel A, Santoni K, Péricat D, et al. Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology. PLoS Pathog. 2021; 17:e1009927.

[126] Murphy TF, Parameswaran GI. Moraxella catarrhalis,a human respiratory tract pathogen. Clin Infect Dis. 2009; 49: 124–131.

[127] Dissanayake E, Brockman-Schneider RA, Stubbendieck RM, Helling BA, Zhang Z, Bochkov YA, et al. Rhinovirus increases Moraxella catarrhalis adhesion to the respiratory epithelium. Front Cell Infect Microbiol. 2022; 12:1060748.

[128] Sasaki N, Miyamoto K, Maslowski KM, Ohno H, Kanai T, Sato T. Development of a scalable coculture system for gut anaerobes and human colon epithelium. Gastroenterology. 2020; 159: 388–390.e5.

[129] Co JY, Margalef-Català M, Li X, Mah AT, Kuo CJ, Monack DM, et al. Controlling epithelial polarity: a human enteroid model for host-pathogen interactions. Cell Rep. 2019; 26: 2509–2520.e4.

[130] Abuaita BH, Lawrence A-LE, Berger RP, Hill DR, Huang S, Yadagiri VK, et al. Comparative transcriptional profiling of the early host response to infection by typhoidal and non-typhoidal Salmonella serovars in human intestinal organoids. PLoS Pathog. 2021; 17:e1009987.

[131] Nakamoto N, Sasaki N, Aoki R, Miyamoto K, Suda W, Teratani T, et al. Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis. Nat Microbiol. 2019; 4: 492–503.

[132] Pleguezuelos-Manzano C, Puschhof J, Rosendahl Huber A, van Hoeck A, Wood HM, Nomburg J, et al. Mutational signature in colorectal cancer caused by genotoxic pks⁺E. coli. Nature. 2020; 580: 269–273.

[133] Forbester JL, Lees EA, Goulding D, Forrest S, Yeung A, Speak A, et al. Interleukin-22 promotes phagolysosomal fusion to induce protection against Salmonella enterica Typhimurium in human epithelial cells. Proc Natl Acad Sci USA. 2018; 115: 10118–10123.

[134] Kim S, Shin YC, Kim TY, Kim Y, Lee YS, Lee SH, et al. Mucin degrader Akkermansia muciniphila accelerates intestinal stem cell-mediated epithelial development. Gut Microbes. 2021; 13: 1–20.

[135] Arnauts K, Sudhakar P, Verstockt S, Lapierre C, Potche S, Caenepeel C, et al. Microbiota, not host origin drives ex vivo intestinal epithelial responses. Gut Microbes. 2022; 14:2089003.

[136] Arnold JW, Roach J, Fabela S, Moorfield E, Ding S, Blue E, et al. The pleiotropic effects of prebiotic galacto-oligosaccharides on the aging gut. Microbiome. 2021; 9: 31.

[137] Kim HJ, Li H, Collins JJ, Ingber DE. Contributions of microbiome and mechanical deformation to intestinal bacterial overgrowth and inflammation in a human gut-on-a-chip. Proc Natl Acad Sci USA. 2016; 113: E7–E15.

[138] Bartfeld S, Bayram T, van de Wetering M, Huch M, Begthel H, Kujala P, et al. In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. Gastroenterology. 2015; 148: 126–136.e6.

[139] Mommersteeg MC, Simovic I, Yu B, van Nieuwenburg SAV, Bruno MJ, Doukas M, et al. Autophagy mediates ER stress and inflammation in Helicobacter pylori-related gastric cancer. Gut Microbes. 2022; 14:2015238.

[140] Cao L, Zhu S, Lu H, Soutto M, Bhat N, Chen Z, et al. Helicobacter pylori-induced RASAL2 through activation of nuclear factor-κB promotes gastric tumorigenesis via β-catenin signaling axis. Gastroenterology. 2022; 162: 1716–1731.e17.

[141] Wu B, Blimkie TM, Haney EF, Falsafi R, Akhoundsadegh N, Hancock REW. Host response of human epidermis to methicillin-resistant Staphylococcus aureus biofilm infection and synthetic antibiofilm peptide treatment. Cells. 2022; 11: 3459.

