Biology subjects

De Palma, G.

Publications and source records attributed to De Palma, G..

4 recordsLinked to original sources

bioRxiv2025

The fecal microbiota transplantation from drug-naive schizophrenia patients distinctively changes gut microbiome and metabolic profiles in male and female mice

BackgroundEmerging evidence suggests a role for the gut microbiome in schizophrenia (SCZ) and antipsychotic-induced metabolic perturbations. Using human fecal microbiota transplantation (FMT) in mice, this study investigated the role of gut microbiome in metabolic changes related to SCZ and antipsychotic (olanzapine) treatment. Methods5-6 weeks old germ-free NIH Swiss mice of both sexes received microbiota from either SCZ patients (SCZ-FMT) or healthy controls (HC-FMT) followed by a diet with or without olanzapine for six-weeks. Food intake and body weight were monitored weekly, and an intraperitoneal glucose tolerance test and open field test were performed. Serum glucose, and insulin were measured. Gut microbiome characterization and short-chain fatty acids (SCFAs) quantification were performed in the cecal samples using 16S rRNA gene sequencing and gas chromatography-mass spectrometry, respectively. ResultsOlanzapine treatment decreased the locomotor activity in the open field test, irrespective of sex or microbiota. Female SCZ-FMT recipient mice exhibited insulin resistance compared to HC-FMT, irrespective of olanzapine treatment. Female SCZ-FMT mice showed significantly lower alpha-diversity compared to HC-FMT, whereas olanzapine treatment increased alpha-diversity. SCZ-FMT and olanzapine treatment differentially altered the microbial abundances, and metabolic pathways in male and female mice. Interestingly, cecal SCFAs, mainly acetate levels, were significantly decreased in female SCZ-FMT mice compared to HC-FMT, while olanzapine treatment increased acetate levels in male mice. Both male and female SCZ-FMT mice showed elevated levels of isovaleric acid compared to HC-FMT. ConclusionThese preliminary findings suggest that gut microbiome could be a predisposing factor contributing to the intrinsic risk of developing type 2 diabetes associated with SCZ in females. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/675957v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@8cfd10org.highwire.dtl.DTLVardef@3a6031org.highwire.dtl.DTLVardef@813428org.highwire.dtl.DTLVardef@87609e_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

neuroscience↗

bioRxiv2025

Dietary tryptophan enhances aryl hydrocarbon receptor activation and reduces colitis through microbial metabolism

Background & AimDisrupted microbial tryptophan metabolism and impaired aryl hydrocarbon receptor (AhR) activation are implicated in inflammatory bowel disease (IBD) pathogenesis. However, strategies to restore this pathway through diet or microbial modulation remain poorly defined. This study investigates how dietary tryptophan and human and mouse microbiota modulate metabolism, AhR activation, and intestinal inflammation in preclinical models. MethodsGnotobiotic mice colonized with microbiota of varying complexity or human fecal microbiota from ulcerative colitis (UC) patients and healthy controls were used to assess the impact of microbiota and dietary tryptophan supplementation on AhR activation and colitis severity. Chemically induced and spontaneous colitis models were investigated. ResultsIBD fecal samples showed reduced AhR activation compared to healthy controls, and fecal microbiota transplantation into germ-free mice demonstrated that impaired AhR is microbiota-dependent. Mice colonized with minimal microbiota had impaired microbial tryptophan metabolism, lower AhR activation, and worsened colitis severity compared to those colonized with complex microbiota. Dietary tryptophan supplementation in conventional and UC-humanized mice enhanced microbial production of AhR agonists, restored AhR activation, and reduced colitis severity in an AhR-dependent manner. Co-colonization with a tryptophan-metabolizing bacterium, Clostridium sporogenes, further improved tryptophan metabolism and colitis severity in mice with impaired microbial tryptophan metabolism. ConclusionsMicrobial tryptophan metabolism is critical for determining intestinal inflammation. Dietary tryptophan supplementation restores microbial metabolic pathways, mitigates colitis severity in preclinical models, and may address key metabolic deficiencies in IBD patients with impaired tryptophan metabolism. This study demonstrates the therapeutic potential of targeting microbial metabolism with diet in IBD management.

