The metabolites of gut microbiota: their role in ferroptosis in inflammatory bowel disease Original paper

What was reviewed?

This review examined how gut microbiota–derived metabolites shape ferroptosis pathways in inflammatory bowel disease (IBD), with the goal of explaining how microbe-host chemistry may worsen or calm epithelial injury in Crohn’s disease and ulcerative colitis. The authors centered the discussion on three metabolite families that change in IBD and plausibly regulate ferroptosis in intestinal epithelial cells: short-chain fatty acids (SCFAs), tryptophan-derived indoles and related products, and bile acids.

Who was reviewed?

The article synthesized evidence from clinical observations in people with IBD (including differences in fecal metabolites and inferred microbial shifts) and from mechanistic studies in cell and animal colitis models that measure ferroptosis features such as iron accumulation, glutathione depletion, GPX4 suppression, and lipid peroxidation in intestinal epithelial cells. It also drew on studies of microbiota-targeted interventions to connect microbial ecology with ferroptosis-linked inflammation.

What were the most important findings?

The review links IBD activity to a ferroptosis-prone intestinal environment driven by oxidative stress, iron handling, and lipid peroxidation, and it argues that microbial metabolites can push this balance toward injury or protection through pathways that converge on System Xc− (SLC7A11), GPX4, and Nrf2/HO-1 signaling. As major microbial associations relevant to a signatures database, the paper highlights that IBD commonly shows lower SCFAs and fewer butyrate-associated taxa, including reduced Lachnospiraceae and Faecalibacterium prausnitzii, plus a reported reduction in Roseburia hominis, patterns that align with weaker barrier support and less anti-inflammatory tone. It also describes bile acid remodeling in active IBD—higher conjugated bile acids with lower secondary bile acids—and emphasizes that secondary bile acids such as lithocholic acid (LCA) and deoxycholic acid (DCA) can signal through FXR/TGR5 to influence inflammation and ferroptosis, while excess DCA can promote iron-driven epithelial ferroptosis and inflammasome activation. Finally, the review connects altered tryptophan metabolism to reduced microbe-derived AhR ligands and impaired barrier repair, while proposing that kynurenine and other tryptophan products can counter ferroptosis by lowering reactive oxygen species and limiting lipid peroxidation.

What are the greatest implications of this review?

For clinicians, the key implication is that ferroptosis is not just a cell-death label in IBD; it is a metabolite-sensitive injury program that the gut microbiome can tune, which makes microbial metabolites and their upstream microbial producers plausible biomarkers and treatment levers. The review supports a practical framework: restore SCFA-linked functions (barrier support, anti-inflammatory signaling, mitochondrial resilience), normalize bile acid signaling (FXR/TGR5 balance and secondary bile acid recovery), and rebuild tryptophan–AhR ligand activity to reduce epithelial oxidative stress and ferroptosis pressure. It also cautions that microbiota-directed therapies (antibiotics, probiotics, prebiotics, and fecal microbiota transplantation) may help by shifting these metabolite pools, but variability across patients and incomplete mechanism-to-clinic translation still limit precision use today.