[142] Hotterbeekx A, Kumar-Singh S, Goossens H, Malhotra-Kumar S. In vivo and in vitro interactions between Pseudomonas aeruginosa and Staphylococcus spp. Front Cell Infect Microbiol. 2017; 7: 106.

[143] Alford MA, Mann S, Akhoundsadegh N, Hancock REW. Competition between Pseudomonas aeruginosa and Staphylococcus aureus is dependent on intercellular signaling and regulated by the NtrBC two-component system. Sci Rep. 2022; 12: 9027.

[144] Brown JL, Townsend E, Short RD, Williams C, Woodall C, Nile CJ, et al. Assessing the inflammatory response to in vitro polymicrobial wound biofilms in a skin epidermis model. NPJ Biofilms Microbiomes. 2022; 8: 19.

[145] Iakobachvili N, Leon-Icaza SA, Knoops K, Sachs N, Mazères S, Simeone R, et al. Mycobacteria-host interactions in human bronchiolar airway organoids. Mol Microbiol. 2022; 117: 682–692.

[146] Tang M, Liao S, Qu J, Liu Y, Han S, Cai Z, et al. Evaluating bacterial pathogenesis using a model of human airway organoids infected with Pseudomonas aeruginosa biofilms. Microbiol Spectr. 2022; 10:e0240822.

[147] Alcaraz M, Roquet-Banères F, Leon-Icaza SA, Abendroth J, Boudehen Y-M, Cougoule C, et al. Efficacy and mode of action of a direct inhibitor of Mycobacterium abscessus InhA. ACS Infect Dis. 2022; 8: 2171–2186.

[148] Liao S, Huang Y, Zhang J, Xiong Q, Chi M, Yang L, et al. Vitamin D promotes epithelial tissue repair and host defense responses against influenza H1N1 virus and Staphylococcus aureus infections. Respir Res. 2023; 24: 175.

[149] Swart AL, Laventie B-J, Sütterlin R, Junne T, Lauer L, Manfredi P, et al. Pseudomonas aeruginosa breaches respiratory epithelia through goblet cell invasion in a microtissue model. Nat Microbiol. 2024; 9: 1725–1737.

[150] Rossy T, Distler T, Meirelles LA, Pezoldt J, Kim J, Talà L, et al. Pseudomonas aeruginosa type IV pili actively induce mucus contraction to form biofilms in tissue-engineered human airways. PLoS Biol. 2023; 21:e3002209.

[151] Carey RM, Palmer JN, Adappa ND, Lee RJ. Loss of CFTR function is associated with reduced bitter taste receptor-stimulated nitric oxide innate immune responses in nasal epithelial cells and macrophages. Front Immunol. 2023; 14:1096242.

[152] Laucirica DR, Schofield CJ, McLean SA, Margaroli C, Agudelo-Romero P, Stick SM, et al. Pseudomonas aeruginosa modulates neutrophil granule exocytosis in an in vitro model of airway infection. Immunol Cell Biol. 2022; 100: 352–370.

[153] Chan LLY, Anderson DE, Cheng HS, Ivan FX, Chen S, Kang AEZ, et al. The establishment of COPD organoids to study host-pathogen interaction reveals enhanced viral fitness of SARS-CoV-2 in bronchi. Nat Commun. 2022; 13: 7635.

[154] Poh WP, Kicic A, Lester SE, Nguyen PT, Bakaletz LO, Reynolds PN, et al. COPD-related modification to the airway epithelium permits intracellular residence of nontypeable haemophilus influenzae and may be potentiated by macrolide arrest of autophagy. Int J Chronic Obstruct Pulm Dis. 2020; 15: 1253–1260.

[155] Ren D, Nelson KL, Uchakin PN, Smith AL, Gu XX, Daines DA. Characterization of extended co-culture of non-typeable Haemophilus influenzae with primary human respiratory tissues. Exp Biol Med. 2012; 237: 540–547.

[156] Schrumpf JA, Amatngalim GD, Veldkamp JB, Verhoosel RM, Ninaber DK, Ordonez SR, et al. Proinflammatory cytokines impair vitamin D-induced host defense In cultured airway epithelial cells. Am J Respir Cell Mol Biol. 2017; 56: 749–761.

[157] Thacker VV, Dhar N, Sharma K, Barrile R, Karalis K, McKinney JD. A lung-on-chip model of early Mycobacterium tuberculosis infection reveals an essential role for alveolar epithelial cells in controlling bacterial growth. eLife. 2020; 9:e59961.

