Advances in the Application of Mouse Models to Study Digestive Mucosal Immunity and Infectious Diseases

doi:10.12300/j.issn.1674-5817.2021.170

Abstract

Abstract:

The host digestive tract comprises trillions of commensal microbes, collectively called microbiota. These microbes interact with a various host cell types and have a significant impact on health and disease. High-throughput sequencing technologies have accelerated the identification of numerous poorly studied microbes associated with health and disease. Genetic and humanized mouse models with and without environmental exposure were established to study the roles of these microbes in human physiologies and pathologies. Important findings related to the microbiota, mucosal immunity, and infectious diseases in mouse models are summarized. Furthermore, challenges and opportunities in leveraging genetic approaches and environmental exposure to optimize mouse models are discussed.

Key words: Mouse model, Microbiota, Host-microbial interactions, Mucosal immunity, Infectious disease

CLC Number:

R-332

Shiyan YU. Advances in the Application of Mouse Models to Study Digestive Mucosal Immunity and Infectious Diseases[J]. Laboratory Animal and Comparative Medicine, 2022, 42(1): 3-10. DOI: 10.12300/j.issn.1674-5817.2021.170.

References 75

1	FISHER M C, HENK D A, BRIGGS C J, et al. Emerging fungal threats to animal, plant and ecosystem health[J]. Nature, 2012, 484(7393):186-194. DOI:10.1038/nature10947 .
2	GROUSSIN M, MAZEL F, ALM E J. Co-evolution and co-speciation of host-gut bacteria systems[J]. Cell Host Microbe, 2020, 28(1):12-22. DOI:10.1016/j.chom.2020.06.013 .
3	CHO I, BLASER M J. The human microbiome: at the interface of health and disease[J]. Nat Rev Genet, 2012, 13(4):260-270. DOI:10.1038/nrg3182 .
4	CLEMENTE J C, URSELL L K, PARFREY L W, et al. The impact of the gut microbiota on human health: an integrative view[J]. Cell, 2012, 148(6):1258-1270. DOI:10.1016/j.cell.2012.01.035 .
5	SOMMER F, BÄCKHED F. The gut microbiota: Masters of host development and physiology[J]. Nat Rev Microbiol, 2013, 11(4):227-238. DOI:10.1038/nrmicro2974 .
6	FALONY G, VIEIRA-SILVA S, RAES J. Microbiology meets big data: the case of gut microbiota-derived trimethylamine[J]. Annu Rev Microbiol, 2015, 69:305-321. DOI:10.1146/annurev-micro-091014-104422 .
7	DZUTSEV A, BADGER J H, PEREZ-CHANONA E, et al. Microbes and cancer[J]. Annu Rev Immunol, 2017, 35:199-228. DOI:10.1146/annurev-immunol-051116-052133 .
8	FERREYRA J A, WU K J, HRYCKOWIAN A J, et al. Gut microbiota-produced succinate promotes C. difficile infection after antibiotic treatment or motility disturbance[J]. Cell Host Microbe, 2014, 16(6):770-777. DOI:10.1016/j.chom. 2014.11.003 .
9	NG K M, FERREYRA J A, HIGGINBOTTOM S K, et al. Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens[J]. Nature, 2013, 502(7469):96-99. DOI:10.1038/nature12503 .
10	JONES M K, WATANABE M, ZHU S, et al. Enteric bacteria promote human and mouse Norovirus infection of B cells[J]. Science, 2014, 346(6210):755-759. DOI:10.1126/science. 1257147 .
