Gut microbiota-derived tryptophan metabolites improve total parenteral nutrition-associated infections by regulating Group 3 innate lymphoid cells

Abstract

Clinical nutritional support is recognized by Klinefner's Surgery as one of the four pivotal advancements in surgical practice during the 20th century. Surgeons regard clinical nutrition as a “life-saving” discipline, pivotal in preserving the lives of numerous critically ill patients and facilitating the success of many surgical procedures. Parenteral nutrition (PN) support serves as a crucial component of clinical nutritional therapy, while a range of complications associated with total parenteral nutrition (TPN) can significantly undermine the efficacy of patient treatment. Impaired intestinal homeostasis is strongly associated with the occurrence and progression of TPN-related infections, yet the underlying mechanisms remain poorly understood. In this study, RNA sequencing and single-cell RNA sequencing (scRNA-Seq) revealed that reduced secretion of interleukin-22 (IL-22) by intestinal Group 3 innate lymphoid cells (ILC3s) is a significant factor contributing to the onset of TPN-related infections. Additionally, through 16S ribosomal RNA (16S rRNA) gene sequencing of the gut microbiota from patients with chronic intestinal failure and metagenomic sequencing analysis of the gut microbiota from mice, we observed that TPN reduced the abundance of Lactobacillus murinus (L. murinus), while supplementation with L. murinus could promote IL-22 secretion by ILC3s. Mechanistically, L. murinus upregulates indole-3-carboxylic acid, which activates the nuclear receptor Rorγt to stimulate IL-22 secretion by ILC3s. This pathway strengthens gut barrier integrity and reduces infection susceptibility. Our findings enhance our understanding of the mechanisms driving the onset of TPN-related infections, highlighting the critical role of gut microbiota in maintaining immune homeostasis and improving clinical outcomes.

Keywords

Group 3 innate lymphoid cells / gut microbiota / indole-3-carboxylic acid / intestinal barrier integrity / lactobacillus murinus / TPN-associated infection

References

[1] Pironi, Loris, Cristina Cuerda, Palle Bekker Jeppesen, Francisca Joly, Cora Jonkers, Željko Krznarić, Simon Lal, et al. 2023. “ESPEN Guideline on Chronic Intestinal Failure in Adults-Update 2023.” Clinical Nutrition 42: 1940-2021. https://doi.org/10.1016/j.clnu.2023.07.019

[2] Brown, Sarah Kate, Natalie Davies, Enda Smyth, Nicky Heather, Caroline Cole, Simon Charles Keys, Robert Mark Beattie, and Akshay Batra. 2018. “Intestinal Failure: The Evolving Demographic and Patient Outcomes on Home Parenteral Nutrition.” Acta Paediatrica 107: 2207-2211. https://doi.org/10.1111/apa.14401

[3] Wan, Xiao, Jingcheng Bi, Xuejin Gao, Feng Tian, Xinying Wang, Ning Li, and Jieshou Li. 2015. “Partial Enteral Nutrition Preserves Elements of Gut Barrier Function, Including Innate Immunity, Intestinal Alkaline Phosphatase (IAP) Level, and Intestinal Microbiota in Mice.” Nutrients 7: 6294-6312. https://doi.org/10.3390/nu7085288

[4] Sun, Haifeng, Jingcheng Bi, Qiucheng Lei, Xiao Wan, Tingting Jiang, Chao Wu, and Xinying Wang. 2018. “Partial Enteral Nutrition Increases Intestinal sIgA Levels in Mice Undergoing Parenteral Nutrition in a Dose-Dependent Manner.” International Journal of Surgery 49: 74-79. https://doi.org/10.1016/j.ijsu.2017.12.011

[5] Gustafsson, Jenny K., and Malin E. V. Johansson. 2022. “The Role of Goblet Cells and Mucus in Intestinal Homeostasis.” Nature Reviews Gastroenterology & Hepatology 19: 785-803. https://doi.org/10.1038/s41575-022-00675-x

