Abstract
BackgroundRett syndrome (RTT) is a neurological disorder mainly caused by mutations in MeCP2 gene. It has been shown that MeCP2 impairments can lead to cytokine dysregulation due to MeCP2 regulatory role in T-helper and T-reg mediated responses, thus contributing to the pro-inflammatory status associated with RTT. Furthermore, RTT subjects suffer from an intestinal dysbiosis characterized by an abnormal expansion of the Candida population, a known factor responsible for the hyper-activation of pro-inflammatory immune responses. Therefore, we asked whether the intestinal fungal population of RTT subjects might contribute the sub-inflammatory status triggered by MeCP2 deficiency.MethodsWe evaluated the cultivable gut mycobiota from a cohort of 50 RTT patients and 29 healthy controls characterizing the faecal fungal isolates for their virulence-related traits, antifungal resistance and immune reactivity in order to elucidate the role of fungi in RTT’s intestinal dysbiosis and gastrointestinal physiology.ResultsCandida parapsilosis, the most abundant yeast species in RTT subjects, showed distinct genotypic profiles if compared to healthy controls’ isolates as measured by hierarchical clustering analysis from RAPD genotyping. Their phenotypical analysis revealed that RTT’s isolates produced more biofilm and were significantly more resistant to azole antifungals compared to the isolates from the healthy controls. In addition, the high levels of IL-1β and IL-10 produced by peripheral blood mononuclear cells and the mixed Th1/Th17 cells population induced by RTT C. parapsilosis isolates suggest the capacity of these intestinal fungi to persist within the host, being potentially involved in chronic, pro-inflammatory responses.ConclusionsHere we demonstrated that intestinal C. parapsilosis isolates from RTT subjects hold phenotypic traits that might favour the previously observed low-grade intestinal inflammatory status associated with RTT. Therefore, the presence of putative virulent, pro-inflammatory C. parapsilosis strains in RTT could represent an additional factor in RTT’s gastrointestinal pathophysiology, whose mechanisms are not yet clearly understood.
Highlights
Rett syndrome (RTT) is a neurological disorder mainly caused by mutations in methyl-CpG binding protein 2 (MeCP2) gene
RTT gut mycobiota shows a reduction of C. albicans and an increase of C. parapsilosis populations We identified 122 fungal isolates belonging to different species (Additional file 1: Table S1)
While in RTT subjects 4 out of 24 fungal isolates belonged to C. albicans (16.7%) and 14 out of 24 belonged to C. parapsilosis (58.3%), in the Healthy Controls (HC) 49 out of 98 fungal isolates belonged to C. albicans (50%) and 15 out of 98 belonged to C. parapsilosis (15.3%) (Additional file 2: Figure S1)
Summary
Rett syndrome (RTT) is a neurological disorder mainly caused by mutations in MeCP2 gene. It has been shown that MeCP2 impairments can lead to cytokine dysregulation due to MeCP2 regulatory role in T-helper and T-reg mediated responses, contributing to the pro-inflammatory status associated with RTT. RTT subjects suffer from an intestinal dysbiosis characterized by an abnormal expansion of the Candida population, a known factor responsible for the hyper-activation of pro-inflammatory immune responses. We asked whether the intestinal fungal population of RTT subjects might contribute the sub-inflammatory status triggered by MeCP2 deficiency. The shift between pro-inflammatory and tolerogenic dendritic cells (DCs) responses are mediated by the kynurenine pathway of tryptophan catabolism, in which the expression of indoleamine 2,3-dioxygenase (IDO1) has a key role on plasticity of DCs activities in balancing between CD4+ effector Th cells and regulatory T (T-reg) cells [2, 5]. Alterations of the levels of kynurenine, a neuroprotective agent, have been implicated in several pathologies, including autism spectrum disorders [14]
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