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

Abstract

Background & aims: Transarterial chemoembolization (TACE) is widely used for treating unresectable hepatocellular carcinoma (HCC). Liver injury induced by TACE (TACE-LI) is the most common complication of TACE which limits long-term outcomes of HCC. Beyond traditional cognition of the direct damage induced by TACE on normal liver tissue, deeper mechanism underlying TACE-LI remains unclear. We aimed to further elucidate the unclear 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 gut microbiota depleted by antibiotics and rats that received fecal transplants from donor rats or HCC patients that had undergone TACE showed 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 (fldH) to generate ILA, which inhibited the ATPase activity of heat shock protein 90 to deactivate NOD-like receptor protein 3-inflammasome in macrophages and suppressed hepatic pro-inflammatory response. Reduced levels of L. reuteri and ILA were correlated with aggravated LI and poor 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 significant cause of TACE-LI. L. reuteri and ILA administration serves as promising therapeutic approach for TACE-LI, which is crucial for reducing TACE adverse effects to achieve better prognosis in HCC.

Impact and implications: The majority of patients with hepatocellular carcinoma (HCC) are diagnosed losing the chance of surgical resection. Transarterial chemoembolization (TACE) is widely used for treating unresectable HCC; however, its long-term outcome is significantly limited by its main complication, i.e., liver injury (LI). In addition to traditional cognition of the direct liver damage of the ischemic necrosis or regional chemotherapy induced by TACE, the deeper mechanisms underlying TACE-induced LI (TACE-LI) remain largely unclear. Gut microbiota can modulate various liver diseases but its exact role in TACE-LI has not been reported. We found that TACE could disturb the gut microbiota. This disturbance was characterized by reduced levels of Limosilactobacillus reuteri (L. reuteri) and its metabolite indole-3-lactic acid (ILA), which were correlated with aggravated TACE-LI and poor overall survival in HCC. Administration of L. reuteri or ILA significantly improved TACE-LI by inhibiting the inflammation of macrophages. Our study is the first report highlighting gut microbiota disturbances as an important cause of TACE-LI; administration of L. reuteri or ILA represents a viable and secure strategy for preventing TACE-LI, thereby reducing the adverse effects of TACE and yielding better prognoses in patients with HCC.

Keywords: Limosilactobacillus reuteri; gut microbiota; hepatoprotective therapy; liver injury; transarterial chemoembolization.