# Microbial tryptophan metabolism activates host lysosomal activity to facilitate lipid breakdown

## TL;DR

This study shows how gut bacteria metabolize tryptophan to produce indole, which activates lysosomes in worms and human liver cells to break down lipids.

## Contribution

The novel finding is that microbial tryptophan metabolism, specifically via indole, activates lysosomal activity to enhance lipid breakdown in both C. elegans and mammalian cells.

## Key findings

- Bacterial tryptophan catabolism via TnaA induces lysosomal lipid chaperone LBP-8 to mobilize lipids in C. elegans.
- Indole, a tryptophan metabolite, enhances lysosomal acidification and degradation in mammalian hepatocytes.
- Lysosomal lipase activity promotes mitochondrial β-oxidation, and this pathway is conserved across species.

## Abstract

Lysosomes are central to lipid metabolism, yet how gut microbiota-derived metabolites regulate lysosomal function to influence host lipid homeostasis remains unknown. Here, we identify a mechanism in which bacterial tryptophan metabolism activates lysosomal activity to promote lipid breakdown in Caenorhabditis elegans, and show that the bacterial tryptophan metabolite indole recapitulates these effects in mammalian hepatocytes. By developing a lysosomal-responsive lipid reporter in C. elegans to screen for bacterial metabolic states that modulate host lipid storage, we discover that Escherichia coli tryptophan catabolism via tryptophanase TnaA induces lysosomal lipid chaperone LBP-8, driving lipid mobilization. Moreover, tryptophan metabolite indole enhanced lysosomal acidification and degradation capacity, while genetic disruption of lysosomal regulators reversed these effects. Strikingly, bacterial tryptophan metabolism further promoted mitochondrial β-oxidation through lysosomal lipase activity. This pathway was conserved in mammalian hepatocytes, where E. coli-derived tryptophan metabolite indole enhances lysosomal function and reduce lipid accumulation. Our work uncovers microbiota-regulated lysosomal activation as a critical axis in lipid homeostasis, highlighting its potential as a therapeutic target for metabolic disorders linked to lysosomal dysfunction.

Microbial derived metabolites are known to influence host physiology. This study expands the mechanistic understanding of this relationship, by showing that microbial production of indole from bacterial tryptophan catabolism enhances lysosomal acidification and lipase activity in a C. elegans host and in mammalian hepatocytes.