Human Disease Risk Research Articles

High incidence of Trypanosoma cruzi infections in dogs directly detected through longitudinal tracking at 10 multi-dog kennels, Texas, USA.

Canine Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is increasingly recognized as a health concern for dogs in the USA, and infected dogs may signal geographic regions of risk for human disease. Dogs living in multi-dog kennel environments (kennels with more than one dog) where triatomine vectors are endemic may be at high risk for infection. We monitored a cohort of 64 T. cruzi-infected and uninfected dogs across 10 kennels in Texas, USA, to characterize changes in infection status over one year. We used robust diagnostic criteria in which reactivity on multiple independent platforms was required to be considered positive. Among the 30 dogs enrolled as serologically- and/or PCR-positive, all but one dog showed sustained positive T. cruzi diagnostic results over time. Among the 34 dogs enrolled as serologically- and PCR-negative, 10 new T. cruzi infections were recorded over a 12-month period. The resulting incidence rate for dogs initially enrolled as T. cruzi-negative was 30.7 T. cruzi infections per 100 dogs per year. This study highlights the risk of T. cruzi infection to dogs in kennel environments. To protect both dog and human health, there is an urgent need to develop more integrated vector control methods as well as prophylactic and curative antiparasitic treatment options for T. cruzi infection in dogs.

Lymphocyte Activation Gene-3 Regulates Dendritic Cell Metabolic Programing and T Cell Priming Function.

Deficiency of lymphocyte activation gene-3 (LAG3) is significantly associated with increased cardiovascular disease risk with in vitro results demonstrating increased TNF-α and decreased IL-10 secretion from LAG3-deficient human B lymphoblasts. The hypothesis tested in this study was that Lag3 deficiency in dendritic cells (DCs) would significantly affect cytokine expression, alter cellular metabolism, and prime naive T cells to greater effector differentiation. Experimental approaches used included differentiation of murine bone marrow-derived DCs (BMDCs) to measure secreted cytokines, cellular metabolism, RNA sequencing, whole cell proteomics, adoptive OT-II CD4+Lag3 +/+ donor cells into wild-type (WT) C57BL/6 and Lag3 -/- recipient mice, and ex vivo measurements of IFN-γ from cultured splenocytes. Results showed that Lag3 -/- BMDCs secreted more TNF-α, were more glycolytic, used fewer fatty acids for mitochondrial respiration, and glycolysis was significantly reduced by exogenous IL-10 treatment. Under basal conditions, RNA sequencing revealed increased expression of CD40 and CD86 and other cytokine-signaling targets as compared with WT. Whole cell proteomics identified a significant number of proteins up- and downregulated in Lag3 -/- BMDCs, with significant differences noted in exogenous IL-10 responsiveness compared with WT cells. Ex vivo, IFN-γ expression was significantly higher in Lag3 -/- mice as compared with WT. With in vivo adoptive T cell and in vitro BMDC:T coculture experiments, Lag3 -/- BMDCs showed greater T cell effector differentiation and proliferation, respectively, compared with WT BMDCs. In conclusion, Lag3 deficiency in DCs is associated with an inflammatory phenotype that provides a plausible mechanism for increased cardiovascular disease risk in humans with LAG3 deficiency.

Risk factors associated with ticks and Rickettsia spp. exposure in wild boars (Sus scrofa), hunting dogs, and hunters of Brazil.

Background and Aim:Wild boars have recently been implicated as the maintainers and carriers of Amblyomma spp. ticks, which are essential for Rickettsia spp. transmission. Consequently, wild boar hunting may increase the risk of tick exposure and subsequent human tick-borne infection and disease. Therefore, this study was conducted to evaluate the risk factors for ticks and Rickettsia spp. exposure in wild boars, hunting dogs, and hunters in Brazilian biomes.Materials and Methods:The statistical relationship of Rickettsia spp. antibodies were evaluated using the Chi-square test in 80 wild boars, 170 hunting dogs, and 49 hunters.Results:The only statistically significant difference in seropositivity found in this study was between male and female wild boars (p=0.034), probably associated with in-park exposure to Amblyomma brasiliense infected with Rickettsia spp.Conclusion:The absence of statistical differences in the associated risk factors for hunting dogs and hunters may indicate a random exposure to Rickettsia spp.