11	BALDRIDGE M T, NICE T J, MCCUNE B T, et al. Commensal microbes and interferon-λ determine persistence of enteric murine norovirus infection[J]. Science, 2015, 347(6219):266-269. DOI:10.1126/science.1258025 .
12	KUCZYNSKI J, LAUBER C L, WALTERS W A, et al. Experimental and analytical tools for studying the human microbiome[J]. Nat Rev Genet, 2011, 13(1):47-58. DOI:10.1038/nrg3129 .
13	KOSTIC A D, HOWITT M R, GARRETT W S. Exploring host-microbiota interactions in animal models and humans[J]. Genes Dev, 2013, 27(7):701-718. DOI:10.1101/gad.212522.112 .
14	MASOPUST D, SIVULA C P, JAMESON S C. Of mice, dirty mice, and men: using mice to understand human immunology[J]. J Immunol, 2017, 199(2):383-388. DOI:10.4049/jimmunol.1700453 .
15	REESE T A, BI K, KAMBAL A, et al. Sequential infection with common pathogens promotes human-like immune gene expression and altered vaccine response[J]. Cell Host Microbe, 2016, 19(5):713-719. DOI:10.1016/j.chom.2016.04.003 .
16	BEURA L K, HAMILTON S E, BI K, et al. Normalizing the environment recapitulates adult human immune traits in laboratory mice[J]. Nature, 2016, 532(7600):512-516. DOI:10.1038/nature17655 .
17	ROSSHART S P, HERZ J, VASSALLO B G, et al. Laboratory mice born to wild mice have natural microbiota and model human immune responses[J]. Science, 2019, 365(6452): eaaw4361. DOI:10.1126/science.aaw4361 .
18	LIN J D, DEVLIN J C, YEUNG F, et al. Rewilding Nod2 and Atg16l1 mutant mice uncovers genetic and environmental contributions to microbial responses and immune cell composition[J]. Cell Host Microbe, 2020, 27(5):830-840.e4. DOI:10.1016/j.chom.2020.03.001 .
19	ROSSHART S P, VASSALLO B G, ANGELETTI D, et al. Wild mouse gut microbiota promotes host fitness and improves disease resistance[J]. Cell, 2017, 171(5):1015-1028.e13. DOI:10.1016/j.cell.2017.09.016 .
20	FIEGE J K, BLOCK K E, PIERSON M J, et al. Mice with diverse microbial exposure histories as a model for preclinical vaccine testing[J]. Cell Host Microbe, 2021, 29(12):1815-1827.e6. DOI:10.1016/j.chom.2021.10.001 .
21	KERNBAUER E, DING Y, CADWELL K. An enteric virus can replace the beneficial function of commensal bacteria[J]. Nature, 2014, 516(7529):94-98. DOI:10.1038/nature13960 .
22	CADWELL K, PATEL K K, MALONEY N S, et al. Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine[J]. Cell, 2010, 141(7):1135-1145. DOI:10.1016/j.cell.2010.05.009 .
23	HAJISHENGALLIS G, LIANG S, PAYNE M A, et al. Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement[J]. Cell Host Microbe, 2011, 10(5):497-506. DOI:10.1016/j.chom.2011.10.006 .
24	WEISSBROD L, MARSHALL F B, VALLA F R, et al. Origins of house mice in ecological niches created by settled hunter-gatherers in the Levant 15, 000 y ago[J]. Proc Natl Acad Sci USA, 2017, 114(16):4099-4104. DOI:10.1073/pnas.1619137114 .
25	GOODMAN A L, KALLSTROM G, FAITH J J, et al. Extensive personal human gut microbiota culture collections characterized and manipulated in gnotobiotic mice[J]. Proc Natl Acad Sci USA, 2011, 108(15):6252-6257. DOI:10.1073/pnas.1102938108 .
