Schistosoma mansoni-induced host immunopathology is gut microbiota dependent
Authors: Kildemoes Anna M. O. , Schramm Gabriele , Pakkenberg Bente , Krause Fynn , Rasmussen Morten Arendt , Friis Hansen Camilla , Kot Witold , Jensen Anne , Wawrcyniak Jakub , Griffin Julian , Wilson Shona , Skov Soren , Hansen Axel Kornerup , Nielsen Dennis Sandris , Vennervald Birgitte Jyding 
Published: January 2025

Despite progress in schistosomiasis control during recent decades in endemic areas, this parasitic blood-fluke infection continues to pose a substantial public health burden. In depth understanding of the mechanisms behind the complex immunopathology and drivers of morbidity in schistosomiasis is urgently needed. Chronic infection with the parasitic blood fluke Schistosoma mansoni manifests the most severe pathology in relation to egg-induced host immune responses and fibrosis development. Host immune homeostasis is influenced by the commensal gut microbiota, which may therefore also affect systemic immunopathology induced by S. mansoni. Both humans and experimental animal models show metabolomic changes related to gut microbial and liver metabolism during S. mansoni infection, further supporting a link between gut microbiota and regulation of S. mansoni pathology. To investigate whether a radically changed gut microbiota composition would result in changed S. mansoni egg-induced pathology, a mouse model combining antibiotic treatment and infection was established. In the model, the commensal gut microbial composition of female C57BL/6-NTac mice was altered by oral administration of a broad-spectrum ampicillin-vancomycin cocktail prior to infection with S. mansoni and throughout the experiment. An ecosystem view of the host immune milieu was collated by measuring a wide range of parameters: gut microbiome characterisation, immune profiling on the transcriptional level (ileum and liver) supported by flow cytometry of cells (spleen and mesenteric lymph nodes) and bead-based measurements of immune parameters in sera, short-chain fatty acid measurements in sera and caecal content, intestinal permeability assessment, liver enzyme levels in sera, and histology and stereology to characterise immunopathology (ileum and liver). The application of stereological principles to address the non-spherical nature of egg-induced liver granulomas and ileum inflammation supported by liver enzyme levels, collagen deposition, and immune parameters, enabled demonstration of significantly less granuloma formation in livers from antibiotics treated mice compared to controls. The observed difference in the degree of egg-induced inflammatory response in livers from infected mice mediated by antibiotics treatment, was not observed in ileum tissue and could not be explained by infection burden. Our mouse model results demonstrate a role for the gut microbiota and intestinal immune milieu in regulation of systemic S. mansoni infection-driven liver pathology and, hence, potential morbidity. In translational context, these findings warrant that drivers of gut microbial changes and intestinal immune milieu must be considered when pursuing novel holistic interventions for treatment or alleviation of persistent schistosomiasis.