Microbiota-derived IPA protects against colitis by regulating intestinal HMGCS2-mediated ketogenesis to facilitate mucosal healing.

IPA activates PPARα in intestinal epithelial cells to enhance transcription of the ketogenic enzyme HMGCS2.

• IPA (indole-3-propionic acid) is a tryptophan-derived bacterial metabolite identified as a key regulator of mucosal healing.
• PPARα activation by IPA upregulates HMGCS2 (3-hydroxy-3-methylglutaryl-CoA synthase 2) at the transcriptional level.
• This represents a direct mechanistic link between a microbial metabolite and epithelial ketogenic enzyme expression.

HMGCS2-mediated ketogenesis produces β-hydroxybutyrate (BHB), which stimulates LGR5+ intestinal stem cells to accelerate epithelial regeneration.

• BHB (β-hydroxybutyrate) is the downstream ketone body produced via HMGCS2 activity in intestinal epithelial cells.
• BHB stimulates LGR5+ intestinal stem cells, which are the primary cells responsible for intestinal epithelial regeneration.
• This establishes a microbiota-metabolite-stem cell axis: IPA → PPARα → HMGCS2 → BHB → LGR5+ stem cell activation.

Germ-free models demonstrated that dietary tryptophan and specific commensals sustain luminal IPA levels critical for colitis recovery.

• Germ-free models were used to establish the relationship between microbial colonization, tryptophan metabolism, and IPA production.
• Peptostreptococcus russellii was identified as an IPA-producing commensal bacterium.
• Dietary tryptophan availability influences luminal IPA concentrations, linking diet-microbiota interactions to mucosal healing capacity.

Restoration of IPA or BHB attenuates inflammation and barrier defects in colitis models.

• Both IPA supplementation and BHB supplementation were independently capable of attenuating colitis-associated inflammation.
• Barrier defects, a hallmark of inflammatory bowel disease, were also reduced by restoration of either metabolite.
• These findings suggest that either component of the IPA-BHB axis could serve as a therapeutic target.

IPA levels are reduced in colitis, and the IPA-HMGCS2-BHB axis is critical for mucosal healing.

• Luminal IPA levels are critical for recovery in colitis, implying that IPA depletion contributes to impaired mucosal healing.
• The axis connects gut microbiota composition (IPA producers such as P. russellii) to epithelial repair mechanisms.
• Disruption of this axis (e.g., in dysbiosis or germ-free conditions) compromises the ketogenic response in intestinal epithelial cells.

The microbiota-metabolite-stem cell axis identified represents a potential therapeutic target for inflammatory bowel disease and other barrier disorders.

• The IPA → PPARα → HMGCS2 → BHB → LGR5+ stem cell pathway is outlined as a therapeutically targetable axis.
• Therapeutic strategies could include dietary tryptophan supplementation, administration of IPA-producing bacteria such as P. russellii, or direct BHB supplementation.
• The findings are proposed to be relevant beyond IBD, extending to other barrier disorders.