Project description:While strongly implicated in Postural Tachycardia Syndrome (POTS), considerable controversy exists regarding norepinephrine transporter (NET) loss-of-function. POTS is characterized by the clinical symptoms of orthostatic intolerance, light-headedness, tachycardia and syncope or near syncope with upright posture. Abnormal sympathetic nervous system activity is typical, of a type which suggests dysfunction of the NET, with evidence the gene responsible is under tight epigenetic control. Using RNA of isolated chromatin combined with sequencing (RICh-Seq) we show let7i miRNA suppresses NET by MeCP2. Vorinostat restores epigenetic control and NET expression in POTS.
Project description:Postural orthostatic tachycardia syndrome (POTS) is a cardiovascular autonomic disorder leading to debilitating symptoms and the therapeutic alternatives are limited. Proteomics is a large-scale study of proteins that enables a systematic unbiased view on disease and health, allowing stratification on patients based on their protein background. We aimed to explore proteins that may be related with the putative etiology of POTS compared with healthy controls using a highly powerful targeted proteomic mass spectrometry technique. We aimed to explore proteins that may be related with the putative etiology of POTS compared with healthy controls using a highly powerful targeted proteomic mass spectrometry technique.
Project description:The gut microbiota plays an important role in host health. Microbiota dysbiosis has been implicated in the global epidemic of Metabolic Syndrome (MetS) and could impair host metabolism by noxious metabolites. It has been well established that the gut microbiota is shaped by host immune factors. However, the effect of T cells on the gut microbiota is yet unknown. Here, we performed a metagenomic whole-genome shotgun sequencing (mWGS) study of the microbiota of TCRb-/- mice, which lack alpha/beta T cells.
Project description:Postural orthostatic tachycardia syndrome (POTS) is a chronic neurological disorder of the autonomic nervous system (ANS) that is characterized by an excessive increase in heart rate upon orthostatic challenge. The symptoms of POTS are often debilitating, and it primarily affects young females. Even prior to coronavirus disease 2019 (COVID-19) pandemic, POTS was prevalent, affecting an estimated 0.5% to 1% of the entire population in the United States (US). Since the COVID-19 pandemic, the incidence of POTS has acutely risen, adding roughly 6-7 million POTS patients in the US alone. Despite its importance, there is currently no reliable serum biomarker for POTS. One of the major hurdles in identifying biomarkers of POTS is the heterogenous nature of the clinical syndrome. To address this challenge, we focused our analysis on patients from the recent increase in cases of post-COVID-19 onset POTS (PC-POTS). We hypothesized that PC-POTS represents a relatively homogeneous subgroup of POTS, likely triggered by the same pathogen, and presents with symptoms that are more pronounced compared to those in healthy controls. We identified 752 proteins from 18 serum proteome samples composed of 9 PC-POTS patients and 9 health control (HC) individuals, and 31 proteins showed a significant protein abundance difference in PC-POTS. Notably, the majority of the elevated proteins are associated with either actin filaments or immune functions/inflammation. The Weighted Gene Co-Expression Network Analysis (WGCNA) revealed that the module 7 (M7) most highly correlated with the diagnosis also exhibited strong correlations with various sample traits such as the Orthostatic Intolerance Score, Gastrointestinal Score, Pupillomotor Score, and the COMPASS-31 score. The proteins MTPN, TAGLN2, ADP-ribosylation factor 1, PDLIM1, PPIA, CNN2, LGALSL, TXN, TLN1, TUBA4A, IL4, TREML1, GP1BA, and GP6 were identified as common proteins overlapping in various sample traits. Cell-type enrichment analysis revealed that M7 is highly associated with immune and neuronal cells. The main pathways identified in this module include the integrin signaling pathway, blood coagulation, and glycolysis. This suggests that these proteins could potentially serve as biomarkers for PC-POTS. This study utilizes mass spectrometry-based proteomic analysis to identify serum biomarkers that differentiate patients with PC-POTS from HC individuals, thus establishing a foundation for further research and validation.
Project description:Irritable Bowel Syndrome (IBS) is a disorder of the gut-brain axis, characterized by altered gut function and frequent psychiatric co-morbidity. Although altered intestinal microbiome profiles have been documented, their relevance to the clinical expression of IBS is unknown. To evaluate a functional role of the microbiota, we colonized germ-free mice with fecal microbiota from healthy controls or IBS patients with accompanying anxiety, and monitored gut function and behavior. Mouse microbiota profiles clustered according to their human donors. Despite having taxonomically similar composition as controls, mice with IBS microbiota had distinct serum metabolomic profiles related to neuro- and immunomodulation. Mice with IBS, but not control microbiota, exhibited faster gastrointestinal transit, intestinal barrier dysfunction, innate immune activation and anxiety-like behavior. These results support the notion that the microbiota contributes to both intestinal and behavioral manifestations of IBS and rationalize the use of microbiota-directed therapies in ameliorating IBS.
Project description:We have previously demonstrated that the gut microbiota can play a role in the pathogenesis of conditions associated with exposure to environmental pollutants. It is well accepted that diets high in fermentable fibers such as inulin can beneficially modulate the gut microbiota and lessen the severity of pro-inflammatory diseases. Therefore, we aimed to test the hypothesis that hyperlipidemic mice fed a diet enriched with inulin would be protected from the pro-inflammatory toxic effects of PCB 126.
Project description:Changes in microbiome composition have been associated with a wide array of human diseases, turning the human microbiota into an attractive target for therapeutic intervention. Yet clinical translation of these findings requires the establishment of causative connections between specific microbial taxa and their functional impact on host tissues. Here, we infused gut organ cultures with longitudinal microbiota samples collected from therapy-naïve irritable bowel syndrome (IBS) patients under low-FODMAP (fermentable Oligo-, Di-, Mono-saccharides and Polyols) diet. We show that post-diet microbiota regulates intestinal expression of inflammatory and neuro-muscular gene-sets. Specifically, we identify Bifidobacterium adolescentis as a diet-sensitive pathobiont that alters tight junction integrity and disrupts gut barrier functions. Collectively, we present a unique pathway discovery approach for mechanistic dissection and identification of functional diet-host-microbiota modules. Our data support the hypothesis that the gut microbiota mediates the beneficial effects of low-FODMAP diet and reinforce the potential feasibility of microbiome based-therapies in IBS.