[158] Crabbé A, Liu Y, Matthijs N, Rigole P, De La Fuente-Nùñez C, Davis R, et al. Antimicrobial efficacy against Pseudomonas aeruginosa biofilm formation in a three-dimensional lung epithelial model and the influence of fetal bovine serum. Sci Rep. 2017; 7:43321.

[159] Starner TD, Zhang N, Kim G, Apicella MA, McCray Jr. PB Haemophilus influenzae forms biofilms on airway epithelia: implications in cystic fibrosis. Am J Respir Crit Care Med. 2006; 174: 213–220.

[160] Zhang R, Yao F, Huang Y, Liu W, Liao S, He J, et al. Modeling Mycobacterium tuberculosis pathogenesis in lung epithelial organoids reveals strain-specific host responses and intercellular crosstalk. J Biol Chem. 2025; 301:110534.

[161] Chen Y, Qu J, Wang S, Tang M, Liao S, Liu Y, et al. Streptococcus agalactiae infection of a reconstructed human respiratory epithelium revealed infection and host response characteristics by different serotypes. Microb Pathog. 2025; 199:107243.

[162] Flores C, Ling J, Loh A, Maset RG, Aw A, White IJ, et al. A human urothelial microtissue model reveals shared colonization and survival strategies between uropathogens and commensals. Sci Adv. 2023; 9:eadi9834.

[163] Smith YC, Grande KK, Rasmussen SB, O'Brien AD. Novel three-dimensional organoid model for evaluation of the interaction of uropathogenic Escherichia coli with terminally differentiated human urothelial cells. Infect Immun. 2006; 74: 750–757.

[164] Jafari NV, Rohn JL. An immunoresponsive three-dimensional urine-tolerant human urothelial model to study urinary tract infection. Front Cell Infect Microbiol. 2023; 13:1128132.

[165] Horsley H, Owen J, Browning R, Carugo D, Malone-Lee J, Stride E, et al. Ultrasound-activated microbubbles as a novel intracellular drug delivery system for urinary tract infection. J Controlled Release. 2019; 301: 166–175.

[166] Sharma K, Thacker VV, Dhar N, Clapés Cabrer M, Dubois A, Signorino-Gelo F, et al. Early invasion of the bladder wall by solitary bacteria protects UPEC from antibiotics and neutrophil swarms in an organoid model. Cell Rep. 2021; 36:109351.

[167] Kessler M, Hoffmann K, Brinkmann V, Thieck O, Jackisch S, Toelle B, et al. The Notch and Wnt pathways regulate stemness and differentiation in human fallopian tube organoids. Nat Commun. 2015; 6: 8989.

[168] Kessler M, Hoffmann K, Fritsche K, Brinkmann V, Mollenkopf H-J, Thieck O, et al. Chronic Chlamydia infection in human organoids increases stemness and promotes age-dependent CpG methylation. Nat Commun. 2019; 10: 1194.

[169] Vollmuth N, Schlicker L, Guo Y, Hovhannisyan P, Janaki-Raman S, Kurmasheva N, et al. c-Myc plays a key role in IFN-γ-induced persistence of Chlamydia trachomatis. eLife. 2022; 11:e76721.

[170] Galea I. The blood–brain barrier in systemic infection and inflammation. Cell Mol Immunol. 2021; 18: 2489–2501.

[171] Adams Y, Clausen AS, Jensen PØ, Lager M, Wilhelmsson P, Henningson AJ, et al. 3D blood-brain barrier-organoids as a model for Lyme neuroborreliosis highlighting genospecies dependent organotropism. iScience. 2023; 26:105838.

[172] Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. N Engl J Med. 2016; 375: 2369–2379.

[173] Yang L, Wang X, Zhou X, Chen H, Song S, Deng L, et al. A tunable human intestinal organoid system achieves controlled balance between self-renewal and differentiation. Nat Commun. 2025; 16: 315.

[174] Wlodarska M, Luo C, Kolde R, d'Hennezel E, Annand JW, Heim CE, et al. Indoleacrylic acid produced by commensal Peptostreptococcus species suppresses inflammation. Cell Host Microbe. 2017; 22: 25–37.e6.

