Animals; Disease Models, Animal; Environmental Exposure (adverse effects); Gastrointestinal Microbiome (drug effects); Inflammation (chemically induced, enzymology, microbiology, pathology); Intestinal Diseases (chemically induced, enzymology, microbiology, pathology); Male; Mice; Mice, Knockout; Microcystins (administration & dosage, pharmacology); NADPH Oxidase 2 (metabolism); Non-alcoholic Fatty Liver Disease (enzymology, microbiology, pathology)
With increased climate change pressures likely to influence harmful algal blooms, exposure to microcystin, a known hepatotoxin and a byproduct of cyanobacterial blooms can be a risk factor for NAFLD associated comorbidities. Using both in vivo and in vitro experiments we show that microcystin exposure in NAFLD mice cause rapid alteration of gut microbiome, rise in bacterial genus known for mediating gut inflammation and lactate production. Changes in the microbiome were strongly associated with inflammatory pathology in the intestine, gut leaching, tight junction protein alterations and increased oxidative tyrosyl radicals. Increased lactate producing bacteria from the altered microbiome was associated with increased NOX-2, an NADPH oxidase isoform. Activationof NOX2 caused inflammasome activation as shown by NLRP3/ASCII and NLRP3/Casp-1 colocalizations in these cells while use of mice lacking a crucial NOX2 component attenuated inflammatory pathology and redox changes. Mechanistically, NOX2 mediated peroxynitrite species were primary to inflammasome activation and release of inflammatory mediators. Thus, in conclusion, microcystin exposure in NAFLD could significantly alter intestinal pathology especially by the effects on microbiome and resultant redox status thus advancing our understanding of the co-existence of NAFLD-linked inflammatory bowel disease phenotypes in the clinic.
Digital Object Identifier (DOI)
Published in Scientific Reports, Issue 1, 2019.
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Sarkar, S., Kimono, D., Albadrani, M., Seth, R., Busbee, P., & Alghetaa, H. et al. (2019). Environmental microcystin targets the microbiome and increases the risk of intestinal inflammatory pathology via NOX2 in underlying murine model of Nonalcoholic Fatty Liver Disease. Scientific Reports, 9(1). https://doi.org/10.1038/s41598-019-45009-1