Recently, intestinal microbiota analysis revealed that patients with NASH had a lower percentage of Bacteroidetes compared to healthy control, consistent with previous observations made in alcoholic patients. Such correlations are strongly suggestive of the notion
that gut microbiota products promote NAFLD. In accordance, mice maintained on high-fat/simple carbohydrate, i.e., “modern Western,” diets exhibit increased intestinal permeability, elevated levels of serum endotoxin, and modestly elevated levels of proinflammatory cytokines that correlate with various aspect of metabolic syndrome including NAFLD.[39, 40] Increased levels of serum endotoxin may reflect increased permeability and the fairly large shifts Doxorubicin nmr in gut microbiota composition that occur in mice in response to diets designed to mimic Western diets. Evidence that NAFLD is actually driven by responses Dabrafenib nmr to endotoxin and other microbial products include observations that, in mice, diet-induced metabolic syndrome is absent in germfree conditions and that ablation of innate immune signaling by deleting TLR4 ameliorates disease, while the absence of MyD88, which plays a central role in TLR/NLR signaling, appears to eliminate it entirely.[41-43] Similarly, the suppressor of cytokine signaling 1 (SOCS1) protein, a negative-feedback regulator in cytokine signaling induced upon TLR stimulation,
plays a protective role in liver injury, since SOCS1-deficient mice display fulminant hepatitis, characterized by hepatic Cediranib (AZD2171) inflammation, fatty degeneration, and hepatocyte necrosis.[44-46] Thus, overall, these findings suggest that the dramatically increased incidence of NAFLD may,
in part, result from increased consumption of Western diets causing increased activation of proinflammatory signaling due to increased intestinal permeability and/or changing in microbiota composition. A recent study supports the former possibility. Specifically, this study examined mice on a HFD that did and did not develop steatosis, and observed changes in microbiota composition that correlated with this phenotypic difference. Transfer of the microbiota from the steatotic mice to germfree mice promoted development of HFD-induced steatosis relative to germfree mice given the microbiota of nonsteatotic mice. Such steatosis correlated with dysglycemia, suggesting that the altered microbiota was broadly promoting metabolic syndrome. The alterations in gut microbiota involved alterations in numerous bacterial species. As reviewed elsewhere, increased proinflammatory signaling can be a direct cause of liver disease and other aspects of metabolic syndrome. Effects of proinflammatory signaling on metabolism include dysregulating appetite control, thus amplifying events that can drive NAFLD/metabolic syndrome. Inflammation can also alter gut microbiota composition.