High Protein Diet Contributes to Insulin Resistance in Mice via Shaping Gut Microbiota

Insulin resistance (IR) is a risk factor for various diseases. Diet plays a crucial role in the development of IR. The high-protein diet (HPD) is gaining popularity for its weight control benefit. However, some types of protein can be metabolized by gut microbiota into trimethylamine (TMA), subsequently oxidized into trimethylamine N-oxide (TMAO) in the liver. However, the underlying mechanism of HPD-induced IR remains unclear. In this study, we firstly investigated whether the HPD can induce IR. Next, we examined liver function and the signaling pathways involved in IR. At last, we detected changes in the composition and function of gut microbiota, particularly concerning TMA production. Our results demonstrated that the HPD induces IR and liver injury, 41% higher TMA concentration than in the control group. Transcriptome results confirmed that insulin-related pathways were enriched in the HPD group, especially the Insrr gene, which regulates insulin action through its receptor, was downregulated. Disrupted gut microbiota, dominated by 65.0% of Firmicutes, which have high potential in TMA production. Moreover, several amino acid metabolism pathways closely linked to IR were enriched in the HPD group. These findings highlight the need for careful dietary management, as the HPD can induce IR and liver injury, with gut microbiota playing a key role in TMA production.