Physiological genomics最新文献

We developed a novel artificial intelligence (AI) approach based on machine learning to predict general health and food-intake parameters. This approach, named Transcriptome-driven Health status Transversal-predictor Analysis (THTA) is relevant for markers of diabesity and is based on a nontranscriptomic, mathematics-driven approach. The prediction was based on values derived from food consumption, dietary lipids and their bioactive metabolites, peripheral blood mononuclear cell (PBMC) mRNA-based transcriptome signatures, magnetic resonance imaging (MRI), energy metabolism measurements, microbiome analyses, and baseline clinical parameters, as determined in a cohort of 72 subjects. Our novel machine learning approach incorporated transcriptome data from PBMCs as a "one-method" approach to predict 77 general health status markers for the broad stratification of the diabesity phenotype. These markers would usually necessitate measurements using 16 different methods. The PBMC transcriptome was used to determine these 77 basic and background health markers with very high accuracy in a transversal-predictor establishment group (Pearson's correlations r = 0.98 ranging from 0.94 to 0.99). These collected variables provide valuable insides into which individual factor(s) are mainly target diabesity. Based on the "establishment group" prediction approach, a further "confirmation group" prediction approach was performed, achieving a predictive potential r = 0.59 (ranging from 0.19 to 0.98) for these 77 variables. This "one-method" approach enables the simultaneous monitoring of a large number of health-status variables relevant to diabesity and may facilitate the monitoring of therapeutic and preventive strategies. In summary, this novel technique, which is based on PBMC transcriptomics from human blood, can predict a wide range of health-related markers. ClinicalTrial.gov Identifier: NCT01684917.NEW & NOTEWORTHY We developed a novel AI approach based on machine learning to predict general health and food-intake parameters. This approach, named transcriptome-driven health status transversal-predictor analysis, is relevant for markers of diabesity and is based on a mathematics-driven approach. This "one-method" approach enables the simultaneous monitoring of a large number of health-status variables and may facilitate monitoring of therapeutic and preventive strategies. This PBMC transcriptomics-based technique from human blood offers prediction of a wide range of health-related markers.

Dorsal root ganglia (DRG) are essential for transmitting sensory information from visceral organs to the central nervous system. Sensory neuronal hyperactivity and glial reactivity have been reported in DRG in animal models of chronic pain, yet the molecular mechanisms contributing to the pathogenesis of visceral pain remain unclear. In this study, we performed transcriptome profiling of lumbosacral DRG in a mouse model of chronic pelvic pain, focusing on mapping the gene and signaling pathway changes associated with visceral hypersensitivity in lumbosacral DRG transmitting bladder afferent signals. Using the bulk RNA-sequencing method, we identified differentially expressed genes in the lumbosacral DRG between control mice and mice exhibiting visceral pain symptoms, with striking sex differences in identified genes. Hierarchical gene clustering analysis and Ingenuity Pathways Analysis both revealed sex-specific signaling pathway activation associated with visceral pain conditions, including glial activation and nociceptive sensitization in males and heightened immune activation in females. Interestingly, our data also showed enriched gene expression linked to extracellular matrix and immune functions in female control animals compared with male control animals, suggesting molecular sexual dimorphism in sensory ganglia. Finally, our data identified common genes and signaling pathway changes involved in visceral hypersensitivity in both sexes. This study is the first molecular and signaling pathway characterization in the lumbosacral DRG in the context of bladder-origin visceral pain. The sex differences in the molecular profile of lumbosacral DRG in healthy animals and in animals exhibiting visceral pain symptoms suggest sex-specific visceral pain etiology, despite similar symptoms.NEW & NOTEWORTHY This study examined transcriptomics in the lumbosacral DRG in a VEGF-induced visceral pain mouse model. Male and female mice underwent intravesical instillations of VEGF₁₆₅ or saline. Across the four experimental groups, we found significant sex differences in DRG transcriptome between control animals and VEGF-induced molecular changes, suggesting sex-specific visceral pain mechanisms. These findings provide insight into potential targets for alleviating visceral pain symptoms when considering sex as a biological variable.

