The gut microbial metabolic capacity of microbiome-humanized vs. wild type rodents reveals a likely dual role of intestinal bacteria in hepato-intestinal schistosomiasis

Abstract

Increasing evidence shows that the host gut microbiota might be involved in the immunological cascade that culminates with the formation of tissue granulomas underlying the pathophysiology of hepato-intestinal schistosomiasis. In this study, we investigated the impact of Schistosoma mansoni infection on the gut microbial composition and functional potential of both wild type and microbiome-humanized mice. In spite of substantial differences in microbiome composition at baseline, selected pathways were consistently affected by parasite infection. The gut microbiomes of infected mice of both lines displayed, amongst other features, enhanced capacity for tryptophan and butyrate production, which might be linked to the activation of mechanisms aimed to prevent excessive injuries caused by migrating parasite eggs. Complementing data from previous studies, our findings suggest that the host gut microbiome might play a dual role in the pathophysiology of schistosomiasis, where intestinal bacteria may contribute to egg-associated pathology while, in turn, protect the host from uncontrolled tissue damage.

Fig 1. Gut bacterial community composition.

Hierarchical clustering of gut bacterial communities of wild type (WT) and human-microbiota-associated (HMA) mice (columns) grouped according to Pearson correlation between species relative abundances (rows) and explanatory variables indicated at the top of the figure [i.e., experiment, mouse line, infection status and infection burden (EPG = eggs per gram)]. Dark lines on the heatmap separate major clusters in both axes.

Fig 2. Compositional and functional profiles of the gut metagenomes of wild type (WT) and human-microbiota-associated (HMA) mice.

(A) Principal Coordinates Analysis (PCoA) of microbial community composition of all Schistosoma-infected and -uninfected animals in both experiments, determined by mapping of shotgun metagenomic reads against bacterial reference genomes available from the GenBank database. (B) Alpha diversity. (C) Principal Component Analysis (PCA) of pathway relative abundances at community-level as determined by HUMAnN3. Asterisks indicate significant differences between groups determined by unpaired t-test: **p<0.01; ***p<0.0001.

Fig 3. Alterations in gut microbial community composition of wild type (WT) and human-microbiota-associated (HMA) mice associated with Schistosoma mansoni infection.

Principal Coordinates Analyses (PCoA) of microbial community profiles of WT (A) and HMA (B) mice infected with S. mansoni (Sm+) and uninfected controls (Sm-). (C) Bacterial species displaying significant differences in abundance between infected and uninfected samples of each WT and HMA mice, based on Linear Discriminant Analysis Effect Size (LEfSe).

Fig 4. Impact of Schistosoma mansoni infection on the fecal metabolic profiles of wild type (WT) and human-microbiota-associated (HMA) mice.

Principal Component Analysis (PCA) according to infection status (A) and infection-associated changes in gut metagenome capacity for tryptophan biosynthesis (B) and short-chain fatty acids production (C). Asterisks indicate significant differences in pathway abundance between S. mansoni-infected (Sm+) and uninfected controls (Sm-) of each mouse line by both MaAsLin2 (p<0.05) and LEfSe [LDA score (log) > 2]. Hashtags indicate significant differences in the contribution of selected bacterial species to the overrepresentation of corresponding pathway(s) (MaAsLin2, p<0.05). Full pathway denominations: TRPSYN-PWY = L-tryptophan biosynthesis; ANAEROFRUCAT-PWY = homolactic fermentation; PWY-5022 = 4-aminobutanoate degradation V; P461-PWY = hexitol fermentation to lactate, formate, ethanol and acetate; PWY-5676 = acetyl-CoA fermentation to butanoate II; PWY-5100 = pyruvate fermentation to acetate and lactate II; PWY-5677 = succinate fermentation to butanoate.