MICROBIOTA DERIVED INDOLE COMPOUNDS ATTENUATE THE NON-ALCOHOLIC FATTY LIVER DISEASE BY IMPROVING FAT METABOLISM AND INFLAMMATION.

초록

Background: Non-alcoholic liver disease (NAFLD) is known as the most common chronic liver disease and the prevalence has recently increased worldwide. Dietary tryptophan is an essential amino acid that is metabolized by the gut microbiota to indole compounds and affects host physiology. Based on the human data showing the reduction of indole-3-propionic acid (IPA) and indole-3-acetic acid (IAA) as NAFLD progressed, we evaluated the efficacy of IPA and IAA in a Western diet (WD)-induced mice model of NAFLD. Methods: A total of 61 patients’ stools (healthy controls (HC, n=19), nonalcoholic fatty liver (NAFL, n=16), nonalcoholic steatohepatitis (NASH, n=26)) were analyzed by gas/liquid chromatography-mass spectrometry for identification of metabolites biomarker. Subsequently, 6-week-old male C57BL/6J mice were treated with IPA and IAA for 12 weeks in Western diet-induced NAFLD condition. NAFLD severity was defined via histopathology and biochemical markers. Mice liver and cecum samples were collected for mRNA and protein estimation. In vitro experiment, the LPS-induced RAW 264.7 cells were treated with the indole compounds. Results: In the metabolic profile of human feces, IPA and IAA were decreased in NAFL and NASH compared with HC. In a Western diet-induced NAFLD mice model, IPA and IAA supplementation effectively improved NAFLD activity scores, biochemical markers (AST, ALT, total cholesterol, and TG) cytokines (TNF-α), and chemokines (Cxcl10, Ccl2, Ccl5). The TLR4 expression in animal liver was significantly reduced by IPA and IAA treatment compared to Western control. To evaluate the anti-inflammatory effects of indole compounds (IPA and IAA), macrophages were pretreated with IPA and IAA in a dose-dependent manner and then exposed to LPS stimulation. The indole compounds (IPA and IAA) significantly reduced the expression of TNF-α, a proinflammatory cytokine, and improved the expression of CCL2, a macrophage-related chemokine. Conclusion: Tryptophan metabolites, IPA and IAA, inhibit the progression of NAFLD by improving inflammatory response and lipid metabolism. Therefore, our study shows that indole compounds have new preventive or therapeutic potential for NAFLD.