Quantification of Enteric Dysfunction in Cystic Fibrosis: Inter- and Intraindividual Variability.

OBJECTIVES: To test the utility of various biomarkers as indicators of gut dysfunction in cystic fibrosis (CF) and determine whether intraindividual variations in these measures are repeatable over short intervals and whether interindividual variations correlate with clinical outcomes. STUDY DESIGN: We performed a cross-sectional, limited longitudinal study of children with CF aged 1-21 years who provided blood and stool samples at 2 or 3 visits, 2 weeks and 3 months apart, which were assayed for markers of intestinal inflammation (fecal calprotectin [fCal], lipocalin-2 [fLcn2], neopterin), and permeability (plasma lipopolysaccharide [LPS] antibodies, LPS-binding protein) by enzyme immunoassays. Control specimens were obtained from children without CF who had undergone esophagogastroduodenoscopy and had no evidence of gut inflammation. RESULTS: Twenty-six of 29 participants with CF completed the study. Sixty-nine stools (57 case/12 control) and 76 plasmas (60 case/16 control) were analyzed. LPS antibody had reliable intraindividual stability. fCal, fLcn2, and neopterin were significantly greater in CF than in control samples. fCal was negatively correlated with 3-month interval change (Δ) in weight-for-age z-score, body mass index/weight-for-length z-score, and forced expiratory volume in 1 second. fLcn2 was negatively correlated with FEV1 but not with anthropometrics. No marker correlated with Δbody mass index/weight-for-length z-score or ΔFEV1. CONCLUSIONS: fLcn2 is elevated in people with CF and might predict worse interval pulmonary function. Expanded studies are warranted to test if fLcn2 correlates with changes in additional outcomes.

Maternal activation of the EGFR prevents translocation of gut-residing pathogenic Escherichia coli in a model of late-onset neonatal sepsis.

Late-onset sepsis (LOS) is a highly consequential complication of preterm birth and is defined by a positive blood culture obtained after 72 h of age. The causative bacteria can be found in patients' intestinal tracts days before dissemination, and cohort studies suggest reduced LOS risk in breastfed preterm infants through unknown mechanisms. Reduced concentrations of epidermal growth factor (EGF) of maternal origin within the intestinal tract of mice correlated to the translocation of a gut-resident human pathogen Escherichia coli, which spreads systemically and caused a rapid, fatal disease in pups. Translocation of Escherichia coli was associated with the formation of colonic goblet cell-associated antigen passages (GAPs), which translocate enteric bacteria across the intestinal epithelium. Thus, maternally derived EGF, and potentially other EGFR ligands, prevents dissemination of a gut-resident pathogen by inhibiting goblet cell-mediated bacterial translocation. Through manipulation of maternally derived EGF and alteration of the earliest gut defenses, we have developed an animal model of pathogen dissemination which recapitulates gut-origin neonatal LOS.

Pathogen-Specific Effects of Probiotics in Children With Acute Gastroenteritis Seeking Emergency Care: A Randomized Trial.

BACKGROUND: It is unknown if probiotics exert pathogen-specific effects in children with diarrhea secondary to acute gastroenteritis. METHODS: Analysis of patient-level data from 2 multicenter randomized, placebo controlled trials conducted in pediatric emergency departments in Canada and the United States. Participants were 3-48 months with >3 diarrheal episodes in the preceding 24 hours and were symptomatic for <72 hours and <7 days in the Canadian and US studies, respectively. Participants received either placebo or a probiotic preparation (Canada-Lactobacillus rhamnosus R0011/Lactobacillus helveticus R0052; US-L. rhamnosus GG). The primary outcome was post-intervention moderate-to-severe disease (ie, ≥9 on the Modified Vesikari Scale [MVS] score). RESULTS: Pathogens were identified in specimens from 59.3% of children (928/1565). No pathogen groups were less likely to experience an MVS score ≥9 based on treatment allocation (test for interaction = 0.35). No differences between groups were identified for adenovirus (adjusted relative risk [aRR]: 1.42; 95% confidence interval [CI]: .62, 3.23), norovirus (aRR: 0.98; 95% CI: .56, 1.74), rotavirus (aRR: 0.86; 95% CI: .43, 1.71) or bacteria (aRR: 1.19; 95% CI: .41, 3.43). At pathogen-group and among individual pathogens there were no differences in diarrhea duration or the total number of diarrheal stools between treatment groups, regardless of intervention allocation or among probiotic sub-groups. Among adenovirus-infected children, those administered the L. rhamnosus R0011/L. helveticus R0052 product experienced fewer diarrheal episodes (aRR: 0.65; 95% CI: .47, .90). CONCLUSIONS: Neither probiotic product resulted in less severe disease compared to placebo across a range of the most common etiologic pathogens. The preponderance of evidence does not support the notion that there are pathogen specific benefits associated with probiotic use in children with acute gastroenteritis. CLINICAL TRIALS REGISTRATION: NCT01773967 and NCT01853124.

