Evolution, Medicine, and Public Health最新文献

Background and objectives: Several studies have linked longer legs with favorable adult metabolic health outcomes and greater offspring birth weight. A recent Mendelian randomization study suggested a causal link between height and cardiometabolic risk; however, the underlying reasons remain poorly understood.

Methodology: Using a cross-sectional design, we tested in a convenience sample of 70 healthy young women whether birth weight and tibia length as markers of early-life conditions associated more strongly with metabolically beneficial traits like organ size and skeletal muscle mass (SMM) than a statistically derived height-residual variable indexing later, more canalized growth.

Results: Consistent with the 'developmental origins of health and disease' hypothesis, we found relatively strong associations of tibia length-but not birth weight-with adult organ size, brain size, SMM and resting energy expenditure measured by magnetic resonance imaging (MRI), dual-energy X-ray absorptiometry and indirect calorimetry, respectively.

Conclusions and implications: Building on prior work, these results suggest that leg length is a sensitive marker of traits directly impacting metabolic and reproductive health. Alongside findings in the same sample relating tibia length and height-residual to MRI-measured pelvic dimensions, we suggest there may exist a degree of coordination in the development of long bone, lean mass and pelvic traits, possibly centered on early, pre-pubertal growth periods. Such phenotypic coordination has important implications for fitness, serving to benefit both adult health and the health of offspring in subsequent generations.

Background and objectives: The human immune system has evolved to balance protection against infection with control of immune-mediated damage and tolerance of commensal microbes. Such tradeoffs between protection and harm almost certainly extend to the immune system of milk.

Methodology: Among breastfeeding mother-infant dyads in Kilimanjaro, Tanzania, we characterized in vitro proinflammatory milk immune responses to Salmonella enterica (an infectious agent) and Escherichia coli (a benign target) as the increase in interleukin-6 after 24 h of incubation with each bacterium. We characterized incident infectious diseases among infants through passive monitoring. We used Cox proportional hazards models to describe associations between milk immune activity and infant infectious disease.

Results: Among infants, risk for respiratory infections declined with increasing milk in vitro proinflammatory response to S. enterica (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.54, 0.86; P: 0.001), while risk for gastrointestinal infections increased with increasing milk in vitro proinflammatory response to E. coli (HR: 1.44; 95% CI: 1.05, 1.99; P: 0.022). Milk proinflammatory responses to S. enterica and E. coli were positively correlated (Spearman's rho: 0.60; P: 0.000).

Conclusions and implications: These findings demonstrate a tradeoff in milk immune activity: the benefits of appropriate proinflammatory activity come at the hazard of misdirected proinflammatory activity. This tradeoff is likely to affect infant health in complex ways, depending on prevailing infectious disease conditions. How mother-infant dyads optimize proinflammatory milk immune activity should be a central question in future ecological-evolutionary studies of the immune system of milk.

Multiple sclerosis (MS), a neurological autoimmune disorder, has recently been linked to neuro-inflammatory influences from the gut. In this review, we address the idea that evolutionary mismatches could affect the pathogenesis of MS via the gut microbiota. The evolution of symbiosis as well as the recent introduction of evolutionary mismatches is considered, and evidence regarding the impact of diet on the MS-associated microbiota is evaluated. Distinctive microbial community compositions associated with the gut microbiota of MS patients are difficult to identify, and substantial study-to-study variation and even larger variations between individual profiles of MS patients are observed. Furthermore, although some dietary changes impact the progression of MS, MS-associated features of microbiota were found to be not necessarily associated with diet per se. In addition, immune function in MS patients potentially drives changes in microbial composition directly, in at least some individuals. Finally, assessment of evolutionary histories of animals with their gut symbionts suggests that the impact of evolutionary mismatch on the microbiota is less concerning than mismatches affecting helminths and protists. These observations suggest that the benefits of an anti-inflammatory diet for patients with MS may not be mediated by the microbiota per se. Furthermore, any alteration of the microbiota found in association with MS may be an effect rather than a cause. This conclusion is consistent with other studies indicating that a loss of complex eukaryotic symbionts, including helminths and protists, is a pivotal evolutionary mismatch that potentiates the increased prevalence of autoimmunity within a population.

