Gut microbiota-derived indole compounds attenuate metabolic dysfunction-associated steatotic liver disease by improving fat metabolism and inflammation

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, and its prevalence has increased worldwide in recent years. Additionally, there is a close relationship between MASLD and gut microbiota-derived metabolites. However, the mechanisms of MASLD and its metabolites are still unclear. We demonstrated decreased indole-3-propionic acid (IPA) and indole-3-acetic acid (IAA) in the feces of patients with hepatic steatosis compared to healthy controls. Here, IPA and IAA administration ameliorated hepatic steatosis and inflammation in an animal model of WD-induced MASLD by suppressing the NF-κB signaling pathway through a reduction in endotoxin levels and inactivation of macrophages. Bifidobacterium bifidum metabolizes tryptophan to produce IAA, and B. bifidum effectively prevents hepatic steatosis and inflammation through the production of IAA. Our study demonstrates that IPA and IAA derived from the gut microbiota have novel preventive or therapeutic potential for MASLD treatment.

Keywords: Bifidobacterium; Metabolic dysfunction-associated steatotic liver disease; gut microbiome; indole; metabolite.

Graphical abstract

Figure 1.

Human data.

Figure 2.

IPA and IAA ameliorate WD-induced hepatic steatosis.

Figure 3.

Administration of IPA and IAA alleviates WD-induced hepatic steatosis and inflammation in mice.

Figure 4.

Administration of IPA and IAA suppresses the increase in endotoxin and the inflammatory response caused by WD.

Figure 5.

IPA and IAA treatment altered transcriptomic in the liver.

Figure 6.

Modulating microbial taxonomic abundance of IPA and IAA on WD-induced changes.

Figure 7.

B. bifidum ameliorates WD-induced hepatic steatosis.

Figure 8.

Administration of B. bifidum alleviates WD-induced hepatic steatosis and inflammation in mice.