Lactobacillus rhamnosus GG versus Placebo for Acute Gastroenteritis in Children.

BACKGROUND: Acute gastroenteritis develops in millions of children in the United States every year, and treatment with probiotics is common. However, data to support the use of probiotics in this population are limited. METHODS: We conducted a prospective, randomized, double-blind trial involving children 3 months to 4 years of age with acute gastroenteritis who presented to one of 10 U.S. pediatric emergency departments. Participants received a 5-day course of Lactobacillus rhamnosus GG at a dose of 1×1010 colony-forming units twice daily or matching placebo. Follow-up surveys were conducted daily for 5 days and again 14 days after enrollment and 1 month after enrollment. The primary outcome was moderate-to-severe gastroenteritis, which was defined as an illness episode with a total score on the modified Vesikari scale of 9 or higher (scores range from 0 to 20, with higher scores indicating more severe disease), within 14 days after enrollment. Secondary outcomes included the duration and frequency of diarrhea and vomiting, the duration of day-care absenteeism, and the rate of household transmission (defined as the development of symptoms of gastroenteritis in previously asymptomatic household contacts). RESULTS: Among the 971 participants, 943 (97.1%) completed the trial. The median age was 1.4 years (interquartile range, 0.9 to 2.3), and 513 participants (52.9%) were male. The modified Vesikari scale score for the 14-day period after enrollment was 9 or higher in 55 of 468 participants (11.8%) in the L. rhamnosus GG group and in 60 of 475 participants (12.6%) in the placebo group (relative risk, 0.96; 95% confidence interval, 0.68 to 1.35; P=0.83). There were no significant differences between the L. rhamnosus GG group and the placebo group in the duration of diarrhea (median, 49.7 hours in the L. rhamnosus GG group and 50.9 hours in the placebo group; P=0.26), duration of vomiting (median, 0 hours in both groups; P=0.17), or day-care absenteeism (median, 2 days in both groups; P=0.67) or in the rate of household transmission (10.6% and 14.1% in the two groups, respectively; P=0.16). CONCLUSIONS: Among preschool children with acute gastroenteritis, those who received a 5-day course of L. rhamnosus GG did not have better outcomes than those who received placebo. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT01773967 .).

ONCOPEDS: A mobile application to improve early diagnosis and timely referral in childhood cancer in a low- and middle-income country-A pilot study.

BACKGROUND: Diagnosis delay in children and adolescents with cancer is a public health problem in Peru that leads to high rates of advanced disease and mortality. We aimed to assess the implementation feasibility and potential utility of ONCOpeds®, a mobile application that provides consultations with pediatric oncologists, in reducing the latency to diagnosis (LD) and referral time (RT) among children and adolescents in Peru diagnosed with cancer. MATERIAL AND METHODS: A prospective pilot study was conducted in the region of Callao between November 2017 and April 2018. Primary and secondary care providers were trained on the use of ONCOpeds in five educational sessions. Patients younger than 18 years who resided in Callao and were diagnosed with cancer at four pediatric cancer units in Lima were analyzed by referral type: ONCOpeds facilitated or conventional. RESULTS: ONCOpeds was successfully installed in the smartphones of 78 primary and secondary care providers of Callao. During the study period, 23 new cases of cancer in children and adolescents from the region were diagnosed. Ten patients received ONCOpeds-facilitated referrals and 13 received conventional referrals. The RT decreased among those who received ONCOpeds-facilitated referrals by 66% (P = 0.02); however, the LD did not significantly decrease with the use of ONCOpeds. CONCLUSIONS: The implementation of ONCOpeds was found to be feasible in this pilot study, having a potential utility in improving early diagnosis and referral in children and adolescents newly diagnosed with cancer. Directions for future research include multicenter studies with a larger population to further test the application's effectiveness.

Mixed methods evaluation of implementation and outcomes in a community-based cancer prevention intervention.