Background and objectives: A key strategy for resolving the antibiotic resistance crisis is the development of new drugs with antimicrobial properties. The engineered cationic antimicrobial peptide WLBU2 (also known as PLG0206) is a promising broad-spectrum antimicrobial compound that has completed Phase I clinical studies. It has activity against Gram-negative and Gram-positive bacteria including infections associated with biofilm. No definitive mechanisms of resistance to WLBU2 have been identified.

Methodology: Here, we used experimental evolution under different levels of mutation supply and whole genome sequencing (WGS) to detect the genetic pathways and probable mechanisms of resistance to this peptide. We propagated populations of wild-type and hypermutator Pseudomonas aeruginosa in the presence of WLBU2 and performed WGS of evolved populations and clones.

Results: Populations that survived WLBU2 treatment acquired a minimum of two mutations, making the acquisition of resistance more difficult than for most antibiotics, which can be tolerated by mutation of a single target. Major targets of resistance to WLBU2 included the orfN and pmrB genes, previously described to confer resistance to other cationic peptides. More surprisingly, mutations that increase aggregation such as the wsp pathway were also selected despite the ability of WLBU2 to kill cells growing in a biofilm.

Conclusions and implications: The results show how experimental evolution and WGS can identify genetic targets and actions of new antimicrobial compounds and predict pathways to resistance of new antibiotics in clinical practice.

Background and objectives: Theory suggests that some types of vaccines against infectious pathogens may lead to the evolution of variants that cause increased harm, particularly when they infect unvaccinated individuals. This theory was supported by the observation that the use of an imperfect vaccine to control Marek's disease virus in chickens resulted in the virus evolving to be more lethal to unvaccinated birds. This raises the concern that the use of some other vaccines may lead to similar pernicious outcomes. We examine that theory with a focus on considering the regimes in which such outcomes are expected.

Methodology: We evaluate the plausibility of assumptions in the original theory. The previous theory rested heavily on a particular form of transmission-mortality-recovery trade-off and invoked other assumptions about the pathways of evolution. We review alternatives to mortality in limiting transmission and consider evolutionary pathways that were omitted in the original theory.

Results: The regime where the pernicious evolutionary outcome occurs is narrowed by our analysis but remains possible in various scenarios. We propose a more nuanced consideration of alternative models for the within-host dynamics of infections and for factors that limit virulence. Our analysis suggests imperfect vaccines against many pathogens will not lead to the evolution of pathogens with increased virulence in unvaccinated individuals.

Conclusions and implications: Evolution of greater pathogen mortality driven by vaccination remains difficult to predict, but the scope for such outcomes appears limited. Incorporation of mechanistic details into the framework, especially regarding immunity, may be requisite for prediction accuracy.

Lay summary: A virus of chickens appears to have evolved high mortality in response to a vaccine that merely prevented disease symptoms. Theory has predicted this type of evolution in response to a variety of vaccines and other interventions such as drug treatment. Under what circumstances is this pernicious result likely to occur? Analysis of the theory in light of recent changes in our understanding of viral biology raises doubts that medicine-driven, pernicious evolution is likely to be common. But we are far from a mechanistic understanding of the interaction between pathogen and host that can predict when vaccines and other medical interventions will lead to the unwanted evolution of more virulent pathogens. So, while the regime where a pernicious result obtains may be limited, caution remains warranted in designing many types of interventions.

Background: Depression occurs about twice as often in women as in men, a disparity that remains poorly understood. In a previous publication, Hagen and Rosenström predicted and found that grip strength, a highly sexually dimorphic index of physical formidability, mediated much of the effect of sex on depression. Striking results like this are more likely to be published than null results, potentially biasing the scientific record. It is therefore critical to replicate and extend them.