[175] Jose SS, De Zuani M, Tidu F, Hortová Kohoutková M, Pazzagli L, Forte G, et al. Comparison of two human organoid models of lung and intestinal inflammation reveals Toll-like receptor signalling activation and monocyte recruitment. Clin Transl Immunol. 2020; 9:e1131.

[176] Hong Z-X, Zhu S-T, Li H, Luo J-Z, Yang Y, An Y, et al. Bioengineered skin organoids: from development to applications. Mil Med Res. 2023; 10: 40.

[177] Lee J, Rabbani CC, Gao H, Steinhart MR, Woodruff BM, Pflum ZE, et al. Hair-bearing human skin generated entirely from pluripotent stem cells. Nature. 2020; 582: 399–404.

[178] Xie X, Tong X, Li Z, Cheng Q, Wang X, Long Y, et al. Use of mouse primary epidermal organoids for USA300 infection modeling and drug screening. Cell Death Dis. 2023; 14: 15.

[179] Stabell AR, Lee GE, Jia Y, Wong KN, Wang S, Ling J, et al. Single-cell transcriptomics of human-skin-equivalent organoids. Cell Rep. 2023; 42:112511.

[180] Jahanshahi M, Hamdi D, Godau B, Samiei E, Sanchez-Lafuente C, Neale K, et al. An engineered infected epidermis model for in vitro study of the skin's pro-inflammatory response. Micromachines. 2020; 11: 227.

[181] Invernizzi R, Lloyd CM, Molyneaux PL. Respiratory microbiome and epithelial interactions shape immunity in the lungs. Immunology. 2020; 160: 171–182.

[182] Hewitt RJ, Lloyd CM. Regulation of immune responses by the airway epithelial cell landscape. Nat Rev Immunol. 2021; 21: 347–362.

[183] Stölting H, Baillon L, Frise R, Bonner K, Hewitt RJ, Molyneaux PL, et al. Distinct airway epithelial immune responses after infection with SARS-CoV-2 compared to H1N1. Mucosal Immunol. 2022; 15: 952–963.

[184] Timm MR, Russell SK, Hultgren SJ. Urinary tract infections: pathogenesis, host susceptibility and emerging therapeutics. Nat Rev Microbiol. 2025; 23: 72–86.

[185] Huang Y, Liu T, Huang Q, Wang Y. From organ-on-a-chip to human-on-a-chip: a review of research progress and latest applications. ACS Sens. 2024; 9: 3466–3488.

[186] Singh D, Mathur A, Arora S, Roy S, Mahindroo N. Journey of organ on a chip technology and its role in future healthcare scenario. Appl Surf Sci Adv. 2022; 9:100246.

[187] Barkal LJ, Procknow CL, Álvarez-García YR, Niu M, Jiménez-Torres JA, Brockman-Schneider RA, et al. Microbial volatile communication in human organotypic lung models. Nat Commun. 2017; 8: 1770.

[188] Sharma K, Dhar N, Thacker VV, Simonet TM, Signorino-Gelo F, Knott GW, et al. Dynamic persistence of UPEC intracellular bacterial communities in a human bladder-chip model of urinary tract infection. eLife. 2021; 10:e66481.

[189] Kim J, Lee K-T, Lee JS, Shin J, Cui B, Yang K, et al. Fungal brain infection modelled in a human-neurovascular-unit-on-a-chip with a functional blood–brain barrier. Nat Biomed Eng. 2021; 5: 830–846.

[190] Andersen TE, Khandige S, Madelung M, Brewer J, Kolmos HJ, Møller-Jensen J. Escherichia coli uropathogenesis in vitro: invasion, cellular escape, and secondary infection analyzed in a human bladder cell infection model. Infect Immun. 2012; 80: 1858–1867.

[191] Jalili-Firoozinezhad S, Gazzaniga FS, Calamari EL, Camacho DM, Fadel CW, Bein A, et al. A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip. Nat Biomed Eng. 2019; 3: 520–531.

[192] Olvera A, Carter H, Rajan A, Carlin LG, Yu X, Zeng XL, et al. Enteropathogenic Escherichia coli infection in cancer and immunosuppressed patients. Clin Infect Dis. 2021; 72: e620–e629.