Chromatographic determination of organohalogen compounds in swimming pool water

The purpose of the work was to search for a sorbent with good selective properties for water purification. For this purpose, we determined the organohalogen compounds in the water of a swimming pool. A method of gas-liquid chromatography was used, using packed and capillary chromatographic columns. To concentrate the impurities of the organohalogen compounds, an automatic vapour-phase dispenser was used. This established that the swimming pool water, taken in the evening, had a complex composition of components, including 33 organohalogens, which have different toxicities for the human body. These are classed as belonging to the first and second groups of hazards. Identification of the individual component composition was carried out by determining the relative retention times of the test compounds and standard samples of the organohalogen compounds dissolved in methanol. Out of the entire range of the organohalogen compounds contained in the swimming pool water it was determined that the highest concentration of chloroform was 0.024 mg/dm3 and the highest concentration of carbon tetrachloride was 0.018 mg/dm3. The total content of organohalogen substances in the swimming pool water was 0.370 mg/dm3, which increases the risk of human diseases while the swimming pool is in operation. It is proposed to clean the water in the swimming pools from toxic impurities by an adsorption method using rocks containing zeolite from the Tatar-Shatrashan deposit, which are characterized by a sufficiently high sorption capacity in relation to the organohalogen compounds.

NOD2 Genotypes Affect the Symptoms and Mortality in the Porcine Circovirus 2-Spreading Pig Population.

The nucleotide oligomerization domain (NOD)-like receptor 2 (NOD2) is an intracellular pattern recognition receptor that detects components of peptidoglycans from bacterial cell walls. NOD2 regulates bowel microorganisms, provides resistance against infections such as diarrhea, and reduces the risk of inflammatory bowel diseases in humans and mice. We previously demonstrated that a specific porcine NOD2 polymorphism (NOD2-2197A > C) augments the recognition of peptidoglycan components. In this study, the relationships between porcine NOD2-2197A/C genotypes affecting molecular functions and symptoms in a porcine circovirus 2b (PCV2b)-spreading Duroc pig population were investigated. The NOD2 allele (NOD2-2197A) with reduced recognition of the peptidoglycan components augmented the mortality of pigs at the growing stage in the PCV2b-spreading population. Comparison of NOD2 allele frequencies in the piglets before and after invasion of PCV2b indicated that the ratio of NOD2-2197A decreased in the population after the PCV2b epidemic. This data indicated that functional differences caused by NOD2-2197 polymorphisms have a marked impact on pig health and livestock productivity. We suggest that NOD2-2197CC is a PCV2 disease resistant polymorphism, which is useful for selective breeding by reducing mortality and increasing productivity.

Trade and Deforestation Predict Rat Lungworm Disease, an Invasive-Driven Zoonosis, at Global and Regional Scales.

The introduction of non-native species and deforestation are both important drivers of environmental change that can also facilitate the geographic spread of zoonotic pathogens and increase disease risk in humans. With ongoing trends in globalization and land-use conversions, introduced species and deforestation are ever more likely to pose threats to human health. Here, we used rat lungworm disease, an emerging zoonotic disease caused by Angiostrongylus cantonensis and maintained by invasive rats and snails, to explore how these two forms of environmental change can impact zoonotic disease risk. We used logistic regressions to examine the role of global trade in the introduction of A. cantonensis at a country level and used model estimates to predict the probability of introduction as a function of trade. We then used hurdle-based regression models to examine the association between deforestation and rat lungworm disease in two regions where A. cantonensis is already established: Hawaii and Thailand. At the global scale, we found the trade of horticultural products to be an important driver in the spread of A. cantonensis and that the majority of countries at high risk of future A. cantonensis introduction are islands. At country scales, we found deforestation to increase the per-capita risk of A. cantonensis exposure in Hawaii and Thailand. Our study provides a preliminary view of the associations between species introductions, deforestation, and risk of A. cantonensis exposure in people. Better understanding how these two widespread and overlapping forms of environmental change affect human health can inform international biosecurity protocols, invasive species management, and land-use policies.

