Fucoidan alleviates chemotherapy-induced steatohepatitis by regulating the gut-liver axis.

CPT-11 treatment induced steatohepatitis in mice associated with intestinal barrier disruption.

• Mice were treated with CPT-11 (irinotecan) to establish a chemotherapy-induced steatohepatitis model.
• Intestinal barrier function was monitored using in vivo imaging.
• CPT-11-induced barrier disruption was identified as a key initiating event in hepatotoxicity.
• Steatohepatitis was described as a critical dose-limiting toxicity of CPT-11 clinical use.

CPT-11-induced intestinal barrier disruption allowed bacterial LPS to translocate to the liver, triggering neutrophil extracellular trap (NETs) formation.

• Barrier disruption permitted lipopolysaccharide (LPS) to reach the liver.
• Hepatic NETs formation was identified as a pivotal driver of hepatic inflammation in this model.
• The mechanism linking gut barrier dysfunction to liver injury was described as the gut-liver axis.
• NETs accumulation in the liver was characterized as a central pathological feature of CPT-11-induced steatohepatitis.

Fucoidan administration restored intestinal tight junction proteins in CPT-11-treated mice.

• Fucoidan is described as a fucose-rich sulfated polysaccharide.
• Treatment with fucoidan restored intestinal tight junction proteins disrupted by CPT-11.
• Restoration of tight junction proteins was associated with reduced LPS translocation from gut to liver.
• Fucoidan's effect on the intestinal barrier was a key component of its hepatoprotective mechanism.

Fucoidan partially improved gut microbiota composition in CPT-11-treated mice.

• CPT-11 treatment was associated with alterations in gut microbiota composition.
• Fucoidan administration partially improved gut microbiota composition.
• The partial nature of microbiota restoration was noted, suggesting additional mechanisms of fucoidan action.
• Gut microbiota modulation was identified as one component of fucoidan's multi-faceted protective effects.

Fucoidan suppressed hepatic NETs accumulation in CPT-11-treated mice.

• Fucoidan reduced hepatic NETs accumulation following CPT-11 treatment.
• Suppression of NETs was associated with reduced hepatic inflammation.
• The combination of gut barrier restoration and NETs suppression was described as the mechanism of fucoidan's hepatoprotection.
• Targeting NETs while preserving gut barrier integrity was proposed as a promising strategy to prevent chemotherapy-induced liver injury.

Depletion of gut microbiota with antibiotics worsened CPT-11-induced hepatotoxicity.

• Antibiotic treatment was used to deplete gut microbiota in CPT-11-treated mice.
• Microbiota depletion exacerbated rather than ameliorated CPT-11-induced hepatotoxicity.
• This finding was interpreted as suggesting 'the irreplaceability of fucoidan' in preserving microbiota during chemotherapy.
• The result indicated that an intact gut microbiota plays a protective role against CPT-11-induced liver injury.

The mechanism of irinotecan-induced steatohepatitis involves the gut-liver axis through intestinal barrier dysfunction leading to LPS translocation and subsequent NETs-driven hepatic inflammation.

• The study identified a mechanistic pathway: CPT-11 → intestinal barrier disruption → LPS translocation → hepatic NETs formation → steatohepatitis.
• The authors stated that 'the mechanism of irinotecan-induced steatohepatitis remains unclear' prior to this study.
• Fucoidan's hepatoprotective effects operated through multiple steps of this pathway.
• Targeting this gut-liver axis was proposed as 'a promising and practical strategy to prevent chemotherapy-induced liver injury.'