[193] Shpichka A, Bikmulina P, Peshkova M, Heydari Z, Kosheleva N, Vosough M, et al. Organoids in modelling infectious diseases. Drug Discovery Today. 2022; 27: 223–233.

[194] Han X, Mslati MA, Davies E, Chen Y, Allaire JM, Vallance BA. Creating a more perfect union: modeling intestinal bacteria-epithelial interactions using organoids. Cell Mol Gastroenterol Hepatol. 2021; 12: 769–782.

[195] Qi Q, Xu J, Wang Y, Zhang J, Gao M, Li Y, et al. Decreased sphingosine due to down-regulation of acid ceramidase expression In airway of bronchiectasis patients: a potential contributor to Pseudomonas aeruginosa infection. Infect Drug Resist. 2023; 16: 2573–2588.

[196] Westermann AJ, Gorski SA, Vogel J. Dual RNA-seq of pathogen and host. Nat Rev Microbiol. 2012; 10: 618–630.

[197] Westermann AJ, Vogel J. Cross-species RNA-seq for deciphering host–microbe interactions. Nat Rev Genet. 2021; 22: 361–378.

[198] Huang W, Wang D, Yao YF. Understanding the pathogenesis of infectious diseases by single-cell RNA sequencing. Microb Cell. 2021; 8: 208–222.

[199] Penaranda C, Hung DT. Single-cell RNA sequencing to understand host–pathogen interactions. ACS Infect Dis. 2019; 5: 336–344.

[200] Meng H, Zhang T, Wang Z, Zhu Y, Yu Y, Chen H, et al. High-Throughput host–microbe single-cell RNA sequencing reveals ferroptosis-associated heterogeneity during Acinetobacter baumannii infection. Angew Chem Int Ed. 2024; 63:e202400538.

[201] Lempke S, May D, Ewald SE. Microbial pathogenesis in the era of spatial omics. Infect Immun. 2023; 91:e00442-22.

[202] Sounart H, Lázár E, Masarapu Y, Wu J, Várkonyi T, Glasz T, et al. Dual spatially resolved transcriptomics for human host-pathogen colocalization studies in FFPE tissue sections. Genome Biol. 2023; 24: 237.

[203] Zhou H, Negrón O, Abbondante S, Marshall M, Jones B, Ong E, et al. Spatial transcriptomics identifies novel Pseudomonas aeruginosa virulence factors. Cell Genomics. 2025; 5:100805.

[204] Lötstedt B, Stražar M, Xavier R, Regev A, Vickovic S. Spatial host–microbiome sequencing reveals niches in the mouse gut. Nature Biotechnol. 2024; 42: 1394–1403.

[205] Saarenpää S, Shalev O, Ashkenazy H, Carlos V, Lundberg DS, Weigel D, et al. Spatial metatranscriptomics resolves host–bacteria–fungi interactomes. Nat Biotechnol. 2024; 42: 1384–1393.

[206] Jean Beltran PM, Federspiel JD, Sheng X, Cristea IM. Proteomics and integrative omic approaches for understanding host-pathogen interactions and infectious diseases. Mol Syst Biol. 2017; 13: 922.

[207] Khan MM, Ernst O, Manes NP, Oyler BL, Fraser IDC, Goodlett DR, et al. Multi-omics strategies uncover host–pathogen interactions. ACS Infect Dis. 2019; 5: 493–505.

[208] Bai Y, Liu W, Liu Z, Ding D, Jin H, Xiao S, et al. Multi-omics analysis of glycolytic reprogramming and ROS dynamics in host-specific responses to Salmonella Typhi infection in mice. J Adv Res. 2025; 18:S2090-1232 00345.

[209] Wang H, Fu T, Du Y, Gao W, Huang K, Liu Z, et al. Scientific discovery in the age of artificial intelligence. Nature. 2023; 620: 47–60.

[210] Danneskiold-Samsøe NB, Dias de Freitas Queiroz Barros H, Santos R, Bicas JL, Cazarin CBB, Madsen L, et al. Interplay between food and gut microbiota in health and disease. Food Res Int. 2019; 115: 23–31.

[211] Lim H, Cankara F, Tsai CJ, Keskin O, Nussinov R, Gursoy A. Artificial intelligence approaches to human-microbiome protein-protein interactions. Curr Opin Struct Biol. 2022; 73:102328.

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