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Here, we identify a mechanism in which bacterial tryptophan metabolism activates lysosomal activity to promote lipid breakdown in\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    , and show that the bacterial tryptophan metabolite indole recapitulates these effects in mammalian hepatocytes. By developing a lysosomal-responsive lipid reporter in\n                    <jats:italic>C. elegans<\/jats:italic>\n                    to screen for bacterial metabolic states that modulate host lipid storage, we discover that\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    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 \u03b2-oxidation through lysosomal lipase activity. This pathway was conserved in mammalian hepatocytes, where\n                    <jats:italic>E. coli<\/jats:italic>\n                    -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.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3003685","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T18:40:06Z","timestamp":1772131206000},"page":"e3003685","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Microbial tryptophan metabolism activates host lysosomal activity to facilitate lipid 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