Oral ampicillin inhibits liver regeneration by breaking hepatic innate immune tolerance normally maintained by gut commensal bacteria
Abstract
Unlabelled Commensal bacteria have been proposed to play a role in liver repair after partial (67%) hepatectomy. However, the underlying immune mechanisms remain elusive. Here, we show that liver regeneration was impaired in antibiotic (Atb) water-treated mice and this impairment strongly correlated with commensal bacterial load. Among the various Atbs used in our cocktail, ampicillin-sensitive commensal bacterial was associated with normal liver regeneration. The number of CD1d-dependent natural killer T (NKT) cells in Atb-treated hepatectomized mice was markedly increased, and these NKT cells were functionally overactivated to produce higher interferon-γ. Deficiency of NKT cells or antibody blockade of the CD1d-NKT interaction increased hepatocyte proliferation, which improved liver regeneration. Importantly, an increased number of Kupffer cells were observed in Atb-treated mice, and these Kupffer cells produced higher interleukin-12, which then functioned to activate hepatic NKT cells. Interleukin-12p40 deficiency or treatment with an anti-interleukin-12 antibody significantly inhibited NKT cell overactivation and recovered liver regeneration in Atb-treated mice. Conclusion Commensal bacteria play a critical role in maintaining Kupffer cells in a tolerant state, preventing subsequent NKT cell overactivation during liver regeneration. Moreover, our data suggest that long-term Atb use, which can impair the gut microbiota, may influence liver function by retarding liver regen…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Gut microbiota plays a role in liver regeneration.
“The postulate that gut microbiota plays a role in LR is further supported by studies showing that antibiotic treatment impairs LR following PH.”
From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [47]
Antibiotic treatment impairs liver regeneration following partial hepatectomy.
“The postulate that gut microbiota plays a role in LR is further supported by studies showing that antibiotic treatment impairs LR following PH.”
From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [47]
The use of antibiotics reduces both liver mass recovery and the expression of proliferative markers proliferating cell nuclear antigen and Bromodeoxyuridine (BrdU).
“Research has demonstrated that the use of antibiotics reduces both liver mass recovery and the expression of proliferative markers - proliferating cell nuclear antigen and Bromodeoxyuridine (BrdU).”
From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [47]
Cites
Kim, Y.-G., Udayanga, K. G. S., Totsuka, N., Weinberg, J. B., Núñez, G., & Shibuya, A. (2014) · Cell Host & Microbe · doi:10.1016/j.chom.2013.12.010 · Cited by 366 · see citing works
Wang, J., Li, F., Sun, R., Gao, X., Wei, H., Li, L.-J., & Tian, Z. (2013) · Nature Communications · doi:10.1038/ncomms3106 · Cited by 239 · see citing works
Self-citationT cell-derived lymphotoxin regulates liver regeneration
Tumanov, A. V., Koroleva, E. P., Christiansen, P. A., Khan, M. A., Ruddy, M. J., Burnette, B., Papa, S., Franzoso, G., Nedospasov, S. A., Fu, Y., et al. (2009) · Gastroenterology · doi:10.1053/j.gastro.2008.09.015 · Cited by 89 · see citing works
Corbitt, N., Kimura, S., Isse, K., Specht, S., Chedwick, L., Rosborough, B. R., Lunz, J. G., Murase, N., Yokota, S., & Demetris, A. J. (2013) · The American Journal of Pathology · doi:10.1016/j.ajpath.2012.09.010 · Cited by 87 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Kennedy, E. A., King, K. Y., & Baldridge, M. T. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.01534 · Cited by 602 · see citing works
Gut microbiome and liver diseases
Tilg, H., Cani, P. D., & Mayer, E. A. (2016) · Gut · doi:10.1136/gutjnl-2016-312729 · Cited by 525 · see citing works
Gut microbiome, liver immunology, and liver diseases
Wang, R., Tang, R., Li, B., Ma, X., Schnabl, B., & Tilg, H. (2021) · Cellular & Molecular Immunology · doi:10.1038/s41423-020-00592-6 · Cited by 466 · see citing works
Gut‐liver axis at the frontier of host‐microbial interactions
Brandl, K., Kumar, V., & Eckmann, L. (2017) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00361.2016 · Cited by 201 · see citing works
Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics
Ma, X., Huang, T., Chen, X., Li, Q., Liao, M., Fu, L., Huang, J., Yuan, K., Wang, Z., & Zeng, Y. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02104-8 · Cited by 133 · see citing works
Demircan, T., Ovezmyradov, G., Yıldırım, B., Keskin, İ., İlhan, A. E., Fesçioğlu, E. C., Öztürk, G., & Yıldırım, S. (2018) · Scientific Reports · doi:10.1038/s41598-018-29373-y · Cited by 45 · see citing works
Liver regeneration after partial hepatectomy: Triggers and mechanisms
Korchilava, B., Khachidze, T., Megrelishvili, N., Svanadze, L., Kakabadze, M., Tsomaia, K., Jintcharadze, M., & Kordzaia, D. (2025) · World Journal of Hepatology · doi:10.4254/wjh.v17.i7.107378 · Cited by 21 · see citing works
- Authors
- Wu, X., Sun, R., Chen, Y., Zheng, X., Bai, L., Lian, Z., Wei, H., & Tian, Z.
- Affiliations
- University of Science and Technology of China (CN)
- Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center,University of Science & Technology of China,Hefei,Anhui,China
- Corresponding author
- Tian, Zhigang
- Venue
- Hepatology
- Published
- 2015-04-22
- Volume
- 62
- Issue
- 1
- Pages
- 253-264
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- OpenAlex
- W1923374739
- Cited by
- 71
- References
- 4
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 6 · 2023: 10 · 2022: 6 · 2021: 1 · 2020: 12 · 2019: 4 · 2018: 9 · 2017: 5 · 2016: 4 · 2015: 2
- FWCI
- 3.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81361120388, #31390433)
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- liver regeneration, gut commensal bacteria, NKT cells, CD1d, Kupffer cells, IL-12, interferon-gamma, antibiotic-induced dysbiosis, partial hepatectomy, hepatocyte proliferation
- MeSH terms
- Ampicillin, Animals, Anti-Bacterial Agents, Immune Tolerance, Immunity, Innate, Kupffer Cells, Liver Regeneration, Male, Mice, Inbred C57BL, Symbiosis, Gastrointestinal Tract, Natural Killer T-Cells, Microbiota
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
