Baseline Gut Microbiota Composition Is Associated With Schistosoma mansoni Infection Burden in Rodent Models

Abstract

In spite of growing evidence supporting the occurrence of complex interactions between Schistosoma and gut bacteria in mice and humans, no data is yet available on whether worm-mediated changes in microbiota composition are dependent on the baseline gut microbial profile of the vertebrate host. In addition, the impact of such changes on the susceptibility to, and pathophysiology of, schistosomiasis remains largely unexplored. In this study, mice colonized with gut microbial populations from a human donor (HMA mice), as well as microbiota-wild type (WT) animals, were infected with Schistosoma mansoni, and alterations of their gut microbial profiles at 50 days post-infection were compared to those occurring in uninfected HMA and WT rodents, respectively. Significantly higher worm and egg burdens, together with increased specific antibody responses to parasite antigens, were observed in HMA compared to WT mice. These differences were associated to extensive dissimilarities between the gut microbial profiles of each HMA and WT groups of mice at baseline; in particular, the gut microbiota of HMA animals was characterized by low microbial alpha diversity and expanded Proteobacteria, as well as by the absence of putative immunomodulatory bacteria (e.g. Lactobacillus). Furthermore, differences in infection-associated changes in gut microbiota composition were observed between HMA and WT mice. Altogether, our findings support the hypothesis that susceptibility to S.mansoni infection in mice is partially dependent on the composition of the host baseline microbiota. Moreover, this study highlights the applicability of HMA mouse models to address key biological questions on host-parasite-microbiota relationships in human helminthiases.

Keywords: Schistosoma mansoni; dysbiosis; gut microbial diversity; helminth-gut microbiota interactions; human-microbiota associated mouse models; immune-modulation.

Figure 1

Host microbiome affects susceptibility to Schistosoma mansoni infection. Mean number of (± standard error) male and female worms (A), eggs per gram (EPG) of liver (B), and eggs per female worm (C) recovered from infected wild type (WT) and human microbiota-associated (HMA) mice at 50 days post cercarial exposure. Horizontal lines represent significant differences between mouse lines: *p < 0.05; **p < 0.01.

Figure 2

The composition of the baseline gut microbiota differs extensively between naïve wild type (WT) and human microbiota-associated (HMA) mice. (A) Principal Coordinate Analysis (PCoA) performed at amplicon sequence variant (ASV) level. (B) Differences in microbial alpha diversity; horizontal lines represent significant differences between mouse lines: **p < 0.01. (C) Doughnut charts representing the mean relative abundances (TSS-transformed data) of gut microbial phyla and genera identified in feces of naïve WT (outer ring) and HMA (inner ring) mice. Others = sum of all taxa individually representing >0.5% of the overall microbial community. Unclassified = sum of all unclassified genera. (D) Percentage of bacterial taxa (from phylum to genus) for which significant differences were detected between the gut of naïve WT and HMA mice, according to both LEfSe and ANOVA (see differentially abundant taxa in Supplementary Table 2 ). (E) Percentage of taxa identified (from phylum to genus) solely detected in the gut microbiota of either WT or HMA mice, and in both rodent lines.

Figure 3

Microbial community composition of all fecal samples from Schistosoma mansoni-infected (Sm+) and uninfected (Sm-) wild type (WT) and human microbiota associated (HMA) mice analyzed in this study, at genus level. In the heatmap, columns represent samples and rows represent genera abundance, both ordered by hierarchical clustering. Explanatory variables (i.e. mouse line and infection status) are presented as a separate heatmap at the top of the figure.

Figure 4

Infection by Schistosoma mansoni is associated with significant alterations of the fecal microbiota composition of wild type (WT) and human microbiota-associated (HMA) mice. (A) Canonical Correlation Analysis (CCA) of microbial profiles of WT and HMA mice, performed at amplicon sequence variant (ASV) level and clustered according to infection status [i.e. infected (Sm+) vs. uninfected (Sm-)]. (B) Differences in microbial alpha diversity between the fecal microbial profiles of infected and uninfected animals in each rodent line; horizontal lines represent significant differences between rodent lines: **p < 0.01. (C) Clustering of microbial genera co-occurring in the fecal microbiota of infected and uninfected WT and HMA mice (the full list of differentially abundant taxa is available from Supplementary Table 3 ).