Eubacterium siraeum suppresses fat deposition via decreasing the tyrosine-mediated PI3K/AKT signaling pathway in high-fat diet-induced obesity.

Abstract

Obesity in humans can lead to chronic diseases such as diabetes and cardiovascular disease. Similarly, subcutaneous fat (SCF) in pigs affects feed utilization, and excessive SCF can reduce the feed efficiency of pigs. Therefore, identifying factors that suppress fat deposition is particularly important. Numerous studies have implicated the gut microbiome in pigs' fat deposition, but research into its suppression remains scarce. The Lulai black pig (LL) is a hybrid breed derived from the Laiwu pig (LW) and the Yorkshire pig, with lower levels of SCF compared to the LW. In this study, we focused on these breeds to identify microbiota that regulate fat deposition. The key questions were: Which microbial populations reduce fat in LL pigs compared to LW pigs, and what is the underlying regulatory mechanism? In this study, we identified four different microbial strains, Eubacterium siraeum, Treponema bryantii, Clostridium sp. CAG:413, and Jeotgalibaca dankookensis, prevalent in both LW and LL pigs. Blood metabolome analysis revealed 49 differential metabolites, including tanshinone IIA and royal jelly acid, known for their anti-adipogenic properties. E. siraeum was strongly correlated with these metabolites, and its genes and metabolites were enriched in pathways linked to fatty acid degradation, glycerophospholipid, and glycerolipid metabolism. In vivo mouse experiments confirmed that E. siraeum metabolites curb weight gain, reduce SCF adipocyte size, increase the number of brown adipocytes, and regulate leptin, IL-6, and insulin secretion. Finally, we found that one important pathway through which E. siraeum inhibits fat deposition is by suppressing the phosphorylation of key proteins in the PI3K/AKT signaling pathway through the reduction of tyrosine. We compared LW and LL pigs using fecal metagenomics, metabolomics, and blood metabolomics, identifying E. siraeum as a strain linked to fat deposition. Oral administration experiments in mice demonstrated that E. siraeum effectively inhibits fat accumulation, primarily through the suppression of the PI3K/AKT signaling pathway, a critical regulator of lipid metabolism. These findings provide a valuable theoretical basis for improving pork quality and offer insights relevant to the study of human obesity and related chronic metabolic diseases. Video Abstract.