PP387 - GUT-DERIVED INDOLE-3-LACTIC ACID EXACERBATES ADIPOSE TISSUE LOSS IN CANCER CACHEXIA BY SUPPRESSING ADIPOGENIC SIGNALING

PP387

GUT-DERIVED INDOLE-3-LACTIC ACID EXACERBATES ADIPOSE TISSUE LOSS IN CANCER CACHEXIA BY SUPPRESSING ADIPOGENIC SIGNALING

J. Zheng¹, W. Sun¹, X. Shen^1,*

¹The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

Rationale: This study aims to investigate whether gut dysbiosis mediates adipose metabolic reprogramming via specific metabolites and thereby drives the cachexia process.

Methods: The cachexia mouse model (C26) was established. Fecal 16S rRNA gene sequencing and serum metabolomic profiling were performed to screen for the microbiota-specific metabolite ILA. The effects of ILA supplementation were assessed by evaluating white adipose tissue mass, adipocyte area, and lipid droplet size to determine the extent of depletion. The PPAR signaling pathway was examined to validate adipogenic differentiation capacity. Bulk RNA-seq of tissues and cells was conducted using the Illumina platform. FMT and dietary intervention were employed to confirm the correlation between gut microbiota and ILA. Serum samples were collected from colorectal cancer patients with and without cachexia for clinical validation.

Results: ILA intervention, both in vivo and in vitro, inhibited adipocyte maturation via the AHR–ERK–PPARG signaling axis and accelerated body weight loss in cachectic mice. Anti AHR partially alleviated adipose tissue loss and restored adipogenic capacity. Transplantation of fecal microbiota from cachectic mice or a high ILA-producing strain reproduced elevated serum ILA level and reduced white adipose tissue content. Concurrently, reducing dietary tryptophan intake restored PPARG activity and enhanced adipogenesis. Serum ILA level was significantly elevated in colorectal cancer patients with cachexia and showed a negative correlation with both subcutaneous and visceral fat index.

Conclusion: Elevated levels of gut microbiota-associated indole-3-lactic acid promote adipose tissue loss via the AHR–ERK–PPARG signaling pathway. Targeting this pathway can partially restore adipogenesis and adipose tissue mass.

Disclosure of Interest: None declared