Project description:Fibromyalgia is a chronic pain syndrome characterized by widespread pain. The pathophysiology of fibromyalgia is not clearly understood and there are no specific biomarkers available for accurate diagnosis. Here we define genomic signatures using high throughput RNA sequencing on 96 fibromyalgia and 93 matched controls. Our findings revealed two major fibromyalgia-associated expression signatures. The first group included 44 patients with a signature enriched for gene expression associated with extracellular matrix and downregulation of RhoGDI signaling pathway. The second group included 31 patients and showed a profound reduction in the expression of inflammatory mediators with an increased expression of genes involved in the CLEAR signaling pathway. These results suggest defective tissue homeostasis associated with the extra-cellular matrix and cellular program that regulates lysosomal biogenesis and participates in macromolecule clearance in fibromyalgia. Further elucidation of these pathways will lead to development of accurate diagnostic markers, and effective therapeutic options for fibromyalgia.
Project description:Hypoxic ischemic brain damage (HIBD) is the primary cause of neurological deficits in neonates, leading to long-term cognitive impairment. Recent studies have demonstrated that gut microbiota plays a crucial role in the development of cognitive impairment after brain injury, known as the microbiota-gut-brain axis.
Project description:Fibromyalgia is a complex disorder whose main symptoms are chronic widespread pain and fatigue, and affects between 0.2 and 6.6% of the world population. Nowadays, there are no molecular biomarkers which could facilitate diagnosis, underlining the extreme necessity of basic research on this chronic disorder. The latest efforts by the researchers have focused on studying problems at the level of central nervous system sensitivity, inflammatory and oxidative disorders, and even imbalances related to the intestinal microbiota. A total of 892 women were initially enrolled in the study. For those fulfilling inclusion criteria, a plasma proteome analysis in blood samples was conducted. Briefly, blood was collected, centrifuged and analyzed by liquid nano-chromatography coupled to tandem mass spectrometry. After the raw data analysis, proteins with statistically significant differential abundance and a fold change over 1.2 (20% increase in fibromyalgia compared with control samples) or under 0.8 (20% decrease in fibromyalgia compared with control samples) in fibromyalgia were selected. For fecal metagenome analysis, fecal samples were collected, homogenized and processed for DNA extraction. Amplicon sequencing of V3–V4 regions from the 16S ribosomal RNA gene was performed using the Illumina MiSeq platform Quality control procedures were implemented using thresholds set at 50,000 reads per sample, Q30 Phred Score and an average trimmed read length of 280bp. The statistical analysis was conducted using R v4.3.2 base packages. After applying exclusion criteria, 242 women (199 patients and 43 age- and environmentally paired healthy individuals) provided plasma and feces samples, as well as properly filled health questionnaires. A total of 30 proteins and 19 taxa were differentially expressed in fibromyalgia patients, and its integration into an algorithm allows to discriminate cases and controls. The multiomic approach for biomarker discovery in this study propose a multifactorial connection between gut microbiota and mitochondria-derived oxidative stress and inflammation. Plasma and fecal multiomics analysis suggest an intricate and multifactorial connection between gut microbiota and mitochondria-derived oxidative stress and inflammation in FM patients, with glyceraldehyde-3-phosphate dehydrogenase and Streptococcus salivarius as leading actors.
Project description:Emerging research highlights the gut microbiota's critical role in modulating brain activity via the gut-brain axis. This study explores whether targeted gastrointestinal irradiation induces abscopal effects on the brain proteome, revealing microbiota-mediated neurobiological changes. Male Sinclair minipigs were randomized to receive either sham treatment (n=6) or 8 Gy lower hemibody (gut-targeted) irradiation (n=5). Over 14 days, rectal swabs were collected to monitor microbiota dynamics, followed by frontal cortex proteomic analysis. Irradiation altered gut microbiota composition, notably reducing Chlamydiae and Firmicutes phyla, while increasing Coriobacteriaceae and Acinetobacter. Proteomic analysis identified 75 differentially abundant proteins in the frontal cortex, including a significant decrease in pannexin-1 (PANX1), suggesting modulation of the NLRP3 inflammasome pathway. Functional enrichment analysis revealed immune and neurotransmission-related changes linked to microbial shifts. These results demonstrate that gut-targeted radiation can remotely affect brain protein expression, emphasizing the microbiota's role in neuroimmune regulation and pointing to novel therapeutic opportunities in gut-brain axis disorders.
