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Urte Neniskyte
Life Sciences Center, Vilnius University, Lithuania
Western diet today has excessive fat content, causing increased obesity rates in human population worldwide, including women of reproductive age. There is growing evidence that maternal high-fat diet (mHFD) increases the risk of neurodevelopmental disorders in the offspring. To investigate the pathways that mediate the effect of mHFD on offspring neurodevelopment, we set up mHFD model, in which female C57Bl/6J mice were fed a control diet (CD, 10% fat) or high-fat diet (HFD, 60% fat) from weaning to lactation and were mated with males maintained on normal diet. The offspring were weaned to normal diet. We investigated the phenotype of the offspring social interaction, cognitive function, repetitive behavior and in other behavioral tests. The changes of offspring brain structure were determined by high-resolution voxel-based morphometry. Structural analysis was supplemented by immunohistochemistry of brain tissue sections, while gut microbiota was determined by 16S amplicon sequencing. We found specific deficits in offspring social behaviors that were accompanied by the alterations in olfactory areas of the brain and microglial activation in olfactory bulb. The consumption of HFD changed the relative abundance of different gut bacteria genera in the dams and this dysbiosis was transferred to the offspring as well. Interestingly, observed changes were sex-dependent, as structural brain alterations were more prominent in males, while microbiota changes were more notable in female offspring. Overall our findings suggest that social deficits observed in mHFD models may stem from impaired olfactory interactions in parallel or together with the dysbalance of gut microbiota composition.
Edyta Bulanda, Anna Świątkowska, Tomasz Wypych
Nencki Institute of Experimental Biology PAS, Warsaw, Poland
Our intestines are inhabited by commensal microbes, which interact with human cells to maintain homeostasis. However, one question remains unanswered: how does the gut microbiota influence immune function in distal body organs, such as the brain?
In recent years, we and others have gained important advances towards unravelling the mechanisms that underline the "gut-brain axis", as we pointed to the presence of gut-derived metabolites in this organ. Following up on this, we identified one metabolite which inhibited inflammatory responses in cells from these areas. In glial cells, it ameliorated the production of mediators typically upregulated in multiple sclerosis patients (IL-6, CCL2 or CCL20). Testing the efficacy of metabolite’s isomer pointed to the active site of the molecule and allowed us to construct the library of 20 rationally designed chemical derivatives. Some of these modifications exerted a stronger anti-inflammatory effect than the original compound, and some showed a distinct anti-inflammatory profile (i.e. inhibited different mediators). Collectively, these findings constitute the grounds for exploring the efficacy of identified metabolites in vivo and explaining their mechanisms of action.
Our results may constitute the first step towards developing these compounds as drugs.
Weronika Tomaszewska1, Izabela Lepiarz-Raba1, Taufik Hidayat1, Magdalena Gomółka1, Ismail Gbadamosi1, Aleksandra Cabaj2, Bartłomiej Gielniewski2, Jacek Miłek3, Magdalena Dziembowska3, Ali Jawaid1
1Laboratory for Translational Research in Neuropsychiatric Disorders (TREND), Nencki Institute of Experimental Biology, Warsaw, Poland
2Laboratory of Sequencing, Nencki Institute of Experimental Biology, Warsaw, Poland
3Department of Biology, University of Warsaw, Poland
Adverse childhood experiences (ACE) constitute a major risk factor for adult-onset neuropsychiatric disorders. Susceptibility to the long-term behavioural effects of ACE varies across individuals. However, the mechanisms underlying susceptibility vs. resilience to the pervasive effects of ACE remain largely unknown. Emerging evidence supports a role for metabolic factors in susceptibility to the long-term effects of ACE. We propose microglia as the central mediators of such susceptibility and hypothesize that changes in serum lipids and their associated non-coding RNAs induced by ACE can alter microglial functions. For this, we employ a unique multidisciplinary approach that synergizes investigations of samples from human cohorts with in vitro/ex vivo models of human microglia. Our preliminary investigations demonstrate ACE-induced changes in serum lipids and associated microRNA in children with a recent history of ACE in the form of paternal loss and maternal separation (PLMS). Notably, PLMS children that develop moderate to severe depressive symptoms (PLMS-susceptible) after ACE exhibit decreased high-density lipoproteins (HDLs) and differentially expressed serum microRNAs in comparison to PLMS children with no (or mild) depressive symptoms (PLMS-resilient). Furthermore, treating HMC3 human microglia-like cells with serum from the PLMS-susceptible vs. PLMS-resilient children lead to differential expression of genes involved in glycolysis. These results were corroborated by functional differences in microglial glycolysis after treatment with PLMS-susceptible vs. resilient sera via metabolic flux analysis. Our ongoing research focuses on validating these findings and studying the impact of samples collected from human ACE cohorts on microglia derived from human induced pluripotent stem cells, as well as microglia-containing human brain organoids.
