Bacterial Butyrate in Parkinson's Disease Is Linked to Epigenetic Changes and Depressive Symptoms

Background The gut microbiome and its metabolites can impact brain health and are altered in Parkinson's disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. Objectives Here, we investigate whether the changes in the gut microbiome and associated metabolites are related to PD symptoms and epigenetic markers in leucocytes and neurons. Methods Stool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified genome-wide DNA methylation by targeted bisulfite sequencing. Results We show that lower fecal butyrate and reduced counts of genera Roseburia, Romboutsia, and Prevotella are related to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA regions in PD overlap with those altered in gastrointestinal (GI), autoimmune, and psychiatric diseases. Conclusions Decreased levels of bacterially produced butyrate are related to epigenetic changes in leucocytes and neurons from PD patients and to the severity of their depressive symptoms. PD shares common butyrate-dependent epigenetic changes with certain GI and psychiatric disorders, which could be relevant for their epidemiological relation. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder SocietyPeer reviewe

Small extracellular vesicles from young adipose-derived stem cells prevent frailty, improve health span, and decrease epigenetic age in old mice.

Aging is associated with an increased risk of frailty, disability, and mortality. Strategies to delay the degenerative changes associated with aging and frailty are particularly interesting. We treated old animals with small extracellular vesicles (sEVs) derived from adipose mesenchymal stem cells (ADSCs) of young animals, and we found an improvement in several parameters usually altered with aging, such as motor coordination, grip strength, fatigue resistance, fur regeneration, and renal function, as well as an important decrease in frailty. ADSC-sEVs induced proregenerative effects and a decrease in oxidative stress, inflammation, and senescence markers in muscle and kidney. Moreover, predicted epigenetic age was lower in tissues of old mice treated with ADSC-sEVs and their metabolome changed to a youth-like pattern. Last, we gained some insight into the microRNAs contained in sEVs that might be responsible for the observed effects. We propose that young sEV treatment can promote healthy aging

Parsimonious temporal aggregation

Temporal aggregation is a crucial operator in temporal databases and has been studied in various flavors, including instant temporal aggregation (ITA) and span temporal aggregation (STA), each having its strengths and weaknesses. In this paper we define a new temporal aggregation operator, called parsimonious temporal aggregation (PTA), which comprises two main steps: (i) it computes the ITA result over the input relation and (ii) it compresses this intermediate result to a user-specified size c by merging adjacent tuples and keeping the induced total error minimal; the compressed ITA result is returned as the final result. By considering the distribution of the input data and allowing to control the result size, PTA combines the best features of ITA and STA. We provide two evaluation algorithms for PTA queries. First, the oPTA algorithm computes an exact solution, by applying dynamic programming to explore all possibilities to compress the ITA result and selecting the compression with the minimal total error. It runs in O(n2pc) time and O(n2) space, where n is the size of the input relation and p is the number of aggregation functions in the query. Second, the more efficient gPTA algorithm computes an approximate solution by greedily merging the most similar ITA result tuples, which, however, does not guarantee a compression with a minimal total error. gPTA intermingles the two steps of PTA and avoids large intermediate results. The compression step of gPTA runs in O(np log(c + ?)) time and O(c + ?) space, where ? is a small buffer for ""look ahead"". An empirical evaluation shows good results: considerable reductions of the result size introduce only small errors, and gPTA scales to large data sets and is only slightly worse than the exact solution of PTA

A Greedy Approach Towards Parsimonious Temporal Aggregation

Temporal aggregation is a crucial operator in temporal databases and has been studied in various flavors. In instant temporal aggregation (ITA) the aggregate value at time instant t is computed from the tuples that hold at t. ITA considers the distribution of the input data and works at the smallest time granularity, but the result size depends on the input timestamps and can get twice as large as the input relation. In span temporal aggregation (STA) the user specifies the timestamps over which the aggregates are computed and thus controls the result size. In this paper we introduce a new temporal aggregation operator, called greedy parsimonious temporal aggregation (PTAg), which combines features from ITA and STA. The operator extends and approximates ITA by greedily merging adjacent tuples with similar aggregate values until the number of result tuples is sufficiently small, which can be controlled by the application. Thus, PTAg considers the distribution of the data and allows to control the result size. Our empirical evaluation on real world data shows good results: considerable reductions of the result size introduce small errors only

Integrative Analysis Unveils the Correlation of Aminoacyl-tRNA Biosynthesis Metabolites with the Methylation of the SEPSECS Gene in Huntington’s Disease Brain Tissue

The impact of environmental factors on epigenetic changes is well established, and cellular function is determined not only by the genome but also by interacting partners such as metabolites. Given the significant impact of metabolism on disease progression, exploring the interaction between the metabolome and epigenome may offer new insights into Huntington’s disease (HD) diagnosis and treatment. Using fourteen post-mortem HD cases and fourteen control subjects, we performed metabolomic profiling of human postmortem brain tissue (striatum and frontal lobe), and we performed DNA methylome profiling using the same frontal lobe tissue. Along with finding several perturbed metabolites and differentially methylated loci, Aminoacyl-tRNA biosynthesis (adj p-value = 0.0098) was the most significantly perturbed metabolic pathway with which two CpGs of the SEPSECS gene were correlated. This study improves our understanding of molecular biomarker connections and, importantly, increases our knowledge of metabolic alterations driving HD progression

Epigenetic inactivation of the autophagy–lysosomal system in appendix in Parkinson’s disease

The gastrointestinal tract may be a site of origin for α-synuclein pathology in idiopathic Parkinson’s disease (PD). Disruption of the autophagy-lysosome pathway (ALP) may contribute to α-synuclein aggregation. Here we examined epigenetic alterations in the ALP in the appendix by deep sequencing DNA methylation at 521 ALP genes. We identified aberrant methylation at 928 cytosines affecting 326 ALP genes in the appendix of individuals with PD and widespread hypermethylation that is also seen in the brain of individuals with PD. In mice, we find that DNA methylation changes at ALP genes induced by chronic gut inflammation are greatly exacerbated by α-synuclein pathology. DNA methylation changes at ALP genes induced by synucleinopathy are associated with the ALP abnormalities observed in the appendix of individuals with PD specifically involving lysosomal genes. Our work identifies epigenetic dysregulation of the ALP which may suggest a potential mechanism for accumulation of α-synuclein pathology in idiopathic PD

Reversal of biological age in multiple rat organs by young porcine plasma fraction

Young blood plasma is known to confer beneficial effects on various organs in mice and rats. However, it was not known whether plasma from young adult pigs rejuvenates old rat tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n = 613 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain, liver, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n = 1366 human tissue samples to the training data. We employed these six rat clocks to investigate the rejuvenation effects of a porcine plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers, behavioral responses encompassing cognitive functions. An immunoglobulin G (IgG) N-glycosylation pattern shift from pro- to anti-inflammatory also indicated reversal of glycan aging. Overall, this study demonstrates that a young porcine plasma-derived treatment markedly reverses aging in rats according to epigenetic clocks, IgG glycans, and other biomarkers of aging