Abstract
Non-alcoholic fatty liver disease (NAFLD), the world’s most common chronic liver disease, is increasingly linked to gut dysbiosis. Paneth cells secrete antimicrobial peptides that regulate the gut microbiome, but their role in the pathogenesis of NAFLD remains unclear. Here, we determine the changes in NAFLD development and gut microbial composition and function via the injection of dithizone that can pharmacologically deplete the granules of Paneth cells. Eight-week-old C57BL/6J male mice (n = 31) were given a high-fat diet (HFD) or standard control diet for 12 weeks. Dithizone (10 mg/kg) was intravenously injected every 3 weeks during the period of diet feeding. Metagenomic DNA was extracted from fecal samples for PacBio Single-Molecule Real-Time sequencing to identify changes in microbial composition and predicted function. We observed dithizone-treated HFD mice, when compared to non-treated HFD mice, to have significant reductions in hepatic triglyceride content (28.98 vs. 53.52 mg/g, p = 0.0419); plasma insulin level (2.18 vs. 6.63 ng/ml, p = 0.0079); and relative mRNA levels of fatty acid synthase (0.52 vs. 1.57, p = 0.0428) and stearoyl-CoA desaturase-1 (0.43 vs. 1.20, p = 0.0121). Bacterial taxonomic profiling found dithizone-treated HFD mice, when compared to non-treated HFD mice, had a lower Firmicutes/Bacteroidetes ratio (2.53 vs. 5.26, p = 0.0541); a higher relative abundance of Bacteroides ASV21 and ASV42 (1.04 vs. 0.22%, p = 0.0277 and 0.96 vs. 0.09%, p = 0.0213); and a reduction in microbes belonging to Firmicutes (all p < 0.05). Bacteroides species correlated positively with predicted microbial functions such as L-methionine (r = 0.54, p = 0.0019) and tetrahydrofolate (r = 0.52, p = 0.0029) biosynthesis. Collectively, dithizone treatment was associated with alleviation in the severity of liver steatosis in HFD mice, possibly through gut microbiome modulation involving the increase in Bacteroides, suggesting microbiome-targeted therapies may have a role in the treatment of NAFLD.
Highlights
The general population with non-alcoholic fatty liver disease (NAFLD) is increasing owing to the prevalence of obesity and metabolic risk factors (Bedogni et al, 2005; Cohen et al, 2011)
Many efforts were put on to explain how gut microbiome dysbiosis leads to Non-alcoholic fatty liver disease (NAFLD) development
While a great deal of success had been achieved in explaining how gut microbiome dysbiosis leads to NAFLD development, the exact role remains undetermined
Summary
The general population with non-alcoholic fatty liver disease (NAFLD) is increasing owing to the prevalence of obesity and metabolic risk factors (Bedogni et al, 2005; Cohen et al, 2011). There is emerging evidence demonstrating the gut microbiome as a critical environmental factor that affects the onset and progression of NAFLD. Many efforts were put on to explain how gut microbiome dysbiosis leads to NAFLD development. The increased intestinal permeability caused by gut microbiome dysbiosis promotes translocation of metabolites into portal blood circulation. Responses to this dysbiosis promote liver damage (Miele et al, 2009; Bashiardes et al, 2016; Poeta et al, 2017). Exploring underlying regulatory mechanisms may contribute a deeper understanding of NAFLD and on the potential of microbiomebased interventions
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