physiology↗

bioRxiv2025

Red Blood Cell-derived Extracellular Vesicles enable Cisplatin and Cetuximab Synergistic Therapy against Triple-Negative Breast Cancer

BackgroundTriple-negative breast cancer is an aggressive breast cancer subtype characterized by the absence of human epidermal growth factor receptor 2, estrogen and progesterone receptors, limiting targeted therapy options. Cisplatin, a chemotherapeutic agent, induces DNA damage and exhibits some efficacy against triple-negative breast cancer, but its effectiveness is often reduced by chemoresistance and systemic toxicity. A very promising strategy to augment cisplatin treatment can be based on combining it with the biologic Cetuximab, an epidermal growth factor receptor inhibitor, which boosts cisplatin efficacy by inducing ferroptosis. ResultsTo optimize this strategy in a biocompatible and precise manner, we developed a nanoplatform based on red blood cell-derived extracellular vesicles for the combined delivery of Cetuximab and cisplatin, enabling immune evasion, and the possibility of autologous personalization and GMP-compliant production. Owing to their DNA-free lumen and lack of EGFR, RBC-EVs preserve cisplatin activity and prevent interference with cetuximab. This formulation enhances cisplatins cytotoxicity by up to 50%, as shown in vitro and in patient-derived organoids. It effectively reduces chemoresistance by downregulating hypoxia-related genes and promoting ferroptosis, additionally, it improves cisplatins cytotoxic effects while reducing hemotoxicity compared to the administration of free cisplatin. ConclusionsThese findings highlight the potential of red blood cell-derived extracellular vesicles as a biocompatible delivery system enabling combined therapy and offering a promising strategy to overcome current limitations in TNBC treatment.

cell biology↗

bioRxiv2024

Innate immune system signaling and CD11b+CD11c+CD103+ cell migration to the brain underlie changes in mouse behavior after microbial colonization.

Background and AimsAccumulating evidence suggests the microbiota is a key factor in disorders of gut-brain interaction (DGBI), by affecting host immune and neural systems. However, the underlying mechanisms remain elusive due to their complexity and clinical heterogeneity of patients with DGBIs. We aimed to identify neuroimmune pathways that are critical in microbiota-gut-brain communication during de novo gut colonization. MethodsWe employed a combination of gnotobiotic and state-of-the-art microbial tools, behavioral analysis, immune and pharmacological approaches. Germ-free wild type, MyD88-/- Ticam1-/- and SCID mice were studied before and after colonization with specific pathogen-free microbiota, Altered Schaedler Flora, E. coli or S. typhimurium (permanent or transient colonizers). TLR agonists and antagonists, CCR7 antagonist or immunomodulators were used to study immune pathways. We assessed brain c-Fos, brain-derived neurotrophic factor, and dendritic and glial cells by immunofluorescence, expression of neuroimmune genes by NanoString and performed brain proteomics. ResultsBacterial monocolonization, conventionalization or administration of microbial products to germ-free mice altered mouse behavior similarly, acting through Toll-like receptor or nucleotide-binding oligomerization domain signaling. The process required CD11b+CD11c+CD103+ cell activation and migration into the brain. The change in behavior did not require the continued presence of bacteria and was associated with activation of multiple neuro-immune networks in the gut and the brain. ConclusionsChanges in neural plasticity occur rapidly upon initial gut microbial colonization and involve innate immune signaling to the brain, mediated by CD11b+CD11c+CD103+ cell migration. The results identify a new target with therapeutic potential for DGBIs developing in context of increased gut and blood-brain barrier permeability. HighlightsO_LIMicrobiota impairment is a key factor in disorders of gut-brain interaction (DGBI) C_LIO_LIMicrobial colonization induces changes in brain and behavior via innate immunity C_LIO_LIMicrobial colonization activates multiple neuro-immune networks in gut and brain C_LIO_LIBehavioral change is mediated by CD11b+CD11c+CD103+ cells migration to the brain C_LI

animal behavior and cognition↗