Impaired lactose digestion, primarily resulting from lactase non-persistence (LNP), is widely observed across African and non-African populations; however, its prevalence differs according to genetic background and dietary practices. Although numerous pastoralist cultures in Africa have independently developed lactase persistence (LP), a sizable portion of the population experiences primary or secondary lactose malabsorption, either as a natural genetic trait or as a secondary impairment resulting from intestinal damage. This review summarizes the genetic variants and environmental contributors associated with lactose digestion in Africa, highlighting ancestry-specific variants and the underrepresentation of African populations in prior studies. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020-guided systematic review searched PubMed, African Journals Online, Wiley Online Library, and Google Scholar (1970 to June 2025) for studies on genetic and environmental contributors to lactose digestion in African groups. Inclusion focused on human studies reporting lactase persistence (LP)/LNP or secondary impaired lactose digestion. Data were extracted on variants, diagnostics, and outcomes. Twenty-eight studies were included, predominantly from East African pastoralists (53.3%), where LP alleles, including -13910T and -14010C in MCM6 intron 13, reached frequencies of 40%-43%.Southern or West/North African groups showed LNP rates >70%. Secondary impaired lactose digestion affected 65%-68% of malnourished/infected children, highlighting enteropathy and infections. Genotype-phenotype discrepancies were noted, with statistical associations due to linkage disequilibrium but not direct causation. Impaired lactose digestion in Africa reflects genetic adaptations in pastoralists and environmental stressors like malnutrition. Population-specific diagnostics and interventions are needed, integrating microbiome and dietary research for resource-limited settings.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine-metabolic disorder that adversely affects reproductive, metabolic, and cardiovascular health in females, leading to menstrual irregularities and an increased risk of endometrial malignancies. Emerging research evidence suggests that the gut and extra gastrointestinal microbiome dysbiosis may play a significant role in the pathophysiology of PCOS. This systematic review aims to elucidate the microbiome dysbiosis patterns in patients with PCOS compared with healthy controls. A systematic search was conducted across PubMed, Scopus, and Web of Science from inception until February 28, 2025, encompassing all original cross-sectional, cohort, or case-control studies that examined the gut, oral, blood, and lower genital tract (LGT) microbiomes of patients with PCOS (cases) against healthy females (controls). Of the 4,377 studies identified, 64 were assessed for eligibility through full-text screening, and ultimately, 29 studies met inclusion criteria and were included into the systematic review. The results revealed inconsistent patterns in alpha and beta diversity, with reports of increased, decreased, or unchanged microbial diversity across studies. Key alterations were observed at different taxonomic levels, such as phylum, family, genus, and species. The most significant bacterial alterations include changes in the relative abundance of various bacterial taxa such as Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria, Verrucomicrobia, Gammaproteobacteria, Fusobacteria, Eubacterium, Streptococcus, Paraprevotella, Tucibacter, and Tenericutes. These findings indicate that complex dysbiotic microbial shifts may be involved in the pathogenesis of PCOS. As per the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) assessment, the quality of evidence is low for most of the studies. This systematic review supports the role of microbial dysbiosis in PCOS pathogenesis; however, additional research is required to elucidate these interactions to guide the development of therapeutic strategies in the future.

The menopausal transition is associated with an increased risk of obesity, which can be ameliorated by hormone replacement therapy. However, the independent and interactive effects of obesity and menopause on the gut microbiota, along with the influence of hormone therapy, remain poorly understood. To address this, this study used a mouse model using sham-operated and ovariectomized mice, with or without high-fat diet-induced obesity, to disentangle the roles of menopause and obesity. Ovariectomized mice on a high-fat diet were further treated with estradiol to assess the regulatory effects of hormone supplementation on the gut microbiota. The results showed that obesity and ovariectomy altered the relative abundances of 29 and 7 genera, and 243 and 99 amplicon sequence variants, respectively, indicating a stronger impact of obesity on gut microbial composition. Notably, ovariectomy increased the abundance of Faecalibaculum and enriched microbial taxa capable of producing estrogen-metabolizing enzymes, including Bifidobacterium and Dubosiella species, as well as the predicted abundance of the estrobolome enzyme β-glucuronidase. Estradiol supplementation increased the relative abundance of Bacteroides and decreased Akkermansia, both of which possess distinct β-glucuronidase subtypes. It also reduced the species Faecalibaculum rodentium, that positively associated with adiposity. Together, these findings highlight the distinct and significant impacts of obesity and menopause on the gut microbiota and suggest that estrogen supplementation modulates microbial features linked to metabolic health. These results further implicate the potential of modulating the gut microbiota to improve postmenopausal health outcomes.NEW & NOTEWORTHY This study investigates how obesity, menopause, and estrogen supplementation influence the gut microbiota. The findings highlight the distinct and significant effects of obesity and menopause in shaping microbial composition and suggest that estrogen supplementation modulates microbial features associated with metabolic health.