[6] Abu-Elmagd, Kareem. 2015. “The Concept of Gut Rehabilitation and the Future of Visceral Transplantation.” Nature Reviews Gastroenterology & Hepatology 12: 108-120. https://doi.org/10.1038/nrgastro.2014.216

[7] Shafiekhani, Mojtaba, Hamed Nikoupour, and Mahtabalsadat Mirjalili. 2022. “The Experience and Outcomes of Multidisciplinary Clinical Pharmacist-Led Parenteral Nutrition Service for Individuals With Intestinal Failure in a Center Without Home Parenteral Nutrition.” European Journal of Clinical Nutrition 76: 841-847. https://doi.org/10.1038/s41430-021-01048-4

[8] Wang, Peng, Haifeng Sun, Gulisudumu Maitiabula, Li Zhang, Jianbo Yang, Yupeng Zhang, Xuejin Gao, et al. 2023. “Total Parenteral Nutrition Impairs Glucose Metabolism by Modifying the Gut Microbiome.” Nature Metabolism 5: 331-348. https://doi.org/10.1038/s42255-023-00744-8

[9] Oterdoom, Leendert Harmen, Suzanne Marije Ten Dam, Sabine Dorine Willemine de Groot, Willy Arjaans, and Adriaan Anthonie van Bodegraven. 2014. “Limited Long-Term Survival After In-Hospital Intestinal Failure Requiring Total Parenteral Nutrition.” The American Journal of Clinical Nutrition 100: 1102-1107. https://doi.org/10.3945/ajcn.114.087015

[10] Bond, A., A. Teubner, M. Taylor, C. Cawley, J. Varden, A. Abraham, P. R. Chadwick, et al. 2019. “Catheter-Related Infections in Patients With Acute Type II Intestinal Failure Admitted to a National Centre: Incidence and Outcomes.” Clinical Nutrition 38: 1828-1832. https://doi.org/10.1016/j.clnu.2018.07.019

[11] De Vos, Willem M., Herbert Tilg, Matthias Van Hul, and Patrice D. Cani. 2022. “Gut Microbiome and Health: Mechanistic Insights.” Gut 71: 1020-1032. https://doi.org/10.1136/gutjnl-2021-326789

[12] Hsu, Cynthia L., and Bernd Schnabl. 2023. “The Gut-Liver Axis and Gut Microbiota in Health and Liver Disease.” Nature Reviews Microbiology 21: 719-733. https://doi.org/10.1038/s41579-023-00904-3

[13] Bajaj, Jasmohan S., Siew C. Ng, and Bernd Schnabl. 2022. “Promises of Microbiome-Based Therapies.” Journal of Hepatology 76: 1379-1391. https://doi.org/10.1016/j.jhep.2021.12.003

[14] Kayama, Hisako, Ryu Okumura, and Kiyoshi Takeda. 2020. “Interaction Between the Microbiota, Epithelia, and Immune Cells in the Intestine.” Annual Review of Immunology 38: 23-48. https://doi.org/10.1146/annurev-immunol-070119-115104

[15] Li, Ting, Ning Ding, Hanqing Guo, Rui Hua, Zehao Lin, Huohuan Tian, Yue Yu, et al. 2024. “A Gut Microbiota-Bile Acid Axis Promotes Intestinal Homeostasis Upon Aspirin-Mediated Damage.” Cell Host & Microbe 32: 191-208.e9. https://doi.org/10.1016/j.chom.2023.12.015

[16] Hu, Jun, Jianwei Chen, Xiaojian Xu, Qiliang Hou, Jing Ren, and Xianghua Yan. 2023. “Gut Microbiota-Derived 3-phenylpropionic Acid Promotes Intestinal Epithelial Barrier Function via AhR Signaling.” Microbiome 11: 102. https://doi.org/10.1186/s40168-023-01551-9

