An important and potential benefit of virtual clinical trials is that the size of human trials can be reduced by making reliable predictions. ...virtual clinical trials could significantly shorten ...the time-to-market for new drugs or therapeutic strategies and reduce the costs of development. Importantly, it must be ensured that the data come from different populations to avoid model bias. ...data collection issues affect digital twin methods to some extent. Digital twin models involve uncertainty, which arises from observational uncertainty, uncertainty in model structure, and uncertainty in model parameters.
Changes in the gut microenvironment may influence the pathogenesis of autism spectrum disorders (ASD). Here, we investigated the composition of the gut microbiota and metabolites in children with ...ASD. Ninety-two children with ASD and 42 age-matched children exhibiting typical development (TD) were enrolled in the two-stage study. In the discovery stage, shotgun metagenomic sequencing and liquid chromatography-mass spectrometry (LC-MS) were performed simultaneously on fecal samples obtained from 43 children in the ASD group and 31 children in the TD group. Systematic bioinformatic analyses were performed to identify gut metabolites associated with altered gut microbiota composition. At the validation stage, differential metabolites were tested using LC-MS with an additional 49 and 11 children in the ASD and TD groups, respectively. Altered glutamate metabolites were found in the ASD group, along with a decline in 2-keto-glutaramic acid and an abundance of microbiota associated with glutamate metabolism. These changes in glutamate metabolism were correlated with lower levels of the highly abundant bacteria Bacteroides vulgatus and higher levels of the potentially harmful Eggerthella lenta and Clostridium botulinum. Lower gut cortisol levels have also been identified in the ASD group and associated with changes in gut microbiota glutamate metabolism. Finally, gut 2-keto-glutaramic acid was validated as a potential biomarker for ASD. The significant changes in the gut microenvironment in children with ASD may provide new insight into the cause of ASD and aid in the search for diagnostic and therapeutic approaches.
Multiple lines of evidence suggest that the gut microbiota may play an important role in the pathogenesis of ASD, but the specific mechanism is still unclear. Through a comprehensive gut metagenomic and metabolome study of children with ASD, alterations in gut metabolite composition were found in children with ASD, and these alterations were linked to changes in gut microbiota composition. This may give us a deeper understanding of the role of gut microbiota in the pathogenesis of ASD.
Diverse evidence including clinical, genetic and microbiome studies support a major role of the gut microbiome in the common immune-mediated arthropathy, ankylosing spondylitis (AS). We set out to ...(1) further define the key microbial characteristics driving disease, and (2) examine the effects of tumour necrosis factor-inhibitor (TNFi) therapy upon the microbiome.
The stools from a case-control cohort of 250 Han-Chinese subjects underwent shotgun metagenomic sequencing. All subjects were genotyped using the Illumina CoreExome SNP microarray.
Previous reports of gut dysbiosis in AS were reconfirmed and several notable bacterial species and functional categories were differentially abundant. TNFi therapy was correlated with a restoration the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. Enrichment of bacterial peptides homologous to HLA-B27-presented epitopes was observed in the stools of patients with AS, suggesting that either HLA-B27 fails to clear these or that they are involved in driving HLA-B27-associated immune reactions. TNFi therapy largely restored the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. TNFi therapy of patients with AS was also associated with a reduction of potentially arthritogenic bacterial peptides, relative to untreated patients.
These findings emphasise the key role that the gut microbiome plays in driving the pathogenesis of AS and highlight potential therapeutic and/or preventative targets.
Assessment and characterization of gut microbiota has become a major research area in human disease, including type 2 diabetes, the most prevalent endocrine disease worldwide. To carry out analysis ...on gut microbial content in patients with type 2 diabetes, we developed a protocol for a metagenome-wide association study (MGWAS) and undertook a two-stage MGWAS based on deep shotgun sequencing of the gut microbial DNA from 345 Chinese individuals. We identified and validated approximately 60,000 type-2-diabetes-associated markers and established the concept of a metagenomic linkage group, enabling taxonomic species-level analyses. MGWAS analysis showed that patients with type 2 diabetes were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria and an increase in various opportunistic pathogens, as well as an enrichment of other microbial functions conferring sulphate reduction and oxidative stress resistance. An analysis of 23 additional individuals demonstrated that these gut microbial markers might be useful for classifying type 2 diabetes.
Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic ...heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.
To assess and compare the oral health status of children with and without autism spectrum disorders (ASD) in China.
This study recruited 144 children with ASD and 228 unrelated children with typical ...development (TD) aged 3-16 years from China. Data were collected using parent-reported questionnaires. Oral problems (oral symptoms and habits), oral health measures (oral hygiene practice and dental care experience), and the impact on the child's quality of life (based on a modified version of the Parental-Caregiver Perception Questionnaire) were assessed and compared between the two groups.
Children with ASD had worse oral health status than children with TD. Oral symptoms were more prevalent in the ASD group, especially halitosis (p < 0.001), food impaction (p < 0.001), and oral lesions (p < 0.001), than the TD group. The rate of damaging oral habits, including mouth breathing (p < 0.001) and object biting (p < 0.05), was also high in the ASD group. Compared with the TD group, more children with ASD did not brush their teeth independently and frequently (p < 0.001), had difficulty accessing dental care (p < 0.01), and reported unpleasant dental experiences (p < 0.001). The presence of ASD was associated with decreased oral health-related quality of life (p < 0.001) in these children and their families.
