Hepatoprotective Effects of Indole, a Gut Microbial Metabolite, in Leptin-Deficient Obese Mice

Abstract

Background The gut microbiota plays a role in the occurrence of nonalcoholic fatty liver disease (NAFLD), notably through the production of bioactive metabolites. Indole, a bacterial metabolite of tryptophan, has been proposed as a pivotal metabolite modulating inflammation, metabolism, and behavior. Objectives The aim of our study was to mimic an upregulation of intestinal bacterial indole production and to evaluate its potential effect in vivo in 2 models of NAFLD. Methods Eight-week-old leptin-deficient male ob/ob compared with control ob/+ mice (experiment 1), and 4–5-wk-old C57BL/6JRj male mice fed a low-fat (LF, 10 kJ%) compared with a high-fat (HF, 60 kJ%) diet (experiment 2), were given plain water or water supplemented with a physiological dose of indole (0.5 mM, n ≥6/group) for 3 wk and 3 d, respectively. The effect of the treatments on the liver, intestine, adipose tissue, brain, and behavior was assessed. Results Indole reduced hepatic expression of genes involved in inflammation [C-C motif chemokine ligand 2 (Ccl2), C-X-C motif chemokine ligand 2 (Cxcl2); 3.3- compared with 5.0-fold, and 2.4- compared with 3.3-fold of control ob/+ mice, respectively, P < 0.05], and in macrophage activation [Cd68, integrin subunit α X (Itgax); 2.1- compared with 2.5-fold, and 5.0- compared with 6.4-fold of control ob/+ mice, respectively, P < 0.01] as well as markers of hepatic damage (alaninine aminotransferase; −32%, P < 0.001) regardless of genotype in experiment 1. Indole had no effect on hepatic inflammation in mice fed the LF or HF diet in experiment 2. Indole did not change hepatic lipid content, anxiety-like behavior, or inflammation in the ileum, adipose tissue, and brain in experiment 1. Conclusions Our results support the efficacy of indole to reduce hepatic damage and associated inflammatory response and macrophage activation in ob/ob mice. These modifications appear to be attributable to direct effects of indole on the liver, rather than through effects on the adipose tissue or intestinal barrier.

Biological Effects of Indole-3-Propionic Acid, a Gut Microbiota-Derived Metabolite, and Its Precursor Tryptophan in Mammals’ Health and Disease

“…So far, research projects on bacterial metabolism of tryptophan focused mainly on actions of indole [10,11], and its liver metabolite, indoxyl sulfate (IS) [12,13]. Indole decreases intestinal inflammation and has positive impact on gastrointestinal and liver homeostasis [10,14]. On the other hand, IS can be classified as uremic toxin, as its concentration increases significantly in chronic kidney disease [9,15].…”

Interactions Between Ephedra sinica and Prunus armeniaca: From Stereoselectivity to Deamination as a Metabolic Detoxification Mechanism of Amygdalin

“…Herb-herb interactions, inducing changes in the solubility or generation of a new compound, may occur during the decoction process. Liver and gut microbes play an important role in drug metabolism (Knudsen et al, 2021;Sodhi and Benet, 2021). Thus, chemical transformations or endogenous metabolism of amygdalin was investigated during decoction and incubation of the rat liver microsome (RLM) and gut microbial enzyme (RGME) preparations, respectively.…”

Intestinal Dysbiosis, the Tryptophan Pathway and Nonalcoholic Steatohepatitis

“…Treatment of high fat diet mice with para-chlorophenylalanine to inhibit 5-HT synthesis or with sarpogrelate to inhibit HTR2A activity reduced hepatic lipid accumulation. 47 , 50 Crane et al 53 found another mechanism for protective effect of inhibition of THP1 on high-fat diet induced NAFLD. Inhibition of THP1 reduced blood levels of 5-HT, which increased brown adipose tissue sensitivity to noradrenaline and beta-adrenergic receptor, leading to increased thermogenesis and thus reduced lipid accumulation and inflammation.…”

“…In animal models, indole and indole derivatives are effective in reducing inflammation in NASH. 47 , 48 , 51 , 52 This provides a potential for indole and indole derivatives to be used in the treatment of NASH. A recent study correlated the anti-inflammatory effects of garvage administration of indole-3-acetic acid in an animal model with an increase of indole-3-acetic acid in obese NAFLD patients after sleeve gastrectomy, which reduced hepatic inflammation.…”