[17] Wang, Jiwei, Feng Tian, Peng Wang, Huijun Zheng, Ying Zhang, Hao Tian, Li Zhang, Xuejin Gao, and Xinying Wang. 2018. “Gut Microbiota as a Modulator of Paneth Cells During Parenteral Nutrition in Mice.” Journal of Parenteral and Enteral Nutrition 42: 1280-1287. https://doi.org/10.1002/jpen.1162

[18] Talbot, Jhimmy, Paul Hahn, Lina Kroehling, Henry Nguyen, Dayi Li, and Dan R. Littman. 2020. “Feeding-Dependent VIP Neuron-ILC3 Circuit Regulates the Intestinal Barrier.” Nature 579: 575-580. https://doi.org/10.1038/s41586-020-2039-9

[19] Peng, Ziyao, Jiali Zhang, Meng Zhang, Liping Yin, Ziyang Zhou, Cuiting Lv, Zetian Wang, and Jianguo Tang. 2024. “Tryptophan Metabolites Relieve Intestinal Candida Albicans Infection by Altering the Gut Microbiota to Reduce IL-22 Release From Group 3 Innate Lymphoid Cells of the Colon Lamina Propria.” Food & Function 15: 5364-5381. https://doi.org/10.1039/D4FO00432A

[20] Chen, Mingjun, Yang Feng, Lu Gao, Mingxiong Lin, Shida Wang, and Zhanqi Tong. 2023. “Composite Sophora Colon-Soluble Capsule Ameliorates DSS-Induced Ulcerative Colitis in Mice via Gut Microbiota-Derived Butyric Acid and NCR⁺ ILC3.” Chinese Journal of Integrative Medicine 29: 424-433. https://doi.org/10.1007/s11655-022-3317-1

[21] Gronke, Konrad, Pedro P. Hernández, Jakob Zimmermann, Christoph S. N. Klose, Michael Kofoed-Branzk, Fabian Guendel, Mario Witkowski, et al. 2019. “Interleukin-22 Protects Intestinal Stem Cells Against Genotoxic Stress.” Nature 566: 249-253. https://doi.org/10.1038/s41586-019-0899-7

[22] Bonetti, Lynn, Veronika Horkova, Melanie Grusdat, Joseph Longworth, Luana Guerra, Henry Kurniawan, Davide G. Franchina, et al. 2024. “A Th17 Cell-Intrinsic Glutathione/Mitochondrial-IL-22 Axis Protects Against Intestinal Inflammation.” Cell Metabolism 36: 1726-1744.e10. https://doi.org/10.1016/j.cmet.2024.06.010

[23] Wawrzyniak, M., U. Ochsner, O. Wirz, P. Wawrzyniak, W. van de Veen, C. A. Akdis, and M. Akdis. 2016. “A Novel, Dual Cytokine-Secretion Assay for the Purification of Human Th22 Cells That Do Not Co-Produce IL-17A.” Allergy 71: 47-57. https://doi.org/10.1111/all.12768

[24] Wang, Yaya, John Brian Mumm, Ronald Herbst, Roland Kolbeck, and Yue Wang. 2017. “IL-22 Increases Permeability of Intestinal Epithelial Tight Junctions by Enhancing Claudin-2 Expression.” The Journal of Immunology 199: 3316-3325. https://doi.org/10.4049/jimmunol.1700152

[25] Gury-BenAri, Meital, Christoph A. Thaiss, Nicolas Serafini, Deborah R. Winter, Amir Giladi, David Lara-Astiaso, Maayan Levy, et al. 2016. “The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome.” Cell 166: 1231-1246.e13. https://doi.org/10.1016/j.cell.2016.07.043

[26] Robinette, Michelle L., Anja Fuchs, Victor S. Cortez, Jacob S. Lee, Yaming Wang, Scott K. Durum, Susan Gilfillan, and Marco Colonna. 2015. “Transcriptional Programs Define Molecular Characteristics of Innate Lymphoid Cell Classes and Subsets.” Nature Immunology 16: 306-317. https://doi.org/10.1038/ni.3094

