Niclosamide modulates chronic Cryptosporidium-induced ileocecal adenocarcinoma in immunocompromised infected mice via...

Cryptosporidiosis, a protozoal disease caused by Cryptosporidium parvum (C. parvum), is a globally emerging waterborne infection leading to moderate to severe diarrhea, particularly in immunocompromised individuals. Emerging evidence proposes a potential correlation between chronic infection and digestive cancers, though the underlying mechanisms remain unclear. Therapeutic options are minimal, with nitazoxanide (NTZ) being the only drug available, despite its constrained effectiveness. Niclosamide (NICLO), an anthelmintic drug, exhibits antiparasitic properties and modulates oncogenic signaling pathways, making it a promising candidate for dual therapeutic effects. This study investigated NICLO's efficacy against chronic C. parvum infection and its potential to prevent ileocecal adenocarcinoma development in immunocompromised mice. Mice were immunosuppressed using dexamethasone, infected with C. parvum oocysts, and administered NTZ or NICLO. NICLO administration significantly reduced parasite burden by 90 %, restored histopathological alterations, and suppressed C. parvum-induced inflammation, as evidenced by suppressed IL-6 and IL-22 levels and STAT3 activation. NICLO also counteracted the antiapoptotic effects of infection by downregulating Bcl-2 and upregulating Bax and cleaved caspase-3 levels. Moreover, NICLO deactivated the Wnt/β-catenin pathway and its target genes (survivin, c-myc, and cyclin D) while elevating p53 levels. These findings highlight NICLO's dual therapeutic potential, which effectively targets C. parvum infection and mitigates its tumorigenic effects by disrupting key signaling pathways involved in ileocecal cancer progression. This study provides novel insights into NICLO's chemotherapeutic efficacy in managing cryptosporidiosis and its associated oncogenic potential.