The initiating cellular events in cystic fibrosis (CF) hepatobiliary disease are not well characterized, in part due to the lack of accessibility of primary tissues. However, enhanced longevity due to highly effective modulator therapies has generated renewed interest in the key aspects of liver and gallbladder disease, and how these might be treated in people with cystic fibrosis (pwCF). To extend the CF hepatobiliary knowledge base, we performed a transcriptomic analysis of liver and gallbladder development in the wild-type (WT) and CFTR^-/- sheep. Bulk RNA was extracted from each tissue at specific timepoints through gestation (from 50 days to term) and used for RNA sequencing (RNA-seq). Differentially expressed genes between the timepoints within each genotype and between WT and CFTR^-/- sheep at each timepoint were identified and then used in gene ontology process enrichment analysis to reveal altered biological processes. We find that at the molecular level, the gallbladder in the CFTR^-/- animals is both structurally and functionally compromised by midgestation, consistent with the observed microgallbladder phenotype. In the liver, many aspects of differentiation are apparently well-established early in gestation. However, we find functional immaturity in the CFTR^-/- liver at term, where genes associated with many key metabolic processes do not show the upregulation seen at term in the WT liver. We also show that the regulatory mechanisms for the CFTR gene in ovine gallbladder cells are highly conserved with those elucidated at the human CFTR locus, further enhancing the relevance of these data to advance understanding of hepatobiliary disease in pwCF.NEW & NOTEWORTHY We use a physiological genomics approach to further understand the etiology of cystic fibrosis gallbladder and liver disease by using a large animal (sheep) model of organ development. We find that the gallbladder in the CFTR^-/- animals is both structurally and functionally compromised by midgestation. We also observe functional immaturity in the CFTR^-/- liver at term, where genes associated with many key metabolic processes do not show the upregulation seen at term in wild-type liver.

Periodontal therapy leverages intercellular and intertissue interactions between epithelium and stroma, which mediate healing and regeneration. Importantly, grafting stroma from different regions elicits different healing responses: transplantation of gingival stroma can convert alveolar mucosa into keratinized gingiva, and vice versa. This striking clinical observation suggests that the stromal tissues of oral mucosa and gingiva provide distinct instructional signals. Our aims were to investigate the molecular differences between mucosa and gingiva and the impact of periodontal infection on intertissue interactions. We used human single-cell RNA-sequencing (RNA-seq) data to compare gene expression patterns and intercellular interactions of: 1) adult oral mucosa and gingiva and 2) healthy gingiva and periodontitis-affected gingiva. Altered gene expression in junctional epithelial cells in periodontitis included not only inflammatory but also antioxidant genes, reflecting the potential of oral tissues to maintain health and resist bacterial infection. Many ligand/receptor genes were also enriched in junctional epithelium, highlighting intercellular interactions. Oral mucosal and gingival stroma expressed distinct genes related to signaling and extracellular matrix associated with their tissue phenotypes: for example, collagens and secreted protein acidic and cysteine-rich (SPARC) in the gingiva, and elasticity-related coagulation factor XIII A chain (F13A1) in the mucosa. Ligand-receptor analyses predicted endothelial cells and fibroblasts as the primary senders of signaling ligands. Notably, autocrine signaling was predicted to be prevalent within periodontitis-affected fibroblasts, suggesting potential autofeedback regulation in periodontitis. We present unbiased single-cell molecular characterizations of human oral tissues in health and periodontitis. These findings lay the groundwork for future research into periodontal therapies.NEW & NOTEWORTHY To explore differences between oral mucosa and gingiva in health and disease, we analyzed human single-cell RNA-sequencing data. In periodontitis, altered gene expression in junctional epithelium included not only inflammatory but also antioxidant genes, reflecting the potential of oral tissues to resist bacterial infection. Each cell type-fibroblasts, endothelial, and immune cells-expressed genes that distinguished mucosa from gingiva, as well as healthy from diseased gingiva. These findings provide insights into periodontitis and periodontal therapy.