[27] Mutanen, Annika, Jouko Lohi, Laura Merras-Salmio, Antti Koivusalo, and Mikko P. Pakarinen. 2021. “Prediction, Identification and Progression of Histopathological Liver Disease Activity in Children With Intestinal Failure.” Journal of Hepatology 74: 593-602. https://doi.org/10.1016/j.jhep.2020.09.023

[28] Maitiabula, Gulisudumu, Feng Tian, Peng Wang, Li Zhang, Xuejin Gao, Songlin Wan, Haifeng Sun, et al. 2022. “Liver PP2A-Cα Protects From Parenteral Nutrition-Associated Hepatic Steatosis.” Cellular and Molecular Gastroenterology and Hepatology 14: 669-692. https://doi.org/10.1016/j.jcmgh.2022.05.008

[29] Fligor, Scott C., Savas T. Tsikis, Thomas I. Hirsch, Amy Pan, Kamila Moskowitzova, Lorena Rincon-Cruz, Ashlyn E. Whitlock, et al. 2023. “A Medium-Chain Fatty Acid Analogue Prevents Intestinal Failure-Associated Liver Disease in Preterm Yorkshire Piglets.” Gastroenterology 165: 733-745.e9. https://doi.org/10.1053/j.gastro.2023.05.035

[30] Cerdó, Tomás, José Antonio García-Santos, Anna Rodríguez-Pöhnlein, María García-Ricobaraza, Ana Nieto-Ruíz, Mercedes G. Bermúdez, and Cristina Campoy. 2022. “Impact of Total Parenteral Nutrition on Gut Microbiota in Pediatric Population Suffering Intestinal Disorders.” Nutrients 14: 4691. https://doi.org/10.3390/nu14214691

[31] Xiong, Lifeng, Eric Y. Helm, Joseph W. Dean, Na Sun, Felix R. Jimenez-Rondan, and Liang Zhou. 2023. “Nutrition Impact on ILC3 Maintenance and Function Centers on a Cell-Intrinsic CD71-Iron Axis.” Nature Immunology 24: 1671-1684. https://doi.org/10.1038/s41590-023-01612-z

[32] Godinho-Silva, Cristina, Rita G. Domingues, Miguel Rendas, Bruno Raposo, Hélder Ribeiro, Joaquim Alves da Silva, Ana Vieira, et al. 2019. “Light-Entrained and Brain-Tuned Circadian Circuits Regulate ILC3s and Gut Homeostasis.” Nature 574: 254-258. https://doi.org/10.1038/s41586-019-1579-3

[33] Lyu, Mengze, Hiroaki Suzuki, Lan Kang, fabrina Gaspal, Wenqing Zhou, Jeremy Goc, Lei Zhou, et al. 2022. “ILC3s Select Microbiota-Specific Regulatory T Cells to Establish Tolerance in the Gut.” Nature 610: 744-751. https://doi.org/10.1038/s41586-022-05141-x

[34] Liébana-García, Rebeca, Marta Olivares, Carlos Francés-Cuesta, Teresa Rubio, Valerio Rossini, Guillermo Quintas, and Yolanda Sanz. 2023. “Intestinal Group 1 Innate Lymphoid Cells Drive Macrophage-Induced Inflammation and Endocrine Defects in Obesity and Promote Insulinemia.” Gut Microbes 15: 2181928. https://doi.org/10.1080/19490976.2023.2181928

[35] Singer, Jeffrey R., Emily G. Blosser, Carlene L. Zindl, Daniel J. Silberger, Sean Conlan, Vincent A. Laufer, Daniel DiToro, et al. 2019. “Preventing Dysbiosis of the Neonatal Mouse Intestinal Microbiome Protects Against Late-Onset Sepsis.” Nature Medicine 25: 1772-1782. https://doi.org/10.1038/s41591-019-0640-y

[36] Wilck, Nicola, Mariana G. Matus, Sean M. Kearney, Scott W. Olesen, Kristoffer Forslund, Hendrik Bartolomaeus, Stefanie Haase, et al. 2017. “Salt-Responsive Gut Commensal Modulates T_H17 Axis and Disease.” Nature 551: 585-589. https://doi.org/10.1038/nature24628