BACKGROUND: Community-based educational programs can complement clinical strategies to increase cancer screenings and encourage healthier lifestyles to reduce cancer burden. However, implementation quality can influence program outcomes and is rarely formally evaluated in community settings. This mixed-methods study aimed to characterize implementation of a community-based cancer prevention program using the Consolidated Framework for Implementation Research (CFIR), determine if implementation was related to participant outcomes, and identify barriers and facilitators to implementation that could be addressed. METHODS: This study utilized quantitative participant evaluation data (n = 115) and quantitative and qualitative data from semi-structured interviews with program instructors (N = 13). At the participant level, demographic data (age, sex, insurance status) and behavior change intention were captured. Instructor data included implementation of program components and program attendance to create a 7-point implementation score of fidelity and reach variables. Degree of program implementation (high and low) was operationalized based on these variables (low: 0-4, high: 5-7). Relationships among degree of implementation, participant demographics, and participant outcomes (e.g., intent to be physically active or limit alcohol) were assessed using linear or ordinal logistic mixed effects models as appropriate. Interview data were transcribed and coded deductively for CFIR constructs, and constructs were then rated for magnitude and valence. Patterns between ratings of high and low implementation programs were used to determine constructs that manifested as barriers or facilitators. RESULTS: Program implementation varied with scores ranging from 4 to 7. High implementation was related to greater improvements in intention to be physically active (p <  0.05), achieve a healthy weight (p <  0.05), and limit alcohol (p <  0.01). Eight constructs distinguished between high and low implementation programs. Design quality and packaging, compatibility, external change agents, access to knowledge and information, and experience were facilitators of implementation and formally appointed internal implementation leaders was a barrier to implementation. CONCLUSIONS: As higher implementation was related to improved participant outcomes, program administrators should emphasize the importance of fidelity in training for program instructors. The CFIR can be used to identify barriers and/or facilitators to implementation in community interventions, but results may be unique from clinical contexts.

Gut bacteria dysbiosis and necrotising enterocolitis in very low birthweight infants: a prospective case-control study.

BACKGROUND: Gut bacteria might predispose to or protect from necrotising enterocolitis, a severe illness linked to prematurity. In this observational prospective study we aimed to assess whether one or more bacterial taxa in the gut differ between infants who subsequently develop necrotising enterocolitis (cases) and those who do not (controls). METHODS: We enrolled very low birthweight (1500 g and lower) infants in the primary cohort (St Louis Children's Hospital) between July 7, 2009, and Sept 16, 2013, and in the secondary cohorts (Kosair Children's Hospital and Children's Hospital at Oklahoma University) between Sept 12, 2011 and May 25, 2013. We prospectively collected and then froze stool samples for all infants. Cases were defined as infants whose clinical courses were consistent with necrotising enterocolitis and whose radiographs fulfilled criteria for Bell's stage 2 or 3 necrotising enterocolitis. Control infants (one to four per case; not fixed ratios) with similar gestational ages, birthweight, and birth dates were selected from the population after cases were identified. Using primers specific for bacterial 16S rRNA genes, we amplified and then pyrosequenced faecal DNA from stool samples. With use of Dirichlet multinomial analysis and mixed models to account for repeated measures, we identified host factors, including development of necrotising enterocolitis, associated with gut bacterial populations. FINDINGS: We studied 2492 stool samples from 122 infants in the primary cohort, of whom 28 developed necrotising enterocolitis; 94 infants were used as controls. The microbial community structure in case stools differed significantly from those in control stools. These differences emerged only after the first month of age. In mixed models, the time-by-necrotising-enterocolitis interaction was positively associated with Gammaproteobacteria (p=0·0010) and negatively associated with strictly anaerobic bacteria, especially Negativicutes (p=0·0019). We studied 1094 stool samples from 44 infants in the secondary cohorts. 18 infants developed necrotising enterocolitis (cases) and 26 were controls. After combining data from all cohorts (166 infants, 3586 stools, 46 cases of necrotising enterocolitis), there were increased proportions of Gammaproteobacteria (p=0·0011) and lower proportions of both Negativicutes (p=0·0013) and the combined Clostridia-Negativicutes class (p=0·0051) in infants who went on to develop necrotising enterocolitis compared with controls. These associations were strongest in both the primary cohort and the overall cohort for infants born at less than 27 weeks' gestation. INTERPRETATION: A relative abundance of Gammaproteobacteria (ie, Gram-negative facultative bacilli) and relative paucity of strict anaerobic bacteria (especially Negativicutes) precede necrotising enterocolitis in very low birthweight infants. These data offer candidate targets for interventions to prevent necrotising enterocolitis, at least among infants born at less than 27 weeks' gestation. FUNDING: National Institutes of Health (NIH), Foundation for the NIH, the Children's Discovery Institute.

Patterned progression of bacterial populations in the premature infant gut.

In the weeks after birth, the gut acquires a nