albicans, an important fungal gut microbiota in human 15. Indeed, macrophage phagocytosis is a well-known important fungicidal process 13, 14, especially against C. Macrophage is one of the major immune cells for the control of fungi, especially the yeast-formed fungi, as several immune evasion mechanisms against macrophages are evolutionarily developed by several fungi 10, 12. On the other hand, macrophages are the sentinel immune cells in nearly all organs that, at least in part, critically control the enteric microbes 9 and macrophage abnormalities weaken the host's capacity to resist fungal infections 10, 11. However, Candida non-albicans are mentioned as the common fungi in mouse intestines 8 and studies on the models with self-emerging gut fungi might provide clearer evidence on gut fungal impact. albicans administration in mice worsens sepsis models through profound inflammation from LPS-BG synergy 6, 7. Although studies on the influence of gut fungi or (1 → 3)-β- d-glucan (BG), a major molecule of the fungal cell wall, on bacterial sepsis is still less, C. Among all gut organisms, fungi, especially Candida albicans in human intestines, are the second most abundant organisms (the highest gut organisms are Gram-negative bacteria) that could be facilitated in several conditions, including antibiotic administration and chronic intestinal inflammation 5. In immune-compromised hosts 4, intestinal dysbiosis (microbial community imbalance) and gut permeability defect (gut leakage) could all lead to systemic infection via gut bacterial translocation 5. The gut microbiota refers to trillions of microbes in the GI tract, including bacteria, fungi, viruses, and archaea, that live in a symbiotic relationship with the host and are regulated by the host's immunity 3. Sepsis, the dysfunction of immune responses against systemic infection, is a serious healthcare problem worldwide with significant morbidity and mortality 1, 2. Our data indicated a possible adverse effect of macrophage-depleted therapies on enhanced sepsis severity through spontaneous elevation of fecal fungi. 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. 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. 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. 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). 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.
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.
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