Microbial metabolism dysfunction induced by transarterial chemoembolization aggravates postprocedural liver injury in HCC.

Abstract

BACKGROUND & AIMS: Transarterial chemoembolization (TACE) is widely used to treat unresectable hepatocellular carcinoma (HCC). Liver injury induced by TACE (TACE-LI) is the most common complication and limits long-term outcomes. Beyond the conventional understanding of direct TACE-induced damage to normal liver tissue, the underlying mechanisms of TACE-LI remain unclear. We aimed to elucidate the relationship between gut microbiota disturbances and TACE-LI. METHODS: Microbial multi-omics analysis, genetically engineered bacteria and transcriptomics were used to study microbiota disturbances and host responses in TACE-LI. RESULTS: Rats with antibiotic-depleted gut microbiota, as well as rats receiving fecal transplants from donor rats or patients who had undergone TACE, exhibited more severe TACE-LI. Limosilactobacillus reuteri (L. reuteri) abundance was significantly reduced in TACE-treated rats and patients with HCC. Reduced L. reuteri abundance after TACE led to decreased levels of tryptophan metabolite indole-3-lactic acid (ILA), while administration of live L. reuteri or ILA provided effective protection against TACE-LI. Mechanistically, L. reuteri relied on the key enzyme phenyllactate dehydrogenase to generate ILA. ILA inhibits the ATPase activity of heat shock protein 90, thereby deactivating the NOD-like receptor protein 3-inflammasome in macrophages and suppressing hepatic pro-inflammatory responses. Reduced levels of L. reuteri and ILA were correlated with aggravated LI and poorer overall survival in TACE-treated patients with HCC. CONCLUSIONS: This is the first study to identify gut microbiota disturbance, i.e. deficiency of L. reuteri metabolite ILA, as a significant cause of TACE-LI. Administration of L. reuteri or ILA may serve as a promising therapeutic strategy to mitigate TACE-related adverse effects and improve prognosis in HCC. IMPACT AND IMPLICATIONS: Transarterial chemoembolization (TACE) is widely used to treat unresectable hepatocellular carcinoma (HCC), but its long-term outcomes are limited by liver injury (LI). Beyond direct ischemic- or chemotherapy-induced liver damage, the mechanisms underlying TACE-induced LI (TACE-LI) remain unclear. We found that TACE disturbs the gut microbiota, notably reducing levels of Limosilactobacillus reuteri (L. reuteri) and its metabolite indole-3-lactic acid (ILA). These reductions were associated with aggravated TACE-LI and poorer overall survival in patients with HCC. Administration of L. reuteri or ILA significantly alleviated TACE-LI by suppressing macrophage-driven inflammation. This study is the first to identify gut microbiota disturbances as a key contributor to TACE-LI. Supplementing L. reuteri or ILA represents a safe and promising strategy to prevent TACE-LI, reduce TACE-related adverse effects, and improve prognosis in patients with HCC.