Multi-omics insights into gut microbial dysbiosis and metabolic alterations in immune checkpoint inhibitor-induced thrombocytopenia.

BACKGROUND

Immune checkpoint inhibitors-induced thrombocytopenia (ICIs-TCP) is a rare immune-related adverse events (irAEs). The physiological changes underlying ICIs-TCP remain incompletely elucidated.

METHODS

We performed multi-omics analysis (gut microbiome, plasma metabolomics/proteomics) comparing microbial/metabolic alterations in cancer patients with (n = 8) and without ICIs-TCP (n = 8). Fecal metagenomic shotgun sequencing was performed to assess microbial composition and function, while plasma metabolomics and proteomics analyses identified systemic metabolic and protein expression changes associated with ICIs-TCP.

RESULTS

Patients with ICIs-TCP exhibited distinct gut microbiota profiles, with an increased abundance of Segatella, Prevotella, and Clostridium, alongside a depletion of Bacteroides and Roseburia. Functional analysis revealed significant downregulation of metabolic pathways, including arginine biosynthesis, alanine, aspartate, and glutamate metabolism. Plasma metabolomics identified reduced arginine levels and disruptions in key amino acid and energy metabolism pathways, suggesting systemic arginine depletion. Proteomic analysis further demonstrated down-regulation of folate hydrolase 1 (FOLH1), a key enzyme in glutamate metabolism, implicating metabolic dysregulation in TCP pathogenesis.

CONCLUSION

The depletion of arginine and associated metabolic disruptions are associated with ICIs-TCP and may represent a potential therapeutic target for mitigating TCP risk in patients receiving ICIs.