[37] Hu, Jingjuan, Fan Deng, Bingcheng Zhao, Zebin Lin, Qishun Sun, Xiao Yang, Mei Wu, et al. 2022. “Lactobacillus Murinus Alleviate Intestinal Ischemia/Reperfusion Injury Through Promoting the Release of Interleukin-10 From M2 Macrophages via Toll-Like Receptor 2 Signaling.” Microbiome 10: 38. https://doi.org/10.1186/s40168-022-01227-w

[38] Miao, Hua, Yan-Ni Wang, Xiao-Yong Yu, Liang Zou, Yan Guo, Wei Su, Fei Liu, Gang Cao, and Ying-Yong Zhao. 2024. “Lactobacillus Species Ameliorate Membranous Nephropathy Through Inhibiting the Aryl Hydrocarbon Receptor Pathway via Tryptophan-Produced Indole Metabolites.” British Journal of Pharmacology 181: 162-179. https://doi.org/10.1111/bph.16219

[39] Dai, Juanjuan, Mingjie Jiang, Xiaoxin Wang, Tao Lang, Leilei Wan, and Jingjing Wang. 2024. “Human-Derived Bacterial Strains Mitigate Colitis via Modulating Gut Microbiota and Repairing Intestinal Barrier Function in Mice.” BMC Microbiology 24: 96. https://doi.org/10.1186/s12866-024-03216-5

[40] Zhang, Xingdao, Yuni Zhang, Yu He, Xingwang Zhu, Qing Ai, and Yuan Shi. 2023. “β-glucan Protects Against Necrotizing Enterocolitis in Mice by Inhibiting Intestinal Inflammation, Improving the Gut Barrier, and Modulating Gut Microbiota.” Journal of Translational Medicine 21: 14. https://doi.org/10.1186/s12967-022-03866-x

[41] Sun, Xiaodong, Shenglan Feng, Bingqing Qin, Junjie Ye, Lixia Xie, Jianjun Gui, and Ming Sang. 2024. “Integrated Multi-Omics Profiling Highlights the Benefits of Resveratrol Hydroxypropyl-β-cyclodextrin Inclusion Complex for A53T Transgenic Mice Through the Microbiota-Gut-Brain Axis.” Food & Function 15: 1489-1512. https://doi.org/10.1039/D3FO03667G

[42] Fan, Jinping, Yuhan Zhang, Minyu Zuo, Shixuan Ding, Jingjing Li, Shengkai Feng, Yingping Xiao, and Shiyu Tao. 2024. “Novel Mechanism by Which Extracellular Vesicles Derived From Lactobacillus Murinus Alleviates Deoxynivalenol-Induced Intestinal Barrier Disruption.” Environment International 185: 108525. https://doi.org/10.1016/j.envint.2024.108525

[43] Fong, Winnie, Qing Li, Fenfen Ji, Wei Liang, Harry Cheuk Hay Lau, Xing Kang, Weixin Liu, et al. 2023. “Lactobacillus Gallinarum-Derived Metabolites Boost Anti-PD1 Efficacy in Colorectal Cancer by Inhibiting Regulatory T Cells Through Modulating IDO1/Kyn/AHR Axis.” Gut 72: 2272-2285. https://doi.org/10.1136/gutjnl-2023-329543

[44] Sun, Yubo, Hao Wu, Wenning Zhou, Zhichun Yuan, Jianjun Hao, Xili Liu, and Lirong Han. 2022. “Effects of Indole Derivatives From Purpureocillium Lilacinum in Controlling Tobacco Mosaic Virus.” Pesticide Biochemistry and Physiology 183: 105077. https://doi.org/10.1016/j.pestbp.2022.105077

