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

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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.

Key words

gut-liver axis
microbiota
ob/ob mice
steatosis
tryptophan

Abbreviations

Adgre1
adhesion G protein-coupled receptor E1
AhR
aryl hydrocarbon receptor
Akt
protein kinase B
ALAT
alanine aminotransferase
ASAT
aspartate aminotransferase
BW
body weight
Ccl
C-C motif chemokine ligand
Col1a1
collagen type I α1 chain
Cxcl
C-X-C motif chemokine ligand
Cyp1a1
cytochrome P450 family 1 subfamily A polypeptide 1
Cyp1b1
cytochrome P450 family 1 subfamily B polypeptide 1
FA
fatty acid
FFA
free fatty acid
H&E
hematoxylin and eosin
HF
high-fat diet
HF C
control high-fat-diet–fed mice in experiment 2
HF I
indole-treated high-fat-diet–fed mice in experiment 2
IKBA
NF-κB inhibitor α
Itgax
integrin subunit αX (Cd11c)
KC
Kupffer cell
LF
low-fat diet
LF C
control low-fat-diet–fed mice in experiment 2
LF I
indole-treated low-fat-diet–fed mice in experiment 2
MTOR
mechanistic target of rapamycin
MTORC
mechanistic target of rapamycin complex
NAFLD
nonalcoholic fatty liver disease
NEFA
non-esterified fatty acid
ob/+ C
control ob/+ mice in experiment 1
ob/+ I
indole-treated ob/+ mice in experiment 1
ob/ob C
control ob/ob mice in experiment 1
ob/ob I
indole-treated ob/ob mice in experiment 1
PLS-DA
partial least squares discriminant analysis.

Cited by (0)

CK is a beneficiary of the AgreenSkills+ fellowship program, which has received funding from the EU's Seventh Framework Programme under grant agreement N°FP7-609398 (AgreenSkills+ contract). PDC is a senior research associate at FRS-FNRS (Fonds de la Recherche Scientifique) and recipient of grants from FNRS (WELBIO-CR-2019C-02R, “The Excellence of Science: EOS 30770923”) and the Funds Baillet Latour (Grant for Medical Research 2015). NMD is a recipient of grants from SPW-EER (convention 1610365, ERA-HDHL cofunded call BioNH 2016), from the Fonds de la Recherche Scientifique (FRS-FNRS) [PINT-MULTI R.8013.19 (NEURON-ERANET, call 2019) and PDR T.0068.19], and from the Fédération Wallonie-Bruxelles (Action de Recherche Concertée ARC18-23/092).

Author disclosures: The authors report no conflicts of interest.

Supplemental Figures 1–4, Supplemental Tables 1–5, and Supplemental Methods are available from the “Supplementary data” link in the online posting of the article and from the same link in the online table of contents at https://academic.oup.com/jn/.