Project description:Brain metastases (BrMs) are the most common brain tumors in patients and are associated with poor prognosis. Investigating the systemic and environmental factors regulating BrM biology represents an important strategy to develop effective treatments. Towards this goal, we explored the contribution of the gut microbiome to BrM development by using in vivo breast-BrM models under germ-free conditions or antibiotic treatment. This revealed a detrimental role of gut microbiota in fostering BrM initiation. We thus evaluated the impact of antibiotics and BrM outgrowth on the gut-brain axis. We found the bacterial genus Alistipes was differentially present under antibiotic treatment and BrM progression. In parallel, we quantified circulating metabolites, revealing kynurenic acid as a differentially abundant molecule which impaired the interaction between cancer cells and the brain vasculature in ex vivo functional assays. Together, these results illuminate the potential role of gut microbiota in modulating breast-BrM via the gut-to-brain axis.
Project description:FM is a complex syndrome with physiological, genetics and environmental factors involved. It can present changes in functional neuroimaging, in cortical excitability measurements performed by transcranial magnetic stimulation and in grey matter density. Similarly, it has been shown that patients with FM have abnormal autonomic control, inflammatory profile and dysfunctional hypothalamic–pituitary–adrenal axis leading to disruptive sleep and fatigue. We characterized clinical and neurophysiological parameters and peripheral blood DNA methylation profiles of patients with FM and compared them to sex and age matched healthy controls. We hypothesized that these exploratory analyses could provide mechanistic insights into the pathophysiology of FM and possibly contribute to the future development of biological markers of diagnosis.We showed that patients with fibromyalgia have different (mainly hypo-) methylated CpG sites related to genes implicated in immune system and response to external stress pathways and that this methylation profile is related to a dysfunctional connectivity in pain network, adding evidence to consider fibromyalgia as a DOHAD disorder.
Project description:Brain and central nervous system (CNS) tumors are the leading cause of cancer-related deaths in both adults and children, particularly affecting those aged 0–14 years. Efforts to develop targeted therapies have largely been unsuccessful, with limited improvement in survival rates. This underscores the urgent need for more effective treatments. Recent research highlights the importance of the gut microbiota and its collective genomes, known as the microbiome, in maintaining overall health. The microbiome helps prevent infections and regulates immune responses both locally and throughout the body. There is a strong connection between the gastrointestinal (GI) system and the CNS, as the CNS plays a crucial role in controlling the GI tract’s function and balance. The relationship between the gut microbiota and the brain, referred to as the microbiota-gut-brain axis, is a complex interaction that may influence CNS cancer development and treatment outcomes. In this study, researchers examined the gut microbiota composition in a group of pediatric cancer patients, focusing on those with CNS tumors.
Project description:Major depressive disorder (MDD) is a leading cause of disability around the world and contributes greatly to the global burden of disease. Mounting evidence suggests that gut microbiota dysbiosis may be involved in the pathophysiology of MDD through the microbiota–gut–brain axis. Recent research suggests that epigenetic modifications might relate to depression. However, our knowledge of the role of epigenetics in host–microbe interactions remains limited. In the present study, we used a combination of affinity enrichment and high-resolution liquid chromatography tandem mass spectrometry analysis to identify hippocampal acetylated proteins in germ-free(GF) and specific pathogen-free(SPF) mice. In total, 986 lysine acetylation sites in 543 proteins were identified, of which 747 sites in 427 proteins were quantified. Motif analysis identified several conserved sequences surrounding the acetylation sites, including D*Kac, DKac, KacY, KacD, and D**Kac. Gene ontology annotations revealed that these differentially expressed acetylated proteins were involved in multiple biological functions and mainly located in mitochondria. In addition, pathway enrichment analysis showed that oxidative phosphorylation and the tricarboxylic acid (TCA) cycle II (eukaryotic), both of which are exclusively localized to the mitochondria, were the primarily disturbed functions. Taken together, this study indicates that lysine acetylation changes may play a pivotal role in the mitochondrial dysfunction by which gut microbiota regulate brain function and behavioral phenotypes.
Project description:Gut microbiota play an important role in regulating individual health. It is also increasingly apparent that changes in maternal gut microbiota result can render her offspring more susceptible to diseases later in life. Such bacterial induced changes likely originate in the womb. As the placenta is the primary communication organ between mother and conceptus, it is vulnerable to in utero environmental changes, including those associated with maternal gut microbiota. The placenta also relays nutritional and other factors, including serotonin, to the developing fetal brain that help guide development of this organ. Thus, placental disruptions can influence the placenta-brain axis and subsequently neurobehavioral programming with potential long-term consequences. One mechanism by which changes in maternal gut microbiota might effect the placenta are through alterations in bacterial short chained fatty acids (SCFA). The hypothesis, thus, tested in the current studies is that absence of a maternal gut microbiota, as occurs in germ-free (GF) mice, would impact bacterial SCFA in her fecal samples and in the fetal placenta and brain. Secondarily, we tested whether transcriptomic changes would be evident in the placenta and fetal brain from conceptuses derived from GF relative to multi-pathogen free (MPF) pregnant females.