26	KOREN N, ZUBEIDAT K, SABA Y, et al. Maturation of the neonatal oral mucosa involves unique epithelium-microbiota interactions[J]. Cell Host Microbe, 2021, 29(2):197-209.e5. DOI:10.1016/j.chom.2020.12.006 .
27	EARLE K A, BILLINGS G, SIGAL M, et al. Quantitative imaging of gut microbiota spatial organization[J]. Cell Host Microbe, 2015, 18(4):478-488. DOI:10.1016/j.chom.2015.09.002 .
28	LARSEN S B, COWLEY C J, FUCHS E. Epithelial cells: liaisons of immunity[J]. Curr Opin Immunol, 2020, 62:45-53. DOI:10.1016/j.coi.2019.11.004 .
29	BIRCHENOUGH G M H, NYSTRÖM E E L, JOHANSSON M E V, et al. A sentinel goblet cell guards the colonic crypt by triggering Nlrp6-dependent Muc2 secretion[J]. Science, 2016, 352(6293):1535-1542. DOI:10.1126/science.aaf7419 .
30	SCHNEIDER C, O'LEARY C E, MOLTKE J VON, et al. A metabolite-triggered tuft cell-ILC2 circuit drives small intestinal remodeling[J]. Cell, 2018, 174(2):271-284.e14. DOI:10.1016/j.cell.2018.05.014 .
31	MOLTKE J VON, JI M, LIANG H E, et al. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit[J]. Nature, 2016, 529(7585):221-225. DOI:10.1038/nature16161 .
32	YU S Y, BALASUBRAMANIAN I, LAUBITZ D, et al. Paneth cell-derived lysozyme defines the composition of mucolytic microbiota and the inflammatory tone of the intestine[J]. Immunity, 2020, 53(2):398-416.e8. DOI:10.1016/j.immuni. u2020.07.010 .
33	VAISHNAVA S, YAMAMOTO M, SEVERSON K M, et al. The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine[J]. Science, 2011, 334(6053):255-258. DOI:10.1126/science. 1209791 .
34	IVANOV I I, ATARASHI K, MANEL N, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria[J]. Cell, 2009, 139(3):485-498. DOI:10.1016/j.cell.2009.09.033 .
35	IVANOV I I, MCKENZIE B S, ZHOU L, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17⁺ T helper cells[J]. Cell, 2006, 126(6):1121-1133. DOI:10.1016/j.cell.2006.07.035 .
36	IVANOV I I, DE LLANOS FRUTOS R, MANEL N, et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine[J]. Cell Host Microbe, 2008, 4(4):337-349. DOI:10.1016/j.chom.2008.09.009 .
37	ATARASHI K, TANOUE T, ANDO M, et al. Th17 cell induction by adhesion of microbes to intestinal epithelial cells[J]. Cell, 2015, 163(2):367-380. DOI:10.1016/j.cell.2015.08.058 .
38	SALZMAN N H, HUNG K, HARIBHAI D, et al. Enteric defensins are essential regulators of intestinal microbial ecology[J]. Nat Immunol, 2010, 11(1):76-83. DOI:10.1038/ni.1825 .
39	CERVANTES-BARRAGAN L, CHAI J N, TIANERO M D, et al. Lactobacillus reuteri induces gut intraepithelial CD4⁺ CD8αα⁺ T cells[J]. Science, 2017, 357(6353):806-810. DOI:10.1126/science.aah5825 .
40	HOWITT M R, LAVOIE S, MICHAUD M, et al. Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut[J]. Science, 2016, 351(6279):1329-1333. DOI:10.1126/science.aaf1648 .
41	LEI W W, REN W W, OHMOTO M, et al. Activation of intestinal tuft cell-expressed Sucnr1 triggers type 2 immunity in the mouse small intestine[J]. Proc Natl Acad Sci USA, 2018, 115(21):5552-5557. DOI:10.1073/pnas.1720758115 .
42	ATARASHI K, TANOUE T, OSHIMA K, et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota[J]. Nature, 2013, 500(7461):232-236. DOI:10.1038/nature12331 .