[45] Pastorczyk, Marta, Ayumi Kosaka, Mariola Piślewska-Bednarek, Gemma López, Henning Frerigmann, Karolina Kułak, Erich Glawischnig, et al. 2020. “The Role of CYP 71A12 Monooxygenase in Pathogen-Triggered Tryptophan Metabolism and Arabidopsis Immunity.” New Phytologist 225: 400-412. https://doi.org/10.1111/nph.16118

[46] Hezaveh, Kebria, Rahul S. Shinde, Andreas Klötgen, Marie Jo Halaby, Sara Lamorte, M. Teresa Ciudad, Rene Quevedo, et al. 2022. “Tryptophan-Derived Microbial Metabolites Activate the Aryl Hydrocarbon Receptor in Tumor-Associated Macrophages to Suppress Anti-Tumor Immunity.” Immunity 55: 324-340.e8. https://doi.org/10.1016/j.immuni.2022.01.006

[47] Cervantes-Barragan, Luisa, Jiani N. Chai, Ma. Diarey Tianero, Blanda Di Luccia, Philip P. Ahern, Joseph Merriman, Victor S. Cortez, et al. 2017. “Lactobacillus Reuteri Induces Gut Intraepithelial CD4⁺ CD8αα⁺ T Cells.” Science 357: 806-810. https://doi.org/10.1126/science.aah5825

[48] Rosser, Elizabeth C., Christopher J. M. Piper, Diana E. Matei, Paul A. Blair, André F. Rendeiro, Michael Orford, Dagmar G. Alber, et al. 2020. “Microbiota-Derived Metabolites Suppress Arthritis by Amplifying Aryl-Hydrocarbon Receptor Activation in Regulatory B Cells.” Cell Metabolism 31: 837-851.e10. https://doi.org/10.1016/j.cmet.2020.03.003

[49] Jarade, Angélique, Zacarias Garcia, Solenne Marie, Abdi Demera, Immo Prinz, Philippe Bousso, James P. Di Santo, and Nicolas Serafini. 2022. “Inflammation Triggers ILC3 Patrolling of the Intestinal Barrier.” Nature Immunology 23: 1317-1323. https://doi.org/10.1038/s41590-022-01284-1

[50] Zhou, Lei, Wenqing Zhou, Ann M. Joseph, Coco Chu, Gregory G. Putzel, Beibei Fang, Fei Teng, et al. 2022. “Group 3 Innate Lymphoid Cells Produce the Growth Factor HB-EGF to Protect the Intestine From TNF-Mediated Inflammation.” Nature Immunology 23: 251-261. https://doi.org/10.1038/s41590-021-01110-0

[51] Aparicio-Domingo, Patricia, Monica Romera-Hernandez, Julien J. Karrich, Ferry Cornelissen, Natalie Papazian, Dicky J. Lindenbergh-Kortleve, James A. Butler, et al. 2015. “Type 3 Innate Lymphoid Cells Maintain Intestinal Epithelial Stem Cells After Tissue Damage.” Journal of Experimental Medicine 212: 1783-1791. https://doi.org/10.1084/jem.20150318

[52] Romera-Hernández, Mónica, Patricia Aparicio-Domingo, Natalie Papazian, Julien J. Karrich, Ferry Cornelissen, Remco M. Hoogenboezem, Janneke N. Samsom, and Tom Cupedo. 2020. “Yap1-Driven Intestinal Repair Is Controlled by Group 3 Innate Lymphoid Cells.” Cell Reports 30: 37-45.e3. https://doi.org/10.1016/j.celrep.2019.11.115

[53] Mortha, Arthur, Aleksey Chudnovskiy, Daigo Hashimoto, Milena Bogunovic, Sean P. Spencer, Yasmine Belkaid, and Miriam Merad. 2014. “Microbiota-Dependent Crosstalk Between Macrophages and ILC3 Promotes Intestinal Homeostasis.” Science 343: 1249288. https://doi.org/10.1126/science.1249288