Epigenomic features related to microglia are associated with attenuated effect of APOE ε4 on Alzheimer's disease risk in humans.

Not all apolipoprotein E (APOE) ε4 carriers who survive to advanced age develop Alzheimer's disease (AD); factors attenuating the risk of ε4 on AD may exist. Guided by the top ε4-attenuating signals from methylome-wide association analyses (N=572, ε4+ and ε4-) of neurofibrillary tangles and neuritic plaques, we conducted a meta-analysis for pathological AD within the ε4+ subgroups (N=235) across four independent collections of brains. Cortical RNA-seq and microglial morphology measurements were used in functional analyses. Three out of the four significant CpG dinucleotides were captured by one principal component (PC1), which interacts with ε4 on AD, and is associated with expression of innate immune genes and activated microglia. In ε4 carriers, reduction in each unit of PC1 attenuated the odds of AD by 58% (odds ratio=2.39, 95% confidence interval=[1.64,3.46], P=7.08×10-6 ). An epigenomic factor associated with a reduced proportion of activated microglia (epigenomic factor of activated microglia, EFAM) appears to attenuate the risk of ε4 on AD.

Abstract MP208: A Shared Fog2 / Tbx5-dependent Gene Regulatory Network Identified By Transcription Factor-dependent Non-coding RNA Profiling Modulates Cardiac Rhythm

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting over 33 million individuals throughout the world. AF is highly heritable and recent genome-wide association studies (GWAS) have cumulatively identified over 100 loci associated with AF risk. Genome-wide association studies (GWAS) often identify transcription factor (TF) loci in association with complex human diseases, implying that a significant transcriptional component underlies human disease risk and etiology. The transcription factors ZFPM2 (FOG2), GATA4, and TBX5 have all been implicated in human AF risk by genetic studies. We hypothesized that FOG2, GATA4, and TBX5 functionally interact to regulate a gene regulatory network essential for atrial rhythm control. We generated a novel mouse model of spontaneous AF based on FOG2 overexpression. FOG2 ChIP-seq identified FOG2 genomic localization at loci co-occupied by GATA4, a known FOG2 binding partner. However, we found that FOG2 OE caused gene expression alterations that correlated more highly with TBX5-dependent rather than GATA4-dependent gene expression, including a module of calcium handling genes required for atrial rhythm homeostasis. We applied TF-dependent non-coding transcriptional profiling to examine the FOG2 dependent atrial GRN, which identified 805 candidate regulatory regions with accessible chromatin and FOG2 dependent ncRNAs. TBX5 removal and FOG2 OE caused highly correlated dysregulation of ncRNA expression at open chromatin regions genome-wide, suggesting a functional interaction between TBX5 and FOG2. Furthermore, FOG2 OE only affected enhancer activity by altered ncRNA abundance at locations of TBX5 co-binding. The shared TBX5/FOG2 genomic interaction predicted a potential genetic interaction, and we found that cardiac rhythm abnormalities caused by Tbx5 haploinsufficiency were rescued by Fog2 haploinsufficiency. Taken together, TF-dependent ncRNA-profiling revealed an interconnected cardiac rhythm gene regulatory network (GRN) between FOG2, TBX5 and GATA4. These data nominate a specific model in which FOG2 is recruited by GATA4 to modulate a co-bound TBX5-dependent atrial gene regulatory network for calcium handling and atrial rhythm homeostasis.

