Subchronic Oral Cylindrospermopsin Exposure Alters the Host Gut Microbiome and Is Associated with Progressive Hepatic Inflammation, Stellate Cell Activation, and Mild Fibrosis in a Preclinical Study

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...

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Bibliographic Details
Published in:	Toxins Vol. 14; no. 12; p. 835
Main Authors:	Saha, Punnag, Upright, Macayla, Bose, Dipro, Roy, Subhajit, Trivedi, Ayushi, More, Madhura, Scott, Geoff I, Brooks, Bryan W, Chatterjee, Saurabh
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 01-12-2022 MDPI
Subjects:	Abundance Analysis Animals Carcinoma, Hepatocellular - metabolism Cell activation Climate change Cyanobacteria Cylindrospermopsin Damage patterns Development and progression Digestive system Drinking water Dysbacteriosis Dysbiosis Endotoxemia Epidemiology Exposure Fibrosis Flora Freshwater lakes Gastrointestinal diseases Gastrointestinal Microbiome - physiology Gastrointestinal tract gut microbiome Health aspects Hepatocellular carcinoma Hepatotoxicity HMGB1 Humans Inflammation Inflammation - metabolism Intestinal microflora Intestine Kupffer Cells - metabolism Kupffer Cells - pathology Leaching Liver Liver - metabolism Liver Cirrhosis - pathology Liver diseases Liver Neoplasms - metabolism Marine toxins Metabolism Metabolites Mice Microbiomes Microbiota Microbiota (Symbiotic organisms) Pathogens Pathology Pharmacokinetics Probiotics Toll-like receptors Water quality United States cylindrospermopsin gut microbiome HMGB1 hepatotoxicity
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Summary:	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 and decreased abundance of probiotic flora such as , and , 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.
ISSN:	2072-6651 2072-6651
DOI:	10.3390/toxins14120835