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Relationship Between Adverse Events and Microbiomes in Advanced Hepatocellular Carcinoma Patients Treated With
Kenta Yamamoto1, Teiji Kuzuya1, Takashi Honda2
1Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Background/Aim:
Sorafenib results in several adverse events, the mechanism and predictors of which are unknown. Recently, it was reported that metabolism by microbiome changes the structure and effects of drugs. The blood levels of sorafenib may be affected by enterohepatic recycling of sorafenib due to microbial enzymes in the gut. We evaluated the relationship between adverse events caused by sorafenib treatment and microbiome in patients with advanced hepatocellular carcinoma.
Materials And Methods:
Twenty-five patients were classified into two groups based on the presence of hand-foot syndrome (HFS) or diarrhea within 12 weeks post-sorafenib treatment. Before sorafenib treatment, the fecal samples were analyzed targeting the V3-V4 region of 16s ribosomal RNA. Microbiome and predicted functional gene were compared between two groups.
Results:
The non-HFS group had a richer abundance of Veillonella, Bacillus, Enterobacter, Faecalibacterium, Lachnospira, Dialister, and Anaerostipes than the HFS group at genus level. Carotenoid biosynthesis and bacterial invasion of epithelial cells were enriched in the HFS group. The former three bacteria are classified as oral-origin bacteria, and the two predicted functions are associated with dysbiosis. The non-diarrhea group had a higher abundance of Butyricimonas and a lower abundance of Citrobacter, Peptostreptococcus, and Staphylococcaceae than the diarrhea group. Eight categories of predicted functional genes were detected with differences between the two groups.
Conclusion:
The non-HFS group had a higher relative abundance of oral-origin bacteria, which likely led to more robust dysbiosis in the gut. This dysbiosis may affect enterohepatic recycling. Additionally, the metabolism of these short-chain fatty acids in the gut may be different between the diarrhea and non-diarrhea groups.
Insights
Gut microbiome alterations are linked to sorafenib adverse events like hand-foot syndrome and diarrhea in advanced hepatocellular carcinoma patients. Oral-origin bacteria may contribute to dysbiosis, impacting drug metabolism and enterohepatic recycling.
Area of Science:
- Microbiome research
- Hepatocellular carcinoma treatment
- Pharmacology
Background:
- Sorafenib, a treatment for advanced hepatocellular carcinoma, causes adverse events with unknown mechanisms.
- Gut microbiome metabolism can alter drug structure and effects, potentially influencing sorafenib's enterohepatic recycling and blood levels.
Purpose of the Study:
- To investigate the relationship between gut microbiome composition and sorafenib-induced adverse events (hand-foot syndrome and diarrhea).
- To identify potential microbiome-based predictors of sorafenib toxicity in advanced hepatocellular carcinoma patients.
Main Methods:
- Fecal samples from 25 advanced hepatocellular carcinoma patients were analyzed using 16S rRNA sequencing before sorafenib treatment.
- Patients were categorized based on the development of hand-foot syndrome or diarrhea within 12 weeks of treatment.
- Microbiome composition and predicted functional genes were compared between patient groups.
Main Results:
- The hand-foot syndrome group showed enrichment in carotenoid biosynthesis and bacterial invasion of epithelial cells, associated with dysbiosis.
- Oral-origin bacteria (Veillonella, Bacillus, Enterobacter) were more abundant in the non-hand-foot syndrome group.
- Microbial differences were also observed between patients who did and did not develop diarrhea, with altered abundance of specific genera and functional gene categories.
Conclusions:
- A higher relative abundance of oral-origin bacteria in the gut may be associated with dysbiosis, potentially influencing sorafenib's enterohepatic recycling.
- Gut dysbiosis could be a contributing factor to sorafenib-induced adverse events.
- Differences in gut microbial metabolism may explain variations in sorafenib-related diarrhea.
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