Select symbionts drive high IgA levels in the mouse intestine.

Immunoglobulin A (IgA) is an important factor in maintaining homeostasis at mucosal surfaces, yet luminal IgA levels vary widely. Total IgA levels are thought to be driven by individual immune responses to specific microbes. Here, we found that the prebiotic, pectin oligosaccharide (pec-oligo), induced high IgA levels in the small intestine in a T cell-dependent manner. Surprisingly, this IgA-high phenotype was retained after cessation of pec-oligo treatment, and microbiome transmission either horizontally or vertically was sufficient to retain high IgA levels in the absence of pec-oligo. Interestingly, the bacterial taxa enriched in the overall pec-oligo bacterial community differed from IgA-coated microbes in this same community. Rather, a group of ethanol-resistant microbes, highly enriched for Lachnospiraceae bacterium A2, drove the IgA-high phenotype. These findings support a model of intestinal adaptive immunity in which a limited number of microbes can promote durable changes in IgA directed to many symbionts.

The Cytidine Deaminase APOBEC3G Contributes to Cancer Mutagenesis and Clonal Evolution in Bladder Cancer.

Mutagenic processes leave distinct signatures in cancer genomes. The mutational signatures attributed to APOBEC3 cytidine deaminases are pervasive in human cancers. However, data linking individual APOBEC3 proteins to cancer mutagenesis in vivo are limited. Here, we showed that transgenic expression of human APOBEC3G promotes mutagenesis, genomic instability, and kataegis, leading to shorter survival in a murine bladder cancer model. Acting as mutagenic fuel, APOBEC3G increased the clonal diversity of bladder cancer, driving divergent cancer evolution. Characterization of the single-base substitution signature induced by APOBEC3G in vivo established the induction of a mutational signature distinct from those caused by APOBEC3A and APOBEC3B. Analysis of thousands of human cancers revealed the contribution of APOBEC3G to the mutational profiles of multiple cancer types, including bladder cancer. Overall, this study dissects the mutagenic impact of APOBEC3G on the bladder cancer genome, identifying that it contributes to genomic instability, tumor mutational burden, copy-number loss events, and clonal diversity. SIGNIFICANCE: APOBEC3G plays a role in cancer mutagenesis and clonal heterogeneity, which can potentially inform future therapeutic efforts that restrict tumor evolution. See related commentary by Caswell and Swanton, p. 487.

The Interaction of Trauma Exposure and DNA Methylation on Blood Pressure Among Black Women in the InterGEN Study.

Objective: Despite evidence that trauma exposure is linked to higher risk of hypertension, epigenetic mechanisms (such as DNA methylation) by which trauma potentially influences hypertension risk among Black adults remain understudied. Methods: Data from a longitudinal study of Black mothers were used to test the hypothesis that direct childhood trauma (ie, personal exposure) and vicarious trauma (ie, childhood trauma experienced by their children) would interact with DNA methylation to increase blood pressure (BP). Separate linear mixed effects models were fitted at each CpG site with the DNA methylation beta-value and direct and vicarious trauma as predictors and systolic and diastolic BP modeled as dependent variables adjusted for age, cigarette smoking, and body mass index. Interaction terms between DNA methylation beta-values with direct and vicarious trauma were added. Results: The sample included 244 Black mothers with a mean age of 31.2 years (SD = ±5.8). Approximately 45% of participants reported at least one form of direct childhood trauma and 49% reported at least one form of vicarious trauma. Epigenome-wide interaction analyses found that no CpG sites passed the epigenome-wide significance level indicating the interaction between direct or vicarious trauma with DNAm did not influence systolic or diastolic BP. Conclusions: This is one of the first studies to simultaneously examine whether direct or vicarious exposure to trauma interact with DNAm to influence BP. Although findings were null, this study highlights directions for future research that investigates epigenetic mechanisms that may link trauma exposure with hypertension risk in Black women.

Experiences of Trauma and DNA Methylation Profiles among African American Mothers and Children.

Potentially traumatic experiences have been associated with chronic diseases. Epigenetic mechanisms, including DNA methylation (DNAm), have been proposed as an explanation for this association. We examined the association of experiences of trauma with epigenome-wide DNAm among African American mothers (n = 236) and their children aged 3-5 years (n = 232; N = 500), using the Life Events Checklist-5 (LEC) and Traumatic Events Screening Inventory-Parent Report Revised (TESI-PRR). We identified no DNAm sites significantly associated with potentially traumatic experience scores in mothers. One CpG site on the ENOX1 gene was methylome-wide-significant in children (FDR-corrected q-value = 0.05) from the TESI-PRR. This protein-coding gene is associated with mental illness, including unipolar depression, bipolar, and schizophrenia. Future research should further examine the associations between childhood trauma, DNAm, and health outcomes among this understudied and high-risk group. Findings from such longitudinal research may inform clinical and translational approaches to prevent adverse health outcomes associated with epigenetic changes.

Paying attention to minutiae: Strain level differences drive disease etiology.

There is increasing interest in and understanding of the role of fungi in the pathogenesis of complex diseases such as inflammatory bowel disease (IBD). Li et al.1 have shown that specific strains of Candida albicans preferentially produce pro-inflammatory phenotypes that could be related to IBD.