Unique microbial-derived volatile organic compounds in portal venous circulation in murine non-alcoholic fatty liver disease

• Published in: Biochimica et biophysica acta 2016-07, Vol.1862 (7), p.1337-1344
• Main Authors: Reid, D.T., McDonald, B., Khalid, T., Vo, T., Schenck, L.P., Surette, M.G., Beck, P.L., Reimer, R.A., Probert, C.S., Rioux, K.P., Eksteen, B.
• Format: Article
• Language: English
• Subjects: Animals; Bacteria - isolation & purification; Cells, Cultured; Disease Models, Animal; Inflammation - microbiology; Inflammation - pathology; Inflammation Mediators - analysis; Liver; Liver - blood supply; Liver - microbiology; Liver - pathology; Macrophages - microbiology; Macrophages - pathology; Male; Metabolomics; Mice, Inbred C57BL; Microbiome; Microbiota; Non-alcoholic Fatty Liver Disease - blood; Non-alcoholic Fatty Liver Disease - microbiology; Non-alcoholic Fatty Liver Disease - pathology; Portal Vein - microbiology; Portal Vein - pathology; Volatile organic compounds; Volatile Organic Compounds - analysis
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2016.04.005

Non-alcoholic fatty liver disease is now the leading liver disease in North America. The progression of non-alcoholic fatty liver disease to the inflammatory condition, non-alcoholic steatohepatitis is complex and currently not well understood. Intestinal microbial dysbiosis has been implicated in the development of non-alcoholic fatty liver disease and progression of non-alcoholic steatohepatitis. Volatile organic compounds are byproducts of microbial metabolism in the gut that may enter portal circulation and have hepatotoxic effects contributing to the pathogenesis of non-alcoholic steatohepatitis. To test this hypothesis, we measured volatile organic compounds in cecal luminal contents and portal venous blood in a mouse model of non-alcoholic steatohepatitis. Gas chromatography–mass spectrometry analysis was conducted on cecal content and portal vein blood for volatile organic compound detection from mice fed a methionine and choline deficient diet, which induces non-alcoholic steatohepatitis. The colonic microbiome was studied by 16S rRNA gene amplification using the Illumina MiSeq platform. Sixty-eight volatile organic compounds were detected in cecal luminal content, a subset of which was also present in portal venous blood. Importantly, differences in portal venous volatile organic compounds were associated with diet-induced steatohepatitis establishing a biochemical link between gut microbiota-derived volatile organic compounds and increased susceptibility to non-alcoholic steatohepatitis. Our model creates a novel tool to further study the role of gut-derived volatile organic compounds in the pathogenesis of non-alcoholic steatohepatitis. Illustration of the impact of microbial-derived VOCs on the development of NASH. During health, VOCs produced by gut microbiota enter the healthy liver and are metabolized. At the onset of obesity, the liver begins to accumulate lipid leading to compromised metabolic function, damaged mitochondria, and reduced insulin sensitivity. Changes in gut-derived VOCs during obesity further disrupt liver function and metabolism. Presence of VOCs in the liver in combination with steatosis creates a microenvironment primed for the initiation of inflammation by release of inflammatory mediators followed by the recruitment of proinflammatory cells into the liver. This combination of detrimental cellular processes ultimately leads to the development of non-alcoholic steatohepatitis. [Display omitted] •Pathogenesis of non-alcoh