Baicalin circumvents anti-PD-1 resistance by regulating the gut microbiota metabolite short-chain fatty acids

Abstract

Baicalin is a small molecule medication used to treat hepatitis. Our research group discovered that administering baicalin orally to mice following fecal microbiota transplantation from patients resistant to ICIs supported anti-PD-1 activity. However, the precise mechanisms behind this effect are presently unknown. In this present study, ATB-treated C57BL/6 J mice received FMT from patients with advanced NSCLC amenable to αPD-1. Additionally, subcutaneous LLC cells were injected into the mice. Baicalin oral gavage and αPD-1 injection were administered to the mice on days 3 and 9 after tumour inoculation. 16 S rRNA, metabolomics, and flow cytometry were utilized to clarify the mechanisms of baicalin's relief of immunosuppression. The results indicated that oral administration of baicalin enriched bacteria such as Akkermansia and Clostridia_UCG-014, resulted in an increase in SCFAs, which improved the ratio of PD-1⁺ (CD8⁺ T cell/Treg) and promoted the levels of IFN-γ⁺ CD8⁺ T cells and TNF-α⁺ CD8⁺ T cells within the tumour microenvironment. In conclusion, baicalin regulates the metabolites of the gut microbiota to improve the PD-1⁺ (CD8⁺ T cell/Treg) balance and circumvent anti-PD-1 resistance. This is achieved through the regulation of short-chain fatty acids.

Keywords: Baicalin; Gut microbiota; PD-1 monoclonal antibody; Short-chain fatty acids (SCFAs).