43	FURUSAWA Y, OBATA Y, FUKUDA S, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells[J]. Nature, 2013, 504(7480):446-450. DOI:10.1038/nature12721 .
44	ATARASHI K, TANOUE T, SHIMA T, et al. Induction of colonic regulatory T cells by indigenous Clostridium species[J]. Science, 2011, 331(6015):337-341. DOI:10.1126/science.1198469 .
45	TANOUE T, MORITA S, PLICHTA D R, et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity[J]. Nature, 2019, 565(7741):600-605. DOI:10.1038/s41586-019-0878-z .
46	LEVY M, KOLODZIEJCZYK A A, THAISS C A, et al. Dysbiosis and the immune system[J]. Nat Rev Immunol, 2017, 17(4):219-232. DOI:10.1038/nri.2017.7 .
47	KAPLAN G G, NG S C. Understanding and preventing the global increase of inflammatory bowel disease[J]. Gastroenterology, 2017, 152(2):313-321.e2. DOI:10.1053/j.gastro.2016.10.020 .
48	KHOR B, GARDET A, XAVIER R J. Genetics and pathogenesis of inflammatory bowel disease[J]. Nature, 2011, 474(7351):307-317. DOI:10.1038/nature10209 .
49	JOSTINS L, RIPKE S, WEERSMA R K, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease[J]. Nature, 2012, 491(7422):119-124. DOI:10.1038/nature11582 .
50	DE LANGE K M, MOUTSIANAS L, LEE J C, et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease[J]. Nat Genet, 2017, 49(2):256-261. DOI:10.1038/ng.3760 .
51	HUANG H L, FANG M, JOSTINS L, et al. Fine-mapping inflammatory bowel disease loci to single-variant resolution[J]. Nature, 2017, 547(7662):173-178. DOI:10.1038/nature22969 .
52	RAMANAN D, TANG M S, BOWCUTT R, et al. Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus[J]. Immunity, 2014, 41(2):311-324. DOI:10.1016/j.immuni.2014.06.015 .
53	BRITTON G J, CONTIJOCH E J, MOGNO I, et al. Microbiotas from humans with inflammatory bowel disease alter the balance of gut Th17 and RORγt⁺ regulatory T cells and exacerbate colitis in mice[J]. Immunity, 2019, 50(1):212-224.e4. DOI:10.1016/j.immuni.2018.12.015 .
54	MATHUR R, OH H, ZHANG D K, et al. A mouse model of Salmonella typhi infection[J]. Cell, 2012, 151(3):590-602. DOI:10.1016/j.cell.2012.08.042 .
55	LAZEAR H M, GOVERO J, SMITH A M, et al. A mouse model of zika virus pathogenesis[J]. Cell Host Microbe, 2016, 19(5):720-730. DOI:10.1016/j.chom.2016.03.010 .
56	SHRESTA S, SHARAR K L, PRIGOZHIN D M, et al. Murine model for dengue virus-induced lethal disease with increased vascular permeability[J]. J Virol, 2006, 80(20):10208-10217. DOI:10.1128/JVI.00062-06 .
57	LECUIT M, VANDORMAEL-POURNIN S, LEFORT J, et al. A transgenic model for listeriosis: role of internalin in crossing the intestinal barrier[J]. Science, 2001, 292(5522):1722-1725. DOI:10.1126/science.1059852 .
58	MCCRAY B A, SKORDALAKES E, TAYLOR J P. Disease mutations in Rab7 result in unregulated nucleotide exchange and inappropriate activation[J]. Hum Mol Genet, 2010, 19(6):1033-1047. DOI:10.1093/hmg/ddp567 .
59	BAO L L, DENG W, HUANG B Y, et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice[J]. Nature, 2020, 583(7818):830-833. DOI:10.1038/s41586-020-2312-y .
