Infection by Strongyloides venezuelensis attenuates chronic colitis induced by Dextran Sodium Sulfate ingestion in BALB/c mice
Graphical abstract
Introduction
Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, are characterized by relapsing chronic inflammation without a specific infectious or environmental cause (Legaki and Gazouli, 2016, Xavier and Podolsky, 2007). Although the pathogenesis of IBD remains unclear, studies indicate that genetic susceptibility and environmental factors contribute to a disruption of the intestinal tract homeostasis. As a consequence, the immune system can no longer distinguish pathogen antigens from the host’s antigens, commensal microbiota, and food, thus leading to an exacerbated immune response to these non-pathogenic antigens and the establishment of chronic intestinal inflammation (Ahluwalia et al., 2018, Halfvarson et al., 2003). The strategy for controlling these chronic inflammatory diseases generally depends on the long-term use of broad-spectrum corticosteroids or immunosuppressants, but not all patients respond well to these drugs and may suffer from their side effects (Motomura et al., 2009).
In 2017, it was estimated that there were 6.8 million cases of IBD in the world and, despite the increased incidence of IBD in some underdeveloped regions, the most dramatic increase was registered in developed countries (Alatab et al., 2019). Concomitant with the increased prevalence of IBD, there has been a rapid decline in helminth infection rates in developed countries (Elliott et al., 2000, Halfvarson et al., 2003). Supporting these epidemiological studies, experimental data from murine models have also demonstrated that infection by different species of helminths or inoculation of worm-derived antigens may reduce the severity of experimentally induced colitis (Varyani et al., 2017).
Indeed, previous data from our group showed that even an acute and transitory helminth infection, such as Strongyloides venezuelensis in mice, was capable of ameliorating the severity of DSS-induced acute colitis, which was accompanied by local reduction of inflammatory cytokine production and increased levels of IL-10 (Rodrigues et al., 2018). Nevertheless, the protective effects of helminth infections against experimental colitis are still controversial, and published data reported that some infections can lead to a worsening of the experimental colitis (Liu et al., 2018, Pastille et al., 2017, Wang et al., 2010). Moreover, randomized clinical studies in which patients with IBD were infected with Trichuris suis or Necator americanus showed conflicting results, with reports of IBD symptoms improving, remaining unchanged or worsening after infection (Croese et al., 2006, Garg et al., 2014, Huang et al., 2018, Summers et al., 2005).
Noteworthy, unlike clinical studies in which the experimental treatment using helminths was administrated in patients with chronic IBD, most of the experimental studies using animal models evaluated the preventive role of helminth infections or inoculation of worms-derived antigens on the induction of experimental acute colitis. There is little data related to the effects of helminth infections on the modulation of intestinal inflammation in experimental models of chronic colitis. Besides, putative mechanisms involved in the modulation of chronically established colitis by helminth infection are still unclear. Therefore, we tested whether S. venezuelensis infection can modulate the severity of chronic DSS-induced colitis in BALB/c mice. Our results revealed that the active infection with S. venezuelensis was able to decrease the severity of colon inflammation induced by chronic DSS ingestion in mice.
Section snippets
Animals
Female specific pathogen-free (SPF) BALB/c mice (six weeks old) mice were used. SPF mice were provided by the Animal Facility of the Federal University of Minas Gerais (UFMG, Brazil). During experimental procedures, mice were maintained at the Animal Facility for Helminth-Infected Animals of the Department of Parasitology (UFMG, Brazil), fed with standard laboratory chow (Presence, Paulínia, SP, Brazil), and provided with tap water ad libitum. The performed experimental procedures were
Prolonged exposure to DSS does not alter Strongyloides venezuelensis burden
Multiple cycles of DSS treatment did not alter S. venezuelensis infection load (Fig. 2). At day 7 post-infection, the number of adult worms recovered from the small intestines (Fig. 2A), the number of parasite eggs eliminated in feces (Fig. 2B), and the fecundity indexes (Fig. 2C) were statistically similar when comparing S. venezuelensis-infected (Sv) with the DSS-exposed and S. venezuelensis-infected (DSS-Sv) mice.
Strongyloides venezuelensis infection reduces the clinical signs of DSS-induced chronic colitis in mice
Chronic colitis was established following three cycles of 2.5% DSS
Discussion
Patients with IBD usually display a chronic condition that demands long-term prescriptions, shows poor curative effects, and produces serious side effects (Ahluwalia et al., 2018, Halfvarson et al., 2003). Although most of the experimental data reported that active helminth infections or their antigens have a preventive effect on experimentally induced colitis, their effect on chronically established models, which are clinically more relevant, are still unknown. Therefore, in the current study,
Conclusions
Based on our data and the published literature, we suggest that S. venezuelensis infection induces regulatory and repair mechanisms through the stimulation of Treg cells, TGF-β, IL-22, and IL-33, which reduce intestinal inflammation and granulocyte infiltration and induce mucus production and repair of the colon epithelium in a model of chronic colitis induced by prolonged exposure to DSS. These findings improve our understanding of the modulatory mechanisms induced by helminth infections and
CRediT authorship contribution statement
Vanessa Fernandes Rodrigues: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing – original draft, Writing - review & editing, Visualization. Genil Mororó Araújo Camelo: Methodology, Writing - review & editing. Michelle Carvalho de Rezende: Methodology. Laura Maggi: Methodology. Jeferson Kelvin Alves Oliveira Silva: Methodology. João Gustavo Mendes Rodrigues: Methodology. Márcio Sobreira Silva Araújo: Methodology, Formal analysis. Olindo Assis
Declaration of Competing Interest
Vanessa Fernandes Rodriguesa, Genil Mororó Araújo Camelo, Michelle Carvalho de Rezende, Laura Maggi, Jeferson Kelvin Alves Oliveira Silva, João Gustavo Mendes Rodrigues, Márcio Sobreira Silva Araújo, Olindo Assis Martins-Filho and Deborah Negrão-Corrêa declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in paper entitled “Infection by Strongyloides venezuelensis attenuates chronic colitis induced by
Acknowledgments
Financial support for reagents, equipment and fellowships used in this work was provided by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-Brazil, grant # 481035/2012-5; grant #140160/2019-1), Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG-Brazil, grant # PPM-00500-15; # APQ-01637-17), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES-Brazil, Basic Parasitology Program, grant # 23038.005297/2011-39, grant #88887.163351/2018-00).
Graphic abstract illustration credits
From Servier Medical Art (https://smart.servier.com/), reproduced under Creative Commons License attribution 3.0 Unported License.
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