Intestinal Microbiota Mediates the Susceptibility to Polymicrobial Sepsis‐Induced Liver Injury by Granisetron Generation in Mice
Abstract
Sepsis‐induced liver injury is recognized as a key problem in intensive care units. The gut microbiota has been touted as an important mediator of liver disease development; however, the precise roles of gut microbiota in regulating sepsis‐induced liver injury are unknown. Here, we aimed to investigate the role of the gut microbiota in sepsis‐induced liver injury and the underlying mechanism. Cecal ligation and puncture (CLP) was used to induce polymicrobial sepsis and related liver injury. Fecal microbiota transplantation (FMT) was used to validate the roles of gut microbiota in these pathologies. Metabolomics analysis was performed to characterize the metabolic profile differences between sepsis‐resistant (Res; survived to 7 days after CLP) and sepsis‐sensitive (Sen; moribund before or approximately 24 hours after CLP) mice. Mice gavaged with feces from Sen mice displayed more‐severe liver damage than did mice gavaged with feces from Res mice. The gut microbial metabolic profile between Sen and Res mice was different. In particular, the microbiota from Res mice generated more granisetron, a 5‐hydroxytryptamine 3 (5‐HT 3) receptor antagonist, than the microbiota from Sen mice. Granisetron protected mice against CLP‐induced death and liver injury. Moreover, proinflammatory cytokine expression by macrophages after lipopolysaccharide (LPS) challenge was markedly reduced in the presence of granisetron. Both treatment with granisetron and genetic knockdown of the 5‐HT 3A receptor in cells suppressed nuclear factor kappa B (NF‐кB) transactivation and phosphorylated p38 (p‐p38) accumulation in macrophages. Gut microbial granisetron levels showed a significantly negative correlation with plasma alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels in septic patients. Conclusion: Our study indicated that gut microbiota plays a key role in the sensitization of sepsis‐induced liver injury and associates granisetron as a hepatoprotective compound during sepsis development.
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Susceptibility to organ injury, especially in the brain, can be modulated by the intestinal microbiota.
“Previous studies have indicated that susceptibility to organ injury, especially in the brain, could be modulated by the intestinal microbiota (9–11).”
From Sepsis-Induced Gut Dysbiosis Mediates the Susceptibility to Sepsis-Associated Encephalopathy in Mice (2022) · cites this paper as [9]
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Self-citationSepsis-Induced Gut Dysbiosis Mediates the Susceptibility to Sepsis-Associated Encephalopathy in Mice
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“FMT was performed according to the modified method described elsewhere (9).”
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“The CLP model was prepared with mice as described previously.(57,58) Briefly, mice were anesthetized with 1.”
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- Authors
- Gong, S., Yan, Z., Liu, Z., Niu, M., Fang, H., Li, N., Huang, C., Li, L., Chen, G., Luo, H., Chen, X., Zhou, H., Hu, J., Yang, W., Huang, Q., Schnabl, B., Chang, P., Billiar, T. R., Jiang, Y., & Chen, P.
- Affiliations
- Zhujiang Hospital (CN)
- Southern Medical University (CN)
- University of California San Diego (US)
- University of Pittsburgh (US)
- Corresponding author
- Chang, Ping
- Jiang, Yong
- Chen, Peng
- ORCID
- Venue
- Hepatology
- Published
- 2019-03-05
- Volume
- 69
- Issue
- 4
- Pages
- 1751-1767
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- OpenAlex
- W2902368543
- Cited by
- 188
- References
- 49
- Citations by year
- 2026: 27 · 2025: 28 · 2024: 32 · 2023: 32 · 2022: 25 · 2021: 25 · 2020: 14 · 2019: 5
- FWCI
- 8.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81372030)
- Topics
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
- Keywords
- gut microbiota, sepsis-induced liver injury, polymicrobial sepsis, granisetron, 5-HT3 receptor, hepatoprotection, cecal ligation and puncture, fecal microbiota transplantation, lipopolysaccharide, NF-κB signaling, p38 MAPK, sepsis susceptibility, alanine aminotransferase, aspartate aminotransferase
- MeSH terms
- RAW 264.7 Cells, Gastrointestinal Microbiome, Animals, Humans, Liver Diseases, Male, Mice, Inbred C57BL, Cytokines, NF-kappa B, Granisetron, Sepsis, Cytochrome P-450 CYP1A1, Receptors, Serotonin, 5-HT3, Toll-Like Receptor 4, Mice, Coinfection
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