Abstract P167: Chronic Circadian Disruption Impairs Cardiovascular Rhythms In Mice

Shift workers have an increased risk of developing hypertension and higher incidence of metabolic syndrome. Circadian rhythm disruption increases cardiometabolic disease risk in humans and animals. We hypothesized that chronic circadian disruption (CCD) disrupts blood pressure, heart rate, and locomotor activity rhythms. Male 8-week old C57BL/6J mice were under a standard light/dark cycle (12-h light, 12-h dark, control) or a CCD protocol (10-h light, 10-h dark, T20) with ad libitum food and water for 10 weeks. T20 mice gained significantly more body weight (n=6, p=0.04; time: p<0.001, light cycle: p<0.001). Mean arterial pressure (MAP), heart rate (HR), and locomotor activity were measured by telemetry after 10 weeks of CCD. Average MAP, HR, and activity were calculated during light and dark periods. MAP between the light and dark periods was significantly different in control mice (12:12 LD), while T20 mice (10:10 LD) did not show diurnal variation (Control 119±3 mm Hg vs.101±2 mm Hg, dark vs. light, respectively, p<0.001; T20 114±13 mm Hg vs.113±12 mm Hg, dark vs. light, respectively, p=0.86; n=3-4 in all groups). Control mice showed a diurnal variation in HR, whereas T20 mice did not show a light-dark difference (Control 584±11 bpm Hg vs. 511±4 bpm, dark vs. light, respectively, p=0.001; T20 537±14 bpm vs. 526±5 bpm, dark vs. light, respectively, p=0.48; n=3-4 in all groups). Dark phase HR was significantly decreased in T20 mice (p=0.01, control dark vs. T20 dark). Control mice showed a light-dark difference in activity, while T20 mice lacked diurnal variation in the activity rhythm (Control 9.6±1.3 counts/min Hg vs. 3.1±0.3 counts/min, dark vs. light, respectively, p<0.001; T20 6.9±0.3 counts/min vs. 6.0±0.8 counts/min, dark vs. light, respectively, p=0.92; n=3-4 in all groups). T20 mice also displayed significantly higher activity during the light phase (p=0.04, control light vs. T20 light). Time of day and the interaction between time of day and light cycle, respectively, were significant between control and T20 mice for MAP, HR, and activity (n=3-4, MAP: p=0.001 and p=0.002; HR: p=0.001 and p=0.004; Activity: p=0.001 and p=0.004). These results indicate that CCD impairs cardiovascular and behavioral rhythms, which may lead to cardiovascular disease.

Application of Genetic Studies to Flow Cytometry Data and Its Impact on Therapeutic Intervention for Autoimmune Disease.

In recent years, systematic genome-wide association studies of quantitative immune cell traits, represented by circulating levels of cell subtypes established by flow cytometry, have revealed numerous association signals, a large fraction of which overlap perfectly with genetic signals associated with autoimmune diseases. By identifying further overlaps with association signals influencing gene expression and cell surface protein levels, it has also been possible, in several cases, to identify causal genes and infer candidate proteins affecting immune cell traits linked to autoimmune disease risk. Overall, these results provide a more detailed picture of how genetic variation affects the human immune system and autoimmune disease risk. They also highlight druggable proteins in the pathogenesis of autoimmune diseases; predict the efficacy and side effects of existing therapies; provide new indications for use for some of them; and optimize the research and development of new, more effective and safer treatments for autoimmune diseases. Here we review the genetic-driven approach that couples systematic multi-parametric flow cytometry with high-resolution genetics and transcriptomics to identify endophenotypes of autoimmune diseases for the development of new therapies.

Red Wine High-Molecular-Weight Polyphenolic Complex: An Emerging Modulator of Human Metabolic Disease Risk and Gut Microbiota.