Oral problems such as halitosis and bad oral habits are more prevalent among children with ASD. These children also lack oral hygiene practice and dental visits. This situation negatively impacts their quality of life, and must be brought to the attention of their treating dentists.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. To identify additional genetic factors, we analyzed exome sequences in a large cohort of Chinese ALS patients and found ...a homozygous variant (p.L700P) in PCDHA9 in three unrelated patients. We generated Pcdhα9 mutant mice harboring either orthologous point mutation or deletion mutation. These mice develop progressive spinal motor loss, muscle atrophy, and structural/functional abnormalities of the neuromuscular junction, leading to paralysis and early lethality. TDP-43 pathology is detected in the spinal motor neurons of aged mutant mice. Mechanistically, we demonstrate that Pcdha9 mutation causes aberrant activation of FAK and PYK2 in aging spinal cord, and dramatically reduced NKA-α1 expression in motor neurons. Our single nucleus multi-omics analysis reveals disturbed signaling involved in cell adhesion, ion transport, synapse organization, and neuronal survival in aged mutant mice. Together, our results present PCDHA9 as a potential ALS gene and provide insights into its pathogenesis.
Autism spectrum disorders (ASD) affect 1% of children. Although there is no cure, early diagnosis and behavioral intervention can relieve the symptoms. The clinical heterogeneity of ASD has created a ...need for improved sensitive and specific laboratory diagnostic methods. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based analysis of the metabolome has shown great potential to uncover biomarkers for complex diseases such as ASD. Here, we used a two-step discovery-validation approach to identify potential novel metabolic biomarkers for ASD. Urine samples from 57 children with ASD and 81 matched children with typical development (TD) were analyzed by LS-MS/MS to assess differences in urinary amino acids and their metabolites (referred to as UAA indicators). A total of 63 UAA indicators were identified, of which 21 were present at significantly different levels in the urine of ASD children compared with TD children. Of these 21, the concentrations of 19 and 10 were higher and lower, respectively, in the urine of ASD children compared with TD children. Using support vector machine modeling and receiver operating characteristic curve analysis, we identified a panel of 7 UAA indicators that discriminated between the samples from ASD and TD children (lysine, 2-aminoisobutyric acid, 5-hydroxytryptamine, proline, aspartate, arginine/ornithine, and 4-hydroxyproline). Among the significantly changed pathways in ASD children were the ornithine/urea cycle (decreased levels of the excitatory amino acid aspartate
= 2.15 × 10
and increased arginine/ornithine
= 5.21 × 10
), tryptophan metabolism (increased levels of inhibitory 5-hydroxytryptamine
= 3.62 × 10
), the methionine cycle (increased methionine sulfoxide
= 1.46 × 10
and decreased homocysteine
= 2.73 × 10
), and lysine metabolism (reduced lysine
= 7.8 × 10
, α-aminoadipic acid
= 1.16 × 10
, and 5-aminovaleric acid
= 1.05 × 10
). Collectively, the data presented here identify a possible imbalance between excitatory and inhibitory amino acid metabolism in ASD children. The significantly altered UAA indicators could therefore be potential diagnostic biomarkers for ASD.
Early colonization of gut microbiota in human gut is a complex process. It remains unclear when gut microbiota colonization occurs and how it proceeds. In order to study gut microbiota composition in ...human early life, the present study recruited 10 healthy pairs of twins, including five monozygotic (MZ) and five dizygotic (DZ) twin pairs, whose age ranged from 0 to 6 years old. 20 fecal samples from these twins were processed by shotgun metagenomic sequencing, and their averaged data outputs were generated as 2G per sample. We used MEGAN5 to perform taxonomic and functional annotation of the metagenomic data, and systematically analyzed those 20 samples, including Jaccard index similarity, principle component, clustering, and correlation analyses. Our findings indicated that within our study group: 1) MZ-twins share more microbes than DZ twins or non-twin pairs, 2) gut microbiota distribution is relatively stable at metabolic pathways level, 3) age represents the strongest factor that can account for variation in gut microbiota, and 4) a clear metabolic pathway shift can be observed, which speculatively occurs around the age of 1 year old. This research will serve as a base for future studies of gut microbiota-related disease research.
Recent evidence suggests that inflammation was participated in the pathogenesis of PD, thus, to understand the potential mechanism of gut microbiota in the pathogenesis of Parkinson’s disease (PD), ...we performed a metagenomic analysis of fecal samples from PD patient and controls. Using a two-stage metagenome-wide association strategy, fecal DNA samples from 69 PD patients and 244 controls in three groups (comprising 66 spouses, 97 age-matched, and 81 normal samples, respectively) were analyzed, and differences between candidate gut microbiota and microbiota-associated epitopes (MEs) were compared. In the study, 27 candidate bacterial biomarkers and twenty-eight candidate epitope peptides were significantly different between the PD patients and control groups. Further, enriched 4 and 13 MEs in PD were positively associated with abnormal inflammatory indicators neutrophil percentage (NEUT.1), monocyte count/percentage (MONO/MONO.1), white blood cell count (WBC) and five candidate bacterial biomarkers (c_Actinobacteria, f_Bifidobacteriaceae,
g_Bifidobacterium
, o_Bifidobacteriales, p_Actinobacteria) from Actinobacteria phylum, and they were also positively associated with histidine degradation and proline biosynthesis pathways, respectively. Additionally, enriched 2 MEs and 1 ME in PD were positively associated with above inflammatory indicators and two bacteria (f_Lactobacillaceae,
g_Lactobacillus
) from Firmicutes phylum, and they were also positively associated with pyruvate fermentation to propanoate I and negatively associated with isopropanol biosynthesis, respectively. Of these MEs, two MEs from GROEL2, RPSC were derived from
Mycobacterium tuberculosis
, triggered the T cell immune response, as previously reported. Additionally, other candidate epitope peptides derived from
Mycobacterium tuberculosis
and
Mycobacterium leprae
may also have potential immune effects in PD. In all, the altered MEs in PD may relate to abnormalities in immunity and glutamate and propionate metabolism, which furthers our understanding of the pathogenesis of PD.
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