[54] Castellanos, Jim G., Viola Woo, Monica Viladomiu, Gregory Putzel, Svetlana Lima, Gretchen E. Diehl, Andrew R. Marderstein, et al. 2018. “Microbiota-Induced TNF-Like Ligand 1A Drives Group 3 Innate Lymphoid Cell-Mediated Barrier Protection and Intestinal T Cell Activation During Colitis.” Immunity 49: 1077-1089.e5. https://doi.org/10.1016/j.immuni.2018.10.014

[55] Caronni, Nicoletta, Federica La Terza, Francesco M. Vittoria, Giulia Barbiera, Luca Mezzanzanica, Vincenzo Cuzzola, Simona Barresi, et al. 2023. “IL-1β⁺ Macrophages Fuel Pathogenic Inflammation in Pancreatic Cancer.” Nature 623: 415-422. https://doi.org/10.1038/s41586-023-06685-2

[56] Simats, Alba, Sijia Zhang, Denise Messerer, Faye Chong, Sude Beşkardeş, Aparna Sharma Chivukula, Jiayu Cao, et al. 2024. “Innate Immune Memory After Brain Injury Drives Inflammatory Cardiac Dysfunction.” Cell 187: 4637-4655.e26. https://doi.org/10.1016/j.cell.2024.06.028

[57] Jorssen, Joseph, Glenn Van Hulst, Kiréna Mollers, Julien Pujol, Georgios Petrellis, Antonio P. Baptista, Sjoerd Schetters, et al. 2024. “Single-Cell Proteomics and Transcriptomics Capture Eosinophil Development and Identify the Role of IL-5 in Their Lineage Transit Amplification.” Immunity 57: 1549-1566.e8. https://doi.org/10.1016/j.immuni.2024.04.027

[58] Abt, Michael C., Lisa C. Osborne, Laurel A. Monticelli, Travis A. Doering, Theresa Alenghat, Gregory F. Sonnenberg, Michael A. Paley, et al. 2012. “Commensal Bacteria Calibrate the Activation Threshold of Innate Antiviral Immunity.” Immunity 37: 158-170. https://doi.org/10.1016/j.immuni.2012.04.011

[59] Chun, Eunyoung, Sydney Lavoie, Diogo Fonseca-Pereira, Sena Bae, Monia Michaud, Hamid R. Hoveyda, Graeme L. Fraser, et al. 2019. “Metabolite-Sensing Receptor Ffar2 Regulates Colonic Group 3 Innate Lymphoid Cells and Gut Immunity.” Immunity 51: 871-884.e6. https://doi.org/10.1016/j.immuni.2019.09.014

[60] Trott, Oleg, and Arthur J. Olson. 2010. “AutoDock Vina: Improving the Speed and Accuracy of Docking With a New Scoring Function, Efficient Optimization, and Multithreading.” Journal of Computational Chemistry 31: 455-461. https://doi.org/10.1002/jcc.21334

[61] Kim, Daehwan, Ben Langmead, and Steven L. Salzberg. 2015. “HISAT: a Fast Spliced Aligner With Low Memory Requirements.” Nature Methods 12: 357-360. https://doi.org/10.1038/nmeth.3317

[62] Anders, Simon, Paul Theodor Pyl, and Wolfgang Huber. 2015. “HTSeq—A Python Framework to Work With High-Throughput Sequencing Data.” Bioinformatics 31: 166-169. https://doi.org/10.1093/bioinformatics/btu638

[63] Robinson, Mark D., Davis J. McCarthy, and Gordon K. Smyth. 2010. “edgeR: A Bioconductor Package for Differential Expression Analysis of Digital Gene Expression Data.” Bioinformatics 26: 139-140. https://doi.org/10.1093/bioinformatics/btp616

[64] Yu, Guangchuang, Ligen Wang, Yanyan Han, and Qingyu He. 2012. “Clusterprofiler: An R Package for Comparing Biological Themes Among Gene Clusters.” Omics: A Journal of Integrative Biology 16: 284-287. https://doi.org/10.1089/omi.2011.0118

RIGHTS & PERMISSIONS

2025 The Author(s). iMeta published by John Wiley & Sons Australia, Ltd on behalf of iMeta Science.