Moderate red wine consumption has been linked to reduced chronic disease risk. Thus far, little has been known about the physicochemical properties and potential biological effects of high-molecular-weight polyphenolic complexes (HPPCs), a major fraction of red wine polyphenols. In this work, the stability and biochemical properties of HPPCs under simulated gastrointestinal conditions in vitro were studied. The results showed that HPPCs were resistant to simulated gastric digestion (SGD) and simulated intestinal digestion (SID). They exhibited significant inhibitory activity against key metabolic syndrome-associated digestive enzymes, achieving 17.1-90.9% inhibition of pancreatic α-amylase, lipase, and cholesterol esterase at 0.02-0.45 mg/mL. HPPCs were metabolized by gut microbiota (GM), leading to significantly enhanced antioxidant capacity when compared with the original, SGD, and SID samples. Furthermore, they favorably modulated GM profiles, which was accompanied by significantly increased short-chain fatty acid generation during the early colonic fermentation phase. These findings suggest that HPPCs are a promising modulator of human metabolic disease risk.

Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases.

Mitochondrial DNA (mtDNA) variants influence the risk of late-onset human diseases, but the reasons for this are poorly understood. Undertaking a hypothesis-free analysis of 5,689 blood-derived biomarkers with mtDNA variants in 16,220 healthy donors, here we show that variants defining mtDNA haplogroups Uk and H4 modulate the level of circulating N-formylmethionine (fMet), which initiates mitochondrial protein translation. In human cytoplasmic hybrid (cybrid) lines, fMet modulated both mitochondrial and cytosolic proteins on multiple levels, through transcription, post-translational modification and proteolysis by an N-degron pathway, abolishing known differences between mtDNA haplogroups. In a further 11,966 individuals, fMet levels contributed to all-cause mortality and the disease risk of several common cardiovascular disorders. Together, these findings indicate that fMet plays a key role in common age-related disease through pleiotropic effects on cell proteostasis.

Detecting methylation quantitative trait loci using a methylation random field method.

DNA methylation may be regulated by genetic variants within a genomic region, referred to as methylation quantitative trait loci (mQTLs). The changes of methylation levels can further lead to alterations of gene expression, and influence the risk of various complex human diseases. Detecting mQTLs may provide insights into the underlying mechanism of how genotypic variations may influence the disease risk. In this article, we propose a methylation random field (MRF) method to detect mQTLs by testing the association between the methylation level of a CpG site and a set of genetic variants within a genomic region. The proposed MRF has two major advantages over existing approaches. First, it uses a beta distribution to characterize the bimodal and interval properties of the methylation trait at a CpG site. Second, it considers multiple common and rare genetic variants within a genomic region to identify mQTLs. Through simulations, we demonstrated that the MRF had improved power over other existing methods in detecting rare variants of relatively large effect, especially when the sample size is small. We further applied our method to a study of congenital heart defects with 83 cardiac tissue samples and identified two mQTL regions, MRPS10 and PSORS1C1, which were colocalized with expression QTL in cardiac tissue. In conclusion, the proposed MRF is a useful tool to identify novel mQTLs, especially for studies with limited sample sizes.

Assessment of Lycopene Derived Fresh and Processed Tomato Products on Human Diet in Eliminating Health Diseases

Tomato which is scientifically known as Lycopersicon esculentum and basically belonging to the Solanaceae family is categorized as one of the most essential horticultural crops. The red colour in tomatoes and other fruits is primarily due to the presence of a carotenoid pigment particularly lycopene which acts as a phytochemical. Higher concentrations of lycopene pigment are particularly found in fruits like tomatoes, watermelon, pink grapefruit, pink guava, red bell pepper, sea buckhorn, wolfberry, and rosehip. Lycopene plays a fundamental role in the process of biosynthesis of several carotenoid pigments specifically available in two forms; Hydrocarbon carotenoids and Xanthophylls thereby responsible for imparting red, yellow, and orange color in addition to photosynthesis and photo-protection in terms of plants, algae and other photosynthetic organisms. It acts as a potential antioxidant among the entire carotenoid pigments because of its characteristics involving strong color and anti-toxicity properties. Vitamins enriched beta carotene provitamin A, and Ascorbic acid in the form of edible compounds have been abundantly found in tomatoes. Daily intake of lycopene through consumption of tomato and processed tomato products helps in reducing the risk of chronic diseases particularly cancer and cardiovascular diseases. Epidemiological studies have indicated the importance of lycopene in eliminating the risk of human diseases thereby preventing it from deterioration of health. Based on the chemical structure of lycopene, it exists in a thermodynamically stable form thereby exhibiting trans-configuration. In this manuscript, major emphasis highlighted in involving an intake of carotenoid enriched fruits and vegetables for further controlling and reducing the risk of occurrence of human diseases has been reviewed. In addition, significance of manufacturing of value added products and its consumption in the form of tomato oil, non-alcoholic flavored drink etc. has also been reviewed. Authentic information in terms of the addition of lycopene in a daily balanced diet either fresh or processed tomato products along with its functions involving the singlet oxygen quenching ability, as well as benefits of consuming lycopene derived fruits has been reviewed in this manuscript.

An abundant biliary fatty acid metabolite derived from dietary omega-3 polyunsaturated fatty acids regulates triglycerides

Background and Aims: Omega-3 fatty acids from fish oil reduce triglyceride levels in mammals, yet the mechanisms underlying this effect have not been fully clarified despite the clinical use of omega-3 ethyl esters to treat severe hypertriglyceridemia and reduce cardiovascular disease risk in humans. Here we identify in bile a class of hypotriglyceridemic omega-3 fatty acid-derived N-acyl taurines (NATs) that, after dietary omega-3 fatty acid supplementation, increase to concentrations similar to those of steroidal bile acids. We aimed to determine physiological function of this metabolite.

Single-cell analysis uncovers osteoblast factor GDF10 as mediator of vascular smooth muscle cell phenotypic modulation associated with plaque rupture in human carotid artery disease

Background and Aims: Vascular smooth muscle cells (VSMC) are not terminally differentiated and undergo complex phenotypic changes during atherosclerosis. However, the complex heterogeneity of VSMC and how VSMC de-differentiation affects human carotid artery disease (CAD) risk has not been clearly established. The aim of the present study is to comprehensively characterized the transcriptomic profile of phenotypically modulated VSMC and to identify mediators of VSMC transition to osteogenic like cells with likely detrimental role for atherosclerosis plaque stability.

Environmental Exposure to Endocrine Disrupting Chemicals Influences Genomic Imprinting, Growth, and Metabolism.

Genomic imprinting is an epigenetic mechanism that results in monoallelic, parent-of-origin-specific expression of a small number of genes. Imprinted genes play a crucial role in mammalian development as their dysregulation result in an increased risk of human diseases. DNA methylation, which undergoes dynamic changes early in development, is one of the epigenetic marks regulating imprinted gene expression patterns during early development. Thus, environmental insults, including endocrine disrupting chemicals during critical periods of fetal development, can alter DNA methylation patterns, leading to inappropriate developmental gene expression and disease risk. Here, we summarize the current literature on the impacts of in utero exposure to endocrine disrupting chemicals on genomic imprinting and metabolism in humans and rodents. We evaluate how early-life environmental exposures are a potential risk factor for adult metabolic diseases. We also introduce our mouse model of phthalate exposure. Finally, we describe the potential of genomic imprinting to serve as an environmental sensor during early development and as a novel biomarker for postnatal health outcomes.

Genetically Determined Chronic Low-Grade Inflammation and Hundreds of Health Outcomes in the UK Biobank and the FinnGen Population: A Phenome-Wide Mendelian Randomization Study.

BackgroundC-reactive protein (CRP) has been used as a biomarker of chronic low-grade inflammation in observational studies. We aimed to determine whether genetically determined CRP was associated with hundreds of human phenotypes to guide anti-inflammatory interventions.MethodsWe used individual data from the UK Biobank to perform a phenome-wide two-stage least squares (2SLS) Mendelian randomization (MR) analysis for CRP with 879 diseases. Summary-level data from the FinnGen consortium were utilized to perform phenome-wide two-sample MR analysis on 821 phenotypes. Systematic two-sample MR methods included MR-IVW, MR-WME, MR-Mod, and MR-PRESSO as sensitivity analyses combined with multivariable MR to identify robust associations. Genetic correlation analysis was applied to identify shared genetic risks.ResultsWe found genetically determined CRP was robustly associated with 15 diseases in the UK Biobank and 11 diseases in the FinnGen population (P < 0.05 for all MR analyses). CRP was positively associated with tongue cancer, bronchitis, hydronephrosis, and acute pancreatitis and negatively associated with colorectal cancer, colon cancer, cerebral ischemia, electrolyte imbalance, Parkinson’s disease, epilepsy, anemia of chronic disease, encephalitis, psychophysical visual disturbances, and aseptic necrosis of bone in the UK Biobank. There were positive associations with impetigo, vascular dementia, bipolar disorders, hypercholesterolemia, vertigo, and neurological diseases, and negative correlations with degenerative macular diseases, metatarsalgia, interstitial lung disease, and idiopathic pulmonary fibrosis, and others. in the FinnGen population. The electrolyte imbalance and anemia of chronic disease in UK Biobank and hypercholesterolemia and neurological diseases in FinnGen pass the FDR corrections. Neurological diseases and bipolar disorders also presented positive genetic correlations with CRP. We found no overlapping causal associations between the populations. Previous causal evidence also failed to support these associations (except for bipolar disorders).ConclusionsGenetically determined CRP was robustly associated with several diseases in the UK Biobank and the FinnGen population, but could not be replicated, suggesting heterogeneous and non-repeatable effects of CRP across populations. This implies that interventions at CRP are unlikely to result in decreased risk for most human diseases in the general population but may benefit specific high-risk populations. The limited causal evidence and potential double-sided effects remind us to be cautious about CRP interventions.

The maternal gut microbiome during pregnancy and offspring allergy and asthma

Environmental exposures during pregnancy that alter both the maternal gut microbiome and the infant's risk of allergic disease and asthma include a traditional farm environment and consumption of unpasteurized cow's milk, antibiotic use, dietary fiber, and psychosocial stress. Multiple mechanisms acting in concert may underpin these associations and prime the infant to acquire immune competence and homeostasis following exposure to the extrauterine environment. Cellular and metabolic products of the maternal gut microbiome can promote the expression of microbial pattern recognition receptors, as well as thymic and bone marrow hematopoiesis relevant to regulatory immunity. At birth, transmission of maternally derived bacteria likely leverages this in utero programming to accelerate postnatal transition from a TH2- to TH1- and TH17-dominant immune phenotype and maturation of regulatory immune mechanisms, which in turn reduce the child's risk of allergic disease and asthma. Although our understanding of these phenomena is rapidly evolving, the field is relatively nascent, and we are yet to translate existing knowledge into interventions that substantially reduce disease risk in humans. Here, we review evidence that the maternal gut microbiome impacts the offspring's risk of allergic disease and asthma, discuss challenges and future directions for the field, and propose the hypothesis that maternal carriage of Prevotella copri during pregnancy decreases the offspring's risk of allergic disease via production of succinate, which in turn promotes bone marrow myelopoiesis of dendritic cell precursors in the fetus.

HPV16 and HPV18 seropositivity and DNA detection among men who have sex with men: a cross-sectional study conducted in a sexual health clinic in London

ObjectivesMen who have sex with men (MSM) have an increased risk of human papillomavirus (HPV) infection and related diseases compared with men who have sex exclusively with women. From April...