Magdalena Gomółka1, Weronika Tomaszewska1, Adria-Jaume Roura Canalda2, Sandra Binias3, Ali Jawaid1
1Laboratory for Translational Research in Exposures and Neuropsychiatric Disorders (TREND), Centre of Excellence for Neural Plasticity and Brain Disorder (BRAINCITY), Nencki Institute of Experimental Biology PAS, Warsaw, Poland
2Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology PAS, Warsaw, Poland
3Laboratory of Sequencing, Nencki Institute of Experimental Biology PAS, Warsaw, Poland
Adverse childhood experiences (ACE) are associated with detrimental effects on adult physical and mental health. Emerging evidence suggests that behavioral and metabolic perturbations associated with ACE are transmissible across generations. However, the exact mechanisms underlying the effects of ACE on germline for such intergenerational transmission of symptoms remain elusive. Synergizing parallel investigation in a mouse model of ACE induced via unpredictable maternal separation and unpredictable maternal stress (MSUS) and human ACE cohorts, we hypothesize that lipid-associated microRNAs (miRNAs) communicate the effects of ACE to the germline for intergenerational transmission.
miRNA sequencing followed by RT-qPCR revealed overlapping miRNA changes in the serum collected from children, as well as the sperm from adult men with history of ACE
Parallel investigations in mice involved intergenerational phenotyping after MSUS, as well as lipid-modifying interventions high-fat diet (HFD) and voluntary exercise (VE). Offspring of MSUS- and HFD-exposed male mice showed impaired glucose tolerance and behavioral deficits. Furthermore, miRNA carriers were isolated from each group and injected into male control and MSUS mice, which were then bred with naive females. Cross-injections from MSUS into control mice recapitulated the offspring phenotype associated with MSUS, whereas, cross-injections from VE mice into MSUS mice partially mitigated the metabolic phenotype associated with MSUS. Together, these studies provide proof-of-concept for a role of lipids and circulating miRNAs in communicating the effects of ACE to the germline for intergenerational sequelae.
Ivan Arzhanov1,7, Ruslan Klassen2,3, Sarka Benesova2,5, Eva Rohlova2,5, Ales Hejcl5,6, Lukas Valihrach2, Nataliya Romanyuk1
1Department of Neuroregeneration, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
2Laboratory of Gene Expression, Institute of Biotechnology of the Czech Academy of Sciences BIOCEV, Vestec, Czech Republic
3Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology, UCT Prague, Prague, Czech Republic
4 Department of Informatics and Chemistry, Faculty of Chemistry and Technology, UCT Prague, Prague, Czech Republic
5TATAA Biocenter AB, Gothenburg, Sweden
6Neurosurgery Department, Masaryk Hospital, J. E. Purkyně University, Ústí nad Labem, Czech Republic
7Department of Neuroscience, 2nd Medical Faculty, Charles University, Prague, Czech Republic
Abstract: Spinal cord injury (SCI) poses a significant challenge in clinical settings, leading to permanent disability in over 180,000 individuals annually worldwide. The extent of the initial injury greatly influences the subsequent secondary response and thus guides the selection of appropriate therapeutic interventions. However, existing clinical measures for assessing SCI severity rely on functional tests that are not immediately applicable post-injury due to factors such as shock, concurrent injuries, and substance use. To address this need for a novel diagnostic indicator during the acute phase of SCI, we conducted comprehensive microRNA (miRNA) profiling in the blood plasma of 16 healthy individuals and 16 injured individuals. Blood samples were collected from injured patients at various intervals post-injury: 3, 12, and 24 hours, as well as 3 and 7 days. These patients were evaluated using ASIA scores and IMR assessments. MiRNA isolation was carried out for all samples, with quality assessment based on hemolysis markers and the concentration of specific endogenous miRNAs. Through our miRNA profiling, we identified miRNAs whose expression levels correlate with the severity of SCI. These findings will be integrated with the individual medical histories of patients to establish robust diagnostic criteria for assessing SCI severity during the acute phase. Our data not only enhances understanding of SCI pathophysiology but also facilitates the development of innovative diagnostic approaches.
Funding: Supported by GACR 18-21942S and NU21-08-00286 and OP JAK CZ.02.01.01/00/22_008/0004562.
