Macrophage-augmented intestinal organoids model virus-host interactions in enteric viral diseases and facilitate therapeutic development

  • Nat Commun. 2025 May 14;16(1):4475. doi: 10.1038/s41467-025-59639-9.
Guige Xu  #  1  2  3 ,  Jiangrong Zhou  #  2 ,  Kuan Liu  #  2  4 ,  Yining Wang  2 ,  Theano Tsikari  5 ,  Fang Qin  6 ,  Francijna van den Hil  5 ,  Patrick P C Boor  2 ,  Ibrahim Ayada  2 ,  Annemarie C de Vries  2 ,  Jiajing Li  2 ,  Shijin Jiang  1 ,  Dewy M Offermans  2 ,  Denis E Kainov  7 ,  Harry L A Janssen  2  8 ,  Maikel P Peppelenbosch  2 ,  Marcel J C Bijvelds  2 ,  Wenshi Wang  6 ,  Valeria V Orlova  5 ,  Qiuwei Pan  2 ,  Pengfei Li  9  10
Affiliations
  • 1. Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, Shandong, 271018, China.
  • 2. Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
  • 3. Precision Medicine Translational Research Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 4. Department of Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands.
  • 5. Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands.
  • 6. Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, 221004, China.
  • 7. Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7028, Trondheim, Norway.
  • 8. Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
  • 9. Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands. [email protected].
  • 10. Precision Medicine Translational Research Center, West China Hospital, Sichuan University, Chengdu, 610041, China. [email protected].
  • # Contributed equally.
PMID: 40368896 DOI: 10.1038/s41467-025-59639-9
Abstract

The pathogenesis of enteric viral infections is attributed to both viral replication and the resultant immune-inflammatory response. To recapitulate this complex pathophysiology, we engineer macrophage-augmented organoids (MaugOs) by integrating human macrophages into primary intestinal organoids. Echovirus 1, echovirus 6, rotavirus, seasonal coronavirus OC43 and SARS-CoV-2- known to directly invade the intestine- are used as disease modalities. We demonstrate that these viruses efficiently propagate in MaugOs and stimulate the host Antiviral response. However, rotavirus, coronavirus OC43 and SARS-CoV-2, but not the two echoviruses, trigger inflammatory responses. Acetate, a microbial metabolite abundantly present in the intestine, potently inhibits virus-induced inflammatory responses in MaugOs, while differentially affecting viral replication in macrophages and organoids. Furthermore, we provide a proof-of-concept of combining Antiviral agent with either anti-inflammatory regimen or acetate to simultaneously inhibit viral Infection and inflammatory response in MaugOs. Collectively, these findings demonstrate that MaugOs are innovative tools for studying the complex virus-host interactions and advancing therapeutic development.

Products