60	CHOUDHARY S K, ARCHIN N M, CHEEMA M, et al. Latent HIV-1 infection of resting CD4^＋ T cells in the humanized Rag2^－/－ γ c^－/－ mouse[J]. J Virol, 2012, 86(1):114-120. DOI:10.1128/jvi.05590-11 .
61	MOTA J, RICO-HESSE R. Humanized mice show clinical signs of dengue fever according to infecting virus genotype[J]. J Virol, 2009, 83(17):8638-8645. DOI:10.1128/JVI.00581-09 .
62	JIMÉNEZ-DÍAZ M B, MULET T, VIERA S, et al. Improved murine model of malaria using plasmodium falciparum competent strains and non-myelodepleted NOD-scid IL2R gamma null mice engrafted with human erythrocytes[J]. Antimicrob Agents Chemother, 2009, 53(10):4533-4536. DOI:10.1128/AAC.00519-09 .
63	WASHBURN M L, BILITY M T, ZHANG L G, et al. A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease[J]. Gastroenterology, 2011, 140(4):1334-1344. DOI:10.1053/j.gastro.2011.01.001 .
64	WAHL A, DE C, FERNANDEZ M A, et al. Precision mouse models with expanded tropism for human pathogens[J]. Nat Biotechnol, 2019, 37(10):1163-1173. DOI:10.1038/s41587-019-0225-9 .
65	SUN J, LI N, OH K S, et al. Comprehensive RNAi-based screening of human and mouse TLR pathways identifies species-specific preferences in signaling protein use[J]. Sci Signal, 2016, 9(409): ra3. DOI:10.1126/scisignal.aab2191 .
66	YUE F, CHENG Y, BRESCHI A, et al. A comparative encyclopedia of DNA elements in the mouse genome[J]. Nature, 2014, 515(7527):355-364. DOI:10.1038/nature13992 .
67	CHEN Q F, KHOURY M, CHEN J Z. Expression of human cytokines dramatically improves reconstitution of specific human-blood lineage cells in humanized mice[J]. Proc Natl Acad Sci USA, 2009, 106(51):21783-21788. DOI:10.1073/pnas. 0912274106 .
68	CHAPPAZ S, FINKE D. The IL-7 signaling pathway regulates lymph node development independent of peripheral lymphocytes[J]. J Immunol, 2010, 184(7):3562-3569. DOI:10.4049/jimmunol.0901647 .
69	LI Y, MASSE-RANSON G, GARCIA Z, et al. A human immune system mouse model with robust lymph node development[J]. Nat Methods, 2018, 15(8):623-630. DOI:10.1038/s41592-018-0071-6 .
70	FISCHBACH M A. Microbiome: focus on causation and mechanism[J]. Cell, 2018, 174(4):785-790. DOI:10.1016/j.cell. 2018.07.038 .
71	MIURA H, QUADROS R M, GURUMURTHY C B, et al. Easi-CRISPR for creating knock-in and conditional knockout mouse models using long ssDNA donors[J]. Nat Protoc, 2018, 13(1):195-215. DOI:10.1038/nprot.2017.153 .
72	ANZALONE A V, RANDOLPH P B, DAVIS J R, et al. Search-and-replace genome editing without double-strand breaks or donor DNA[J]. Nature, 2019, 576(7785):149-157. DOI:10.1038/s41586-019-1711-4 .
73	KOMOR A C, KIM Y B, PACKER M S, et al. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage[J]. Nature, 2016, 533(7603):420-424. DOI:10.1038/nature17946 .
74	GAUDELLI N M, KOMOR A C, REES H A, et al. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage[J]. Nature, 2017, 551(7681):464-471. DOI:10.1038/nature24644 .
75	SCHUTGENS F, CLEVERS H. Human organoids: tools for understanding biology and treating diseases[J]. Annu Rev Pathol, 2020, 15:211-234. DOI:10.1146/annurev-pathmechdis-012419-032611 .

