Disrupted Microbiome-Metabolome networks underlie gut barrier and immune imbalance in severe fever with thrombocytopenia syndrome.

Abstract

Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening tick-borne viral infection with a high mortality rate and limited treatment options. While gastrointestinal symptoms are common, the contribution of gut microbiome disruption to disease progression remains unclear. Previous studies have noted taxonomic shifts in SFTS-associated microbiota, but their functional and metabolic consequences have not been systematically characterized. We conducted an integrated metagenomic and metabolomic analysis of fecal samples from 20 SFTS patients and 20 healthy controls. At the time of admission, patients with SFTS exhibited acute-stage infection, characterized by symptoms such as fever, thrombocytopenia, and gastrointestinal disturbances. Metagenomic sequencing was used to assess the microbial gene content, taxonomic composition, and functional potential. Untargeted metabolomics analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to profile fecal metabolites. The SFTS patients showed a significantly reduced microbial gene richness, alpha diversity, and compositional stability. Short-chain fatty acid (SCFA)-producing genera (e.g., Faecalibacterium and Roseburia) were depleted, while mucin-degrading and opportunistic taxa (e.g., Pseudomonas and Akkermansia) were enriched. Functionally, biosynthetic and homeostatic pathways were suppressed; while stress-adaptive, biofilm-forming, and virulence-associated pathways were elevated. Metabolomic profiling revealed depletion of anti-inflammatory metabolites (e.g., bile acids and curcumin sulfate) and enrichment of proinflammatory compounds (e.g., porphyrins and beta-tyvelose). Multi-omic correlation highlighted strong links between microbial disruption and altered metabolite production. In conclusion, SFTS is associated with significant alterations in the gut microbiome and its metabolic profile, which is characterized by the loss of beneficial microbial taxa and functions, alongside the emergence of virulence factors and stress-related signatures. These findings underscore the role of microbiome dysfunction in SFTS and suggest that microbiota-targeted strategies may offer supportive benefits, particularly in alleviating SFTS-associated gastrointestinal disturbances and secondary microbial imbalance.