Qiuyuan Yin, Lei Zhu; Does co-localization analysis reinforce the results of Mendelian randomization?, Brain, , awad295, https://doi.org/10.1093/brain/awad295

Background: Several recent studies speculated that the gut microbiota is associated with sensorineural hearing loss (SNHL) and proposed the concept of the gut–inner ear axis. However, the causal effect of gut microbiota on SNHL is still unknown. In this study, we performed a two-sample Mendelian randomization (MR) analysis to estimate the causal effect of gut microbiota on SNHL.Methods: Gut microbiota data were obtained from the largest available genome-wide association study (n = 18,340) conducted by the MiBioGen consortium. The summary statistics of SNHL were obtained from the FinnGen consortium R8 release data (28,310 cases and 302,750 controls). The causal effects were estimated with inverse-variance weighted, MR-Egger, and weighted median. Reverse Mendelian randomization analysis was performed on the bacteria that were found to be associated with SNHL in forward Mendelian randomization analysis. We then performed sensitivity analyses, including Cochran's Q-test, MR-Egger intercept test, MR-PRESSO, cML-MA-BIC, and leave-one-out analysis, to detect heterogeneity and pleiotropy.Results: The inverse-variance weighted results suggested that Lachnospiraceae (UCG001) had a significant protective effect against SNHL (odds ratio = 0.85, 95% confidence interval: 0.78–0.93, P = 6.99 × 10⁻⁴). In addition, Intestinimonas (odds ratio = 0.89, 95% confidence interval: 0.82–0.97, P = 8.53 × 10⁻³) presented a suggestively protective effect on SNHL. Rikenellaceae (RC9gutgroup) (odds ratio = 1.08, 95% confidence interval: 1.02–1.15, P = 0.01) and Eubacterium (hallii group) (odds ratio = 1.12, 95% confidence interval: 1.00–1.24, P = 0.048) suggestively increase the risk of SNHL. The results of the reverse MR analysis showed that there is no significant causal effect of SNHL on the gut microbiota. No significant heterogeneity of instrumental variables or pleiotropy was detected.Conclusion: The evidence that the four genera mentioned above are associated with SNHL supports the hypothesis of a gut–inner ear axis. Our study provides microbial markers for the prevention and treatment of SNHL, and further studies are needed to explore the mechanisms of the gut microbiome–inner ear axis in health and diseases.

The L-Ala-D/L-Glu epimerases (AEEs), a subgroup of the enolase superfamily, catalyze the epimerization of L-Ala-D/L-Glu and other dipeptides in bacteria and contribute to the metabolism of the murein peptide of peptidoglycan. Although lacking in peptidoglycan, land plants possess AEE genes that show high similarity to those in bacteria. Similarity searches revealed that the AEE gene is ubiquitous in land plants, from bryophytas to angiosperms. However, other eukaryotes, including green and red algae, do not contain genes encoding proteins with an L-Ala-D/L-Glu_epimerase domain. Homologs of land plant AEE genes were found to only be present in prokaryotes, especially in bacteria. Phylogenetic analysis revealed that the land plant AEE genes formed a monophyletic group with some bacterial homologs. In addition, land plant AEE proteins showed the highest similarity with these bacterial homologs and shared motifs only conserved in land plant and these bacterial AEEs. Integrated information on the taxonomic distribution, phylogenetic relationships and sequence similarity of the AEE proteins revealed that the land plant AEE genes were acquired from bacteria through an ancient horizontal gene transfer (HGT) event. Further evidence revealed that land plant AEE genes had undergone positive selection and formed the main characteristics of exon/intron structures through gaining some introns during the initially evolutionary period in the ancestor of land plants. The results of this study clearly demonstrated that the ancestor of land plants acquired an AEE gene from bacteria via an ancient HGT event. Other findings illustrated that adaptive evolution through positive selection has contributed to the functional adaptation and fixation of this gene in land plants.

