Indole Alleviates Diet‐Induced Hepatic Steatosis and Inflammation in a Manner Involving Myeloid Cell 6‐Phosphofructo‐2‐Kinase/Fructose‐2,6‐Biphosphatase 3

Abstract

BaCKgRoUND aND aIMS: Indole is a microbiota metabolite that exerts anti-inflammatory responses. However, the relevance of indole to human non-alcoholic fatty liver disease (NAFLD) is not clear. It also remains largely unknown whether and how indole acts to protect against NAFLD. The present study sought to examine the association between the circulating levels of indole and liver fat content in human subjects and explore the mechanisms underlying indole actions in mice with diet-induced NAFLD. appRoaCH aND ReSUltS: In a cohort of 137 subjects, the circulating levels of indole were reversely correlated with body mass index. In addition, the circulating levels of indole in obese subjects were significantly lower than those in lean subjects and were accompanied with increased liver fat content. At the whole-animal level, treatment of high-fat diet (HFD)-fed C57BL/6J mice with indole caused significant decreases in the severity of hepatic steatosis and inflammation. In cultured cells, indole treatment stimulated the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a master regulatory gene of glycolysis, and suppressed macrophage proinflammatory activation in a PFKFB3-dependent manner. Moreover, myeloid cell-specific PFKFB3 disruption exacerbated the severity of HFD-induced hepatic steatosis and inflammation and blunted the effect of indole on alleviating diet-induced NAFLD phenotype. CoNClUSIoNS: Taken together, our results demonstrate that indole is relevant to human NAFLD and capable of alleviating diet-induced NAFLD phenotypes in mice in a myeloid cell PFKFB3-dependent manner. Therefore, indole mimetic and/or macrophage-specific PFKFB3 activation may be the viable preventive and/or therapeutic approaches for inflammation-associated diseases including NAFLD. (Hepatology 2020;72:1191-1203). N onalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and progresses to nonalcoholic steatohepatitis (NASH) when the liver displays overt inflammatory damage. (1,2) As the advanced form of NAFLD, NASH is one of the most common causes of liver

Gut Microbiota Metabolites in NAFLD Pathogenesis and Therapeutic Implications

“…In addition, supplementation with indole reduced the severity of colitis that was induced by DDS. In another study, it was shown that circulating indole concentrations were inversely correlated with obesity and liver fat content [ 48 ]. Indole reduced the severity of NAFLD caused by an HFD in mice.…”

The Molecular and Mechanistic Insights Based on Gut–Liver Axis: Nutritional Target for Non-Alcoholic Fatty Liver Disease (NAFLD) Improvement

“…For instance, IAld induced STAT3 (signal transducer and activator of transcription 3) phosphorylation by stimulating the secretion of interleukin-22 (IL-22) via aryl hydrocarbon receptor (AhR) to promote the proliferation of the intestinal epithelial cells, which in turn restores the barrier function [116]. Treatment with indole attenuated high-fat diet-induced severity of hepatic steatosis and inflammation in mice, which was connected with the regulation of PFKFB3 (6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3) and the normalization of gut microbiome [117]. Study on rats revealed that IPA facilitated the protection against steatohepatitis induced by high-fat diet, as demonstrated by the improvement of gut dysbiosis and intestinal epithelial barrier function and the inhibition of pro-inflammatory signaling [118].…”

Targeting the gut microbial metabolic pathway with small molecules decreases uremic toxin production

“…The latest evidence suggests that indole is relevant to human nonalcoholic fatty liver disease, and can significantly reduce the severity of liver steatosis and inflammation. 26 …”