[1]	GONG Leilei, WANG Xiaoxia, FENG Xuewei, LI Xinlei, ZHAO Han, ZHANG Xueyan, FENG Xin. A Mouse Model and Mechanism Study of Premature Ovarian Insufficiency Induced by Different Concentrations of Cyclophosphamide [J]. Laboratory Animal and Comparative Medicine, 2025, 45(4): 403-410.
[2]	JIANG Juan, SONG Ning, LIAN Wenbo, SHAO Congcong, GU Wenwen, SHI Yan. Comparison of Histopathological and Molecular Pathological Phenotypes in Mouse Models of Intrauterine Adhesions Induced by Two Concentrations of Ethanol Perfusion [J]. Laboratory Animal and Comparative Medicine, 2025, 45(4): 393-402.
[3]	SHEN Huangyi, HUANG Yufei, YANG Yunpeng. Research Progress on Characteristics Analysis of Gut Microbiota and Its Sex Differences in Laboratory Animals [J]. Laboratory Animal and Comparative Medicine, 2025, 45(3): 349-359.
[4]	LUO Lianlian, YUAN Yanchun, WANG Junling, SHI Guangsen. Advances in Mouse Models of Amyotrophic Lateral Sclerosis [J]. Laboratory Animal and Comparative Medicine, 2025, 45(3): 290-299.
[5]	PAN Qianjia, GE Junyi, HU Nan, HUA Fei, GU Min. Differential Analysis of Oral Microbiota in db/db Mouse Model of Type 2 Diabetes Utilizing 16S rRNA Sequencing [J]. Laboratory Animal and Comparative Medicine, 2025, 45(2): 147-157.
[6]	YAO Ding, ZHOU Jing, YAN Guofeng, WANG Huiyang, WANG Yadi, MA Zhengwen. Establishment of Salt-sensitive Hypertension Model in C57BL/6J Mice [J]. Laboratory Animal and Comparative Medicine, 2020, 40(4): 314-.
[7]	CHAI Wenjun, SUN Lei, LIU Xiaoli, PAN Hongyu, GUO Tianan, XU Ye, YAN Mingxia. Establishment of Bone Metastasis Mouse Models through Injecting Human Lung Cancer Cells into Left Ventricle#br# under Ultrasound Guidance#br# [J]. Laboratory Animal and Comparative Medicine, 2020, 40(3): 183-.
[8]	JIANG Hongli, MA Hongye, XUE Jinhong, SUN Lingshuang, CHEN Lei. The Role of Villin-1 in Model of Habu Nephritis Mice with Unilateral Nephrectomy [J]. Laboratory Animal and Comparative Medicine, 2020, 40(1): 1-8.
[9]	HE Yi-min, GU Ming-min. Preliminary Phenotypic Analysis of Myh13 Knockout Mouse [J]. Laboratory Animal and Comparative Medicine, 2019, 39(3): 193-200.
[10]	SHEN Yan, XU Wang-yang, ZHU Hou-bao. Research Progress on Pathogenesis of Hereditary Diseases Caused by Mutations of Oxidoreductase DHTKD1 and Related Mouse Models [J]. Laboratory Animal and Comparative Medicine, 2018, 38(6): 468-472.
[11]	JI Lian, MA Tie, DI Zheng-hong, Liu Dong-yan. Establishment of Atopic Dermatitis Mouse Model [J]. Laboratory Animal and Comparative Medicine, 2018, 38(4): 267-271.
[12]	ZHOU Yan, DIAO Chen-xi, ZHANG Yuan-yuan, YU Hai-bo, LU Tao-feng, ZHAO Li-li, CHEN Hong-yan. Composition and Diversity of Fecal Microflora in SPF Chickens at Different Growth Stages [J]. Laboratory Animal and Comparative Medicine, 2017, 37(3): 231-239.
[13]	GU Xiao-wen, SUN Rei-lin, FEI Jian. Construction of Afp-cre-lacZ Transgenic Mouse Model [J]. Laboratory Animal and Comparative Medicine, 2017, 37(2): 89-93.
[14]	PENG Xiu-hua, CHEN Li-xiang, REN Xiao-nan, SHI Bi-sheng, XU Chun-hua, ZHOU Wen-jiang, ZHOU Xiao-hui. Establishment and Preliminary Evaluation of Hepatitis B Virus Transfection Mouse Model by Using Hydrodynamic Injection [J]. Laboratory Animal and Comparative Medicine, 2015, 35(1): 1-5.
[15]	WANG Jian-ming, GENG Teng, CHEN Hang, NI Jun-da, WANG Wen-hua, CHEN Bing, XUE Zheng-feng. Microphthalmia Mutagenesis Mouse Induced by N-ethyl-N-nitrosourea and Its Genetic Tests [J]. Laboratory Animal and Comparative Medicine, 2014, 34(6): 473-475.