Macrophage depletion alters bacterial gut microbiota partly through fungal overgrowth in feces that worsens cecal ligation and puncture sepsis mice

Because macrophage dysfunction from some emerging therapies might worsen gut-derived sepsis, cecal ligation and puncture (CLP) sepsis are performed in mice with clodronate-induced macrophage depletion. Macrophage depletion (non-sepsis) increased fecal Ascormycota, with a subtle change in bacterial microbiota, that possibly induced gut-barrier defect as Candida pintolopesii and Enterococcus faecalis were identified from blood. Sepsis in macrophage-depleted mice was more severe than sepsis control as indicated by mortality, cytokines, organ injury (liver, kidney, and spleen), gut-leakage (FITC-dextran), fecal Proteobacteria, and blood organisms (bacteria and fungi). Lysate of C. pintolopesii or purified (1 → 3)-β-d-glucan (BG; a major component of fungal cell wall) enhanced growth of Klebsiella pneumoniae and Escherichia coli that were isolated from the blood of macrophage-depleted CLP mice implying a direct enhancer to some bacterial species. Moreover, the synergy of LPS and BG on enterocytes (Caco-2) (Transepithelial electrical resistance) and neutrophils (cytokines) also supported an influence of gut fungi in worsening sepsis. In conclusion, macrophage depletion enhanced sepsis through the selectively facilitated growth of some bacteria (dysbiosis) from increased fecal fungi that worsened gut-leakage leading to the profound systemic responses against gut-translocated LPS and BG. Our data indicated a possible adverse effect of macrophage-depleted therapies on enhanced sepsis severity through spontaneous elevation of fecal fungi.