Methodology: Using new data from the 2013-14 cycle of the National Health and Nutrition Examination Survey, a nationally representative sample of US households (n = 3650), we replicated models of the effect of sex and grip strength on depression reported in Hagen and Rosenström, along with additional potential confounds and a new detailed symptom-level exploration.

Results: Overall, the effects from the original paper were reproduced although with smaller effect sizes. Grip strength mediated 38% of the effect of sex on depression, compared to 63% in Hagen and Rosenström. These results were extended with findings that grip strength had a stronger association with some depression symptoms, like suicidality, low interest and low mood than with other symptoms, like appetite changes.

Conclusions: Grip strength is negatively associated with depression, especially its cognitive-affective symptoms, controlling for numerous possible confounds. Although many factors influence depression, few of these reliably occur cross-culturally in a sex-stratified manner and so are unlikely to explain the well-established, cross-cultural sex difference in depression. The sex difference in upper body strength occurs in all populations and is therefore a candidate evolutionary explanation for some of the sex difference in depression. Lay summary: Why are women at twice the risk of developing depression as men? Depression typically occurs during social conflicts, such as physical or sexual abuse. Physically strong individuals can often single-handedly resolve conflicts in their favor, whereas physically weaker individuals often need help from others. We argue that depression is a credible cry for help. Because men generally have greater strength than women, we argue that men may be more likely to resolve conflicts using physical formidability and women to signal others for help. We find that higher grip strength is associated with lower depression, particularly symptoms like feeling down or thoughts of suicide and that strength accounts for part of the sex difference in rates of depression.

Background and objectives: The probiotic Escherichia coli strain Nissle 1917 (EcN) has been shown to effectively prevent and alleviate intestinal diseases. Despite the widespread medical application of EcN, we still lack basic knowledge about persistence and evolution of EcN outside the human body. Such knowledge is important also for public health aspects, as in contrast to abiotic therapeutics, probiotics are living organisms that have the potential to evolve. This study made use of experimental evolution of EcN in an insect host, the red flour beetle Tribolium castaneum, and its flour environment.

Methodology: Using a serial passage approach, we orally introduced EcN to larvae of T.castaneum as a new host, and also propagated it in the flour environment. After eight propagation cycles, we analyzed phenotypic attributes of the passaged replicate EcN lines, their effects on the host in the context of immunity and infection with the entomopathogen Bacillus thuringiensis, and potential genomic changes using WGS of three of the evolved lines.

Results: We observed weak phenotypic differences between the ancestral EcN and both, beetle and flour passaged EcN lines, in motility and growth at 30°C, but neither any genetic changes, nor the expected increased persistence of the beetle-passaged lines. One of these lines displayed distinct morphological and physiological characteristics.

Conclusions and implications: Our findings suggest that EcN remains rather stable during serial passage in an insect. Weak phenotypic changes in growth and motility combined with a lack of genetic changes indicate a certain degree of phenotypic plasticity of EcN.

Lay summary: For studying adaptation of the human probiotic Escherichia coli strain Nissle 1917, we introduced it to a novel insect host system and its environment using a serial passage approach. After passage, we observed weak phenotypic changes in growth and motility but no mutations or changes in persistence inside the host.

Background: Consistent with evolutionarily theorized costs of reproduction (CoR), reproductive history in women is associated with life expectancy and susceptibility to certain cancers, autoimmune disorders and metabolic disease. Immunological changes originating during reproduction may help explain some of these relationships.

Methodology: To explore the potential role of the immune system in female CoR, we characterized leukocyte composition and regulatory processes using DNA methylation (DNAm) in a cross-sectional cohort of young (20-22 years old) women differing in reproductive status.

Results: Compared to nulliparity, pregnancy was characterized by differential methylation at 828 sites, 96% of which were hypomethylated and enriched for genes associated with T-cell activation, innate immunity, pre-eclampsia and neoplasia. Breastfeeding was associated with differential methylation at 1107 sites (71% hypermethylated), enriched for genes involved in metabolism, immune self-recognition and neurogenesis. There were no significant differences in DNAm between nulliparous and parous women. However, compared to nullipara, pregnant women had lower proportions of B, CD4T, CD8T and natural killer (NK) cells, and higher proportions of granulocytes and monocytes. Monocyte counts were lower and NK counts higher among breastfeeding women, and remained so among parous women.

