The gut microbiota metabolite indole alleviates liver inflammation in mice

Abstract

The gut microbiota regulates key hepatic functions, notably through the production of bacterial metabolites that are transported via the portal circulation. We evaluated the effects of metabolites produced by the gut microbiota from aromatic amino acids (phenylacetate, benzoate, p-cresol, and indole) on liver inflammation induced by bacterial endotoxin. Precision-cut liver slices prepared from control mice, Kupffer cell (KC)-depleted mice, and obese mice (ob/ob) were treated with or without LPS and bacterial metabolites. We observed beneficial effects of indole that dose-dependently reduced the LPS-induced up-regulation of proinflammatory mediators at both mRNA and protein levels in precision-cut liver slices prepared from control or ob/ob mice. KC depletion partly prevented the antiinflammatory effects of indole, notably through a reduction of nucleotide-binding domain and leucine-rich repeat containing (NLR) family pyrin domain-containing 3 (NLRP3) pathway activation. In vivo, the oral administration of indole before an LPS injection reduced the expression of key proteins of the NF-κB pathway and downstream proinflammatory gene up-regulation. Indole also prevented LPS-induced alterations of cholesterol metabolism through a transcriptional regulation associated with increased 4β-hydroxycholesterol hepatic levels. In summary, indole appears as a bacterial metabolite produced from tryptophan that is able to counteract the detrimental effects of LPS in the liver. Indole could be a new target to develop innovative strategies to decrease hepatic inflammation.—Beaumont, M., Neyrinck, A. M., Olivares, M., Rodriguez, J., de Rocca Serra, A., Roumain, M., Bindels, L. B., Cani, P. D., Evenepoel, P., Muccioli, G. G., Demoulin, J.-B., Delzenne, N. M. The gut microbiota metabolite indole alleviates liver inflammation in mice.

The Gut Microbiota and Its Metabolites, Novel Targets for Treating and Preventing Non‐Alcoholic Fatty Liver Disease

“…[86] Bansal et al first demonstrated that indole is a beneficial signal for maintaining the intestinal barrier by inhibiting TNF--induced activation of NF-B and pro-inflammatory chemokine IL-8 expression. [87] One study showed that administration of indole before LPS challenge alleviated liver inflammation and altered cholesterol metabolism by ex vivo experiment, [88] and these effects were also demonstrated by inhibiting NLRP3 signaling in KCs. In addition, indoleacetic acid has a protective effect on liver injury in male mice with HFD-induced NAFLD, which is partly dependent on improvements in IR, oxidative stress, and the inflammatory response and reductions in F4/80 + macrophage infiltration and release of liver ROS.…”

Indoles: metabolites produced by intestinal bacteria capable of controlling liver disease manifestation

“…Indole was also shown to prevent LPS‐induced detrimental effects in the liver . Both in vitro and in vivo experiments indicated that indole has anti‐inflammatory properties by reducing the expression of key proteins of the NF‐κB pathway.…”

HMGB1‐associated necroptosis and Kupffer cells M1 polarization underlies remote liver injury induced by intestinal ischemia/reperfusion in rats

“…The liver is the organ in closest contact with the intestine and is particularly vulnerable to the negative consequences of distant intestinal epithelial barrier disruption because the vasculature of these tissues is coupled in series with the intestinal circulation, such as portal circulation. 5,6 Moreover, the pathophysiology of remote liver injury after intestinal I/R remains only partially understood; putative mechanisms include sustained pro-inflammatory cytokine challenge and cytokines that are released or activated after enterocyte damage or death. 7,8 If liver repair and regenerative mechanisms are not activated promptly, especially in patients with chronic liver disease or after liver transplantation, acute liver functional impairment, or poor early graft function will occur.…”