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Hepatology. 2020 Jan 17. doi: 10.1002/hep.31115. [Epub ahead of print]

Indole Alleviates Diet-induced Hepatic Steatosis and Inflammation in a Manner Involving Myeloid Cell PFKFB3.

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Department of Nutrition and Food Science, Texas A&M University, College Station, TX, 77843, USA.
Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
The Laboratory of Lipid & Glucose Metabolism, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
Department of Poultry Science, Texas A&M University, College Station, TX, 77843, USA.
Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX, 77843, USA.
Nebraska Center for Virology, School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA.
Department of Medical Physiology, Texas A&M University College of Medicine, Temple, TX, 76504, USA.
Indiana Center for Liver Research, Richard L. Roudebush VA Medical Center, Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202.


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. 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 with indole caused significant decreases in the severity of hepatic steatosis and inflammation. In cultured cells, indole treatment stimulated the expression of 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 is capable of alleviating diet-induced NAFLD phenotypes in mice in a myeloid cell PFKFB3-dependnet 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.


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