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Schistosoma japonicum (S. japonicum) is one of the etiological agents of schistosomiasis, a widespread zoonotic parasitic disease. However, the mechanism of the balanced co-existence between the host immune system and S. japonicum as well as their complex interaction remains unclear. In this study, 16S rRNA gene sequencing, combined with metagenomic sequencing approach as well as ultraperformance liquid chromatography–mass spectrometry metabolic profiling, was applied to demonstrate changes in the gut microbiome community structure during schistosomiasis progression, the functional interactions between the gut bacteria and S. japonicum infection in BALB/c mice, and the dynamic metabolite changes of the host. The results showed that both gut microbiome and the metabolites were significantly altered at different time points after the infection. Decrease in richness and diversity as well as differed composition of the gut microbiota was observed in the infected status when compared with the uninfected status. At the phylum level, the gut microbial communities in all samples were dominated by Firmicutes, Bacteroidetes, Proteobacteria, and Deferribacteres, while at the genus level, Lactobacillus, Lachnospiraceae NK4A136 group, Bacteroides, Staphylococcus, and Alloprevotella were the most abundant. After exposure, Roseburia, and Ruminococcaceae UCG-014 decreased, while Staphylococcus, Alistipes, and Parabacteroides increased, which could raise the risk of infections. Furthermore, LEfSe demonstrated several bacterial taxa that could discriminate between each time point of S. japonicum infection. Besides that, metagenomic analysis illuminated that the AMP-activated protein kinase (AMPK) signaling pathway and the chemokine signaling pathway were significantly perturbed after the infection. Phosphatidylcholine and colfosceril palmitate in serum as well as xanthurenic acid, naphthalenesulfonic acid, and pimelylcarnitine in urine might be metabolic biomarkers due to their promising diagnostic potential at the early stage of the infection. Alterations of glycerophospholipid and purine metabolism were also discovered in the infection. The present study might provide further understanding of the mechanisms during schistosome infection in aspects of gut microbiome and metabolites, and facilitate the discovery of new targets for early diagnosis and prognostic purposes. Further validations of potential biomarkers in human populations are necessary, and the exploration of interactions among S. japonicum, gut microbiome, and metabolites is to be deepened in the future.

Schistosomiasis is a zoonotic and debilitating parasitic disease caused by Schistosoma japonicum. Praziquantel remains the choice for treating schistosomiasis, but its efficacy could be hampered by emergence of resistance. In this study, using large-scale drug screening, we selected out myricetin, a natural flavonol compound, having a good anti-schistosome effect. We found that myricetin exhibited dose and time-dependent insecticidal effect on S. japonicum in vitro, with an LC50 of 600 μM for 24 h, and inhibited female spawning. The drug mainly destroyed the body structure of the worms and induced apoptosis of the worm cells, which in turn led to death. In addition, oral administration of myricetin in mice infected with S. japonicum showed a deworming effect in vivo, as evidenced by a significant reduction in the liver egg load. H&E staining, quantitative RT-PCR, and Western blotting assays showed that myricetin significantly alleviated liver fibrosis in mice infected with S. japonicum. Myricetin also effectively inhibited the expression of TGFβ1, Smad2, phospho-Smad2, Smad3, phospho-Smad3, ERK, phospho-ERK, Akt, and phospho-Akt in the liver of infected mice, suggesting that myricetin attenuated liver fibrosis in mice via modulating TGFβ1 and Akt signaling. Flow cytometric analysis of Th subtypes (Th1/Th2/Th17/Treg) in the mouse spleen further revealed that myricetin significantly increased the percentage Th1 cells in infected mice and reduced the proportion of Th2 cells and Th17 cells. Immunology multiplex assay further showed that myricetin attenuated S. japonicum-induced rise in the plasma levels of IL-4, IL-5, IL-10, IL-13, and IL-17A in infected mice while increasing the plasma contents of IFN-γ, IL-12, and IL-7. In conclusion, our study provides the first direct evidence that myricin possesses potent anti-schistosome activities in vitro and in vivo, and offers new insights into the mechanisms of action by myricetin. The present findings suggest that myricetin could be further explored as a therapeutic agent for S. japonicum.