Industrialization has driven lifestyle changes in eastern and western Chinese populations, yet we have a poor understanding of the dynamic changes in their gut microbiome and resistome under industrialization, which is essential for the scientific management of public health. Here, this study employed metagenomics to analyze the gut microbiota of 1,382 healthy individuals from China, including 415 individuals from the eastern region of advanced industrialization and 967 individuals from the western region of developing industrialization. Compared with western populations, eastern populations show a significant increase in interindividual dissimilarity of microbial species composition and metabolic pathways but a significant decrease in intraindividual species and functional diversity. Furthermore, our results found significantly less abundance and richness of antibiotic resistance genes (ARGs) in the gut microbiota of eastern populations, alongside a lower prevalence of unique core ARG subtypes. For the 12 core ARG types shared between eastern and western populations, the mean relative abundance of two types was notably higher in the eastern populations, while eight core ARG types had significantly higher mean relative abundance in the western populations. Based on the reconstruction of metagenomic assembled genomes, we found that Escherichia coli genomes from western populations carried more virulence factor genes (VFGs) and mobile genetic elements (MGEs) compared to those from eastern populations. This large-scale study for the first time revealed industrialization potentially led to unexpected alterations of the gut microbiome and resistome between eastern and western populations that provide a vital implication for Chinese public health and may aid in the development of region-specific strategies for managing pathogenic infections. IMPORTANCE: As China experiences rapid but uneven industrialization, understanding its effect on people’s gut bacteria is critical for public health. This study reveals how industrialization may reshape the health risks related to gut bacteria and antibiotic resistance. This work provides crucial information to help create customized public health policies for different regions.

Background: MicroRNAs (miRNAs) have pivotal roles in gene regulation. Circulating miRNAs have been developed as novel candidate non-invasive biomarkers for diagnosis, prognosis, and treatment response for diseases. However, miRNAs that have causal effects on Parkinson’s Disease (PD) remain largely unknown. To investigate the causal relationships between miRNAs and PD, here we conduct a Mendelian randomization (MR) study.Methods: This study utilized the summary-level data of respective genome-wide association studies (GWAS) for 2083 miRNAs and seven PD-related outcomes to comprehensively reveal the causal associations between the circulating miRNAs and PD. Two-sample MR design was deployed and the causal effects were estimated with inverse variance weighted, MR-Egger, and weighted median. Comprehensively sensitive analyses were followed, including Cochran’s Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis, to validate the robustness of our results. Finally, we investigated the potential role of the MR significant miRNAs by predicting their target genes and functional enrichment analysis.Results: Inverse variance weighted estimates suggested that two miRNAs, miR-205-5p (β = −0.46, 95%CI: −0.690 to −0.229, p = 9.3 × 10⁻⁵) and miR-6800-5p (β = −0.389, 95%CI: −0.575 to −0.202, p = 4.32 × 10⁻⁵), significantly decreased the rate of cognitive decline among PD patients. In addition, eight miRNAs were nominally associated with more than three PD-related outcomes each. No significant heterogeneity of instrumental variables or horizontal pleiotropy was found. Gene Ontology (GO) analysis showed that the targets of these causal miRNAs were significantly enriched in cell cycle, apoptotic, and aging pathways.Conclusion: This MR study identified two miRNAs whose genetically regulated expression might have a causal role in the development of PD dementia. Our findings provided potential miRNA biomarkers to make better and early diagnoses and risk assessments of PD.

The secondary metabolites produced by the gut microbiota serve as crucial signaling molecules and substrates for gastrointestinal metabolic reactions, thereby playing a pivotal role in human physiological and pathological processes. In this study, we explore the complex symbiotic relationship between the gut microbiota and the human host by systematically annotating the biosynthetic gene clusters (BGCs) across 4,744 human gut microbiota genomes, sourced from the Unified Human Gastrointestinal Genome database. Our comprehensive analysis compares the differential biosynthetic potentials of microbiota from diverse continents and phyla while also elucidating the biosynthetic profiles of gut archaea. Notably, our findings identify Paenibacillus as a dominant genus within the human gut microbiota, characterized by its extensive biosynthetic capacity. This study presents the first global atlas of BGCs within the human gut microbiome, offering valuable insights into gut-derived secondary metabolic pathways and their intricate interactions with host physiology. These results lay the groundwork for future investigations into the microbiota’s role in health and disease, underscoring the importance of understanding microbiota-derived metabolites in microbiology and gastroenterology. IMPORTANCE: This study provides a comprehensive analysis of biosynthetic gene clusters in the human gut microbiome, revealing a vast diversity of natural products with potential therapeutic applications. We identified Paenibacillus as a key genus with exceptional biosynthetic capabilities, including the production of leinamycin, a potent anticancer compound previously thought to be exclusive to Streptomyces . The findings highlight the gut microbiome as a rich, untapped resource for novel drug discovery, particularly in cancer therapy and immune modulation.