Letter to Editor: Carbon Tetrachloride–Induced Classical Liver Cirrhosis Model: Revisiting the Mode of Action
Authors: Priyankar Dey
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. To the Editor: I read with interest the study by Munoz et al.1 that showed carbon tetrachloride (CCl4)–associated intestinal dysbiosis and altered immune phenotype. Although no hepatic parameters were reported, ileal‐centric data collectively showed that CCl4 oral gavage induced an intestinal proinflammatory phenotype and gut‐barrier dysfunction in association with a bloom of endotoxin‐rich, gram‐negative bacteria. These data are consistent with the gut‐associated etiology of progressive liver disease and metabolic anomalies that centers on gut dysbiosis and loss of barrier function, allowing gut‐to‐hepatic endotoxin translocation through the portal circulation. Zhang et al.2 also recently showed that CCl4 induced modulation of gut microbial abundance, diversity, and functions. Consistent with cytochrome P450–mediated xenobiotic metabolism, they showed enrichment of microbial drug‐metabolism pathways due to CCl4 treatment. Indeed, both studies reported increased Bacteroidetes and decreased Firmicutes associated with CCl4 treatment. Interestingly, although the mechanism remains unclear, Munoz et al.1 emphasized the liver–gut axis (rather the gut–liver axis), claiming that CCl4‐induced hepatic cirrhosis induces intestinal immune dysfunction. That CCl4 treatment affects intestinal microbiota to induce hepatic cirrhosis was validated in antibiotic‐treated rats, which had less severe cirrhosis with CCl4. Also that CCl4‐mediated hepatic injury is in part microbiota‐dependent was shown by hepatoprotection through probiotic treatment, besides demonstrating CCl4‐mediated alterations in gut microbiota.3 As a well‐accepted and extensively studied (yet not well characterized) classical experimental model of hepatic cirrhosis, CCl4 upon oral administration is absorbed in the gastrointestinal tract prior to hepatic translocation. Trichloromethyl radical, i.e., the cytochrome P450–mediated dehalogenation product of CCl4, causes havoc to the hepatic signaling and architecture, primarily through oxidative damage. The bottom line is that the consideration of CCl4‐dependent direct hepatotoxicity seems to be in part rejected by such findings,1 demonstrating the profound effect of CCl4 on the gut microbiota. Therefore, apart from direct hepatotoxicity, these alternative reports support the idea of a microbiota‐dependent role of CCl4 in triggering hepatic cirrhosis and emphasize reconsideration of its mode of action along the gut–liver axis. Considering the dynamic interaction between the luminal microbiota and mucosal immune system along the intestinal length, which depends on several host and microbial factors (e.g., nutrients, hypoxia, microbial load), a thorough intestinal investigation would be essential. Also, that no metabolic parameters were reported and a detailed microbial profiling (e.g., diversity, functionality) was lacking partially limit the understanding of CCl4–microbiota–metabolism interactions. Nevertheless, these discoveries have opened frontiers for CCl4 as a metabolic disease model; it is high time to reconsider the microbiota‐dependent alternative mode of action of CCl4.