Epidemiological studies have reported a strong association between liver injury and incidences of
hepatocellular carcinoma in sections of humans globally. Several preclinical studies have shown a strong link between cyanotoxin exposure and the development of
nonalcoholic steatohepatitis, a precursor of
hepatocellular carcinoma. Among the emerging threats from
cyanotoxins, new evidence shows
cylindrospermopsin release in freshwater lakes. A known hepatotoxin in higher concentrations, we examined the possible role of
cylindrospermopsin in causing host gut
dysbiosis and its association with liver pathology in a mouse model of toxico-pharmacokinetics and hepatic pathology. The results showed that oral exposure to
cylindrospermopsin caused decreased diversity of gut bacteria phyla accompanied by an increased abundance of Clostridioides difficile and decreased abundance of probiotic flora such as Roseburia, Akkermanssia, and Bacteroides thetaiotamicron, a signature most often associated with intestinal and hepatic pathology and underlying
gastrointestinal disease. The altered gut
dysbiosis was also associated with increased Claudin2
protein in the intestinal lumen, a marker of gut leaching and
endotoxemia. The study of liver pathology showed marked liver
inflammation, the release of damage-associated molecular patterns, and activation of
toll-like receptors, a hallmark of consistent and progressive liver damage. Hepatic pathology was also linked to increased Kupffer cell activation and stellate cell activation, markers of progressive liver damage often linked to the development of
liver fibrosis and
carcinoma. In conclusion, the present study provides additional evidence of
cylindrospermopsin-linked progressive liver pathology that may be very well-linked to gut
dysbiosis, though definitive evidence involving this link needs to be studied further.