Implications: Our findings point to widespread differences in DNAm during pregnancy and lactation. These effects appear largely transient, but may accumulate with gravidity become detectable as women age. Nulliparous and parous women differed in leukocyte composition, consistent with more persistent effects of reproduction on cell type. These findings support transient (leukocyte DNAm) and persistent (cell composition) changes associated with reproduction in women, illuminating potential pathways contributing to CoR. Lay Summary: Evolutionary theory and epidemiology support costs of reproduction (CoR) to women's health that may involve changes in immune function. We report differences in immune cell composition and gene regulation during pregnancy and breastfeeding. While many of these differences appear transient, immune cell composition may remain, suggesting mechanisms for female CoR.

Background: National responses to the Covid-19 pandemic varied markedly across countries, from business-as-usual to complete shutdowns. Policies aimed at disrupting the viral transmission cycle and preventing the overwhelming of healthcare systems inevitably exact an economic toll.

Methodology: We developed an intervention policy model that comprised the relative human, implementation and healthcare costs of non-pharmaceutical epidemic interventions and identified the optimal strategy using a neuroevolution algorithm. The proposed model finds the minimum required reduction in transmission rates to maintain the burden on the healthcare system below the maximum capacity.

Results: We find that such a policy renders a sharp increase in the control strength during the early stages of the epidemic, followed by a steady increase in the subsequent ten weeks as the epidemic approaches its peak, and finally the control strength is gradually decreased as the population moves towards herd immunity. We have also shown how such a model can provide an efficient adaptive intervention policy at different stages of the epidemic without having access to the entire history of its progression in the population.

Conclusions and implications: This work emphasizes the importance of imposing intervention measures early and provides insights into adaptive intervention policies to minimize the economic impacts of the epidemic without putting an extra burden on the healthcare system.

Lay summary: We developed an intervention policy model that comprised the relative human, implementation and healthcare costs of non-pharmaceutical epidemic interventions and identified the optimal strategy using a neuroevolution algorithm. Our work emphasizes the importance of imposing intervention measures early and provides insights into adaptive intervention policies to minimize the economic impacts of the epidemic without putting an extra burden on the healthcare system.

Background and objectives: Previously, we showed proof-of-concept in a mouse model that oral administration of cholestyramine prevented enrichment of daptomycin-resistant Enterococcus faecium in the gastrointestinal (GI) tract during daptomycin therapy. Cholestyramine binds daptomycin in the gut, which removes daptomycin selection pressure and so prevents the enrichment of resistant clones. Here, we investigated two open questions related to this approach: (i) can cholestyramine prevent the enrichment of diverse daptomycin mutations emerging de novo in the gut? and (ii) how does the timing of cholestyramine administration impact its ability to suppress resistance?

Methodology: Mice with GI E. faecium were treated with daptomycin with or without cholestyramine, and E. faecium was cultured from feces to measure changes in daptomycin susceptibility. A subset of clones was sequenced to investigate the genomic basis of daptomycin resistance.

Results: Cholestyramine prevented the enrichment of diverse resistance mutations that emerged de novo in daptomycin-treated mice. Whole-genome sequencing revealed that resistance emerged through multiple genetic pathways, with most candidate resistance mutations observed in the clsA gene. In addition, we observed that cholestyramine was most effective when administration started prior to the first dose of daptomycin. However, beginning cholestyramine after the first daptomycin dose reduced the frequency of resistant E. faecium compared to not using cholestyramine at all.

Conclusions and implications: Cholestyramine prevented the enrichment of diverse daptomycin-resistance mutations in intestinal E. faecium populations during daptomycin treatment, and it is a promising tool for managing the transmission of daptomycin-resistant E. faecium.