SRP341458 PRJNA771216 Oral administration of the combination of live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus alleviated Streptococcus pneumoniae infection in immunocompromised rats Streptococcus pneumoniae (SP) is the most common cause of bacterial pneumonia, especially for people with immature or compromised immune systems. In addition to vaccination and antibiotics, immune regulation through microbial intervention has emerged in recent anti-SP infection research. This study investigated the therapeutic effect of a combination of live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus (CBLEB), a widely used immunomodulatory probiotic drug, on SP infection in an immunocompromised SP infection rat model established by intraperitoneal injection of cyclophosphamide and nasal administration of SP strain ATCC49619. We found that CBLEB treatment alleviated SP infection-induced weight loss, inflammation and organ damage, eliminated SP infection-induced increase in basophil percentage, red cell distribution width, and RANTES levels and decrease in total protein and albumin levels. Furthermore, CBLEB treatment alleviated SP infection-induced dysbiosis in gut microbiota, including altered microbial composition and the aberrant abundance of opportunistic pathogenic bacterial taxa such as Eggerthellaceae, and disorders in gut and serum metabolism, including altered metabolomic profiles and differentially enriched metabolites such as 2,4-di-tert-butylphenol in faeces and L-tyrosine in serum. The transcriptome analysis results indicated that the underlying mechanism by which CBLEB fights SP infection is mainly attributed to its regulation of immune-related pathways such as TLR and NLR signalling in the lungs and infection-, inflammation- and metabolism-related pathways such as TCR signalling in the colon. In conclusion, the present study shows a potential value of CBLEB in the treatment of SP infection.