Naringenin Alleviates 5-Fluorouracil-Induced Intestinal Mucositis via Modulating the Gut Microbiota, Bile Acid Metabolism, and PPAR Signaling Pathway.

Naringenin alleviated weight loss and diarrhea in 5-fluorouracil-induced intestinal mucositis mice.

• The study used a mouse model of 5-fluorouracil (5-FU)-induced intestinal mucositis (IM).
• Naringenin (Nar) is a dihydroflavonoid compound present in citrus fruits.
• Nar treatment mitigated weight loss and diarrhea as clinical signs of IM.
• The protective effects were characterized as occurring 'largely via gut microecology-dependent mechanism.'

Naringenin reduced the inflammatory response and intestinal barrier damage in 5-FU-induced intestinal mucositis mice.

• Nar mitigated the inflammatory response associated with 5-FU-induced IM.
• Intestinal barrier damage was reduced following Nar treatment.
• Multiomics analysis was used to explore the mechanisms underlying these protective effects.
• These effects were characterized as being largely dependent on gut microecology.

Naringenin regulated specific intestinal flora associated with inflammation and bile acid metabolism as revealed by 16S rRNA sequencing.

• 16S rRNA sequencing was used to assess gut microbiota composition.
• Nar regulated intestinal flora including Parabacteroides, Actinobacteria, Muribaculaceae, Ruminiclostridium, Clostridium, and Proteobacteria.
• These microbial taxa are associated with inflammation and bile acid metabolism.
• The regulation of gut microbiota was identified as a key mechanism of Nar's protective effects.

Naringenin regulated abnormal secondary bile acids in 5-FU-induced intestinal mucositis mice as shown by targeted bile acid metabolomics.

• Targeted bile acid metabolomics was employed to assess bile acid profiles.
• Nar regulated three abnormal secondary bile acids: hyodeoxycholic acid, deoxycholic acid, and isochenodeoxycholic acid.
• These secondary bile acids were found to be abnormal in the IM mouse model.
• Bile acid metabolism dysregulation was identified as part of the IM pathology addressed by Nar.

Naringenin upregulated key components of the PPAR signaling pathway as demonstrated by transcriptomic and Western blot analysis.

• Transcriptomic analysis and Western blot were used to assess protein and gene expression levels.
• Nar upregulated the expression levels of peroxisome proliferator-activated receptor γ (PPARγ), stearoyl CoA desaturase 1 (SCD1), and phosphoenolpyruvate carboxykinase 1 (PEPCK1).
• These findings indicated that Nar's action mechanism is related to activation of the PPAR signaling pathway.
• The PPAR signaling pathway activation was identified as one of the multipathway mechanisms mediating Nar's anti-IM effects.

The study identified naringenin as a potential adjunctive treatment strategy for chemotherapy-induced intestinal toxicity in cancer patients.

• Naringenin demonstrated multipathway-mediated anti-IM effects.
• The three key pathways identified were gut microbiota regulation, bile acid metabolism, and PPAR signaling pathway activation.
• The findings indicate naringenin's 'promising potential as an adjunctive treatment strategy for chemotherapy-induced intestinal toxicity in cancer patients.'
• The study employed a multiomics approach combining 16S rRNA sequencing, targeted bile acid metabolomics, and transcriptomics.