A commensal protozoan exacerbates acetaminophen-induced liver injury by producing free sphingosine.

The mechanisms by which the gut microbiota influence host disease outcomes remain poorly understood. As an integral yet overlooked component of this microbial community, the role of gut commensal protists in host physiology and pathology is even more ambiguous. Here, we show that the protozoan Tritrichomonas musculis (T. mu) remotely increases host sensitivity to drug-induced liver injury via the production of free sphingosine. Inhibiting sphingosine kinases (SPHKs) with PF543 or K145, or antagonizing sphingosine 1-phosphate receptor (S1PR) with FTY720, abolished the effect of T. mu-mediated exacerbation of acetaminophen (APAP)-induced liver injury (AILI), pointing to a sphingosine-SPHK1/2-S1P-S1PR axis underlying T. mu's remote modulation of hepatic drug sensitivity. Moreover, using U-¹³C‑palmitic acid and U-¹³C‑glucose metabolic flux tracing, we propose a novel model for sphingosine synthesis in T. mu. In this model, T. mu synthesizes sphingosine by using oxaloacetate, likely generated via the glyoxylate cycle, as a two‑carbon unit donor, rather than directly employing intact palmitic acid to supply the long‑chain carbon skeleton. Collectively, these findings not only deepen our understanding of how the gut microbiota, particularly the underappreciated gut protists, influence extra-intestinal disease outcomes via the gut-distal organ axis, but also reveal the tip of the iceberg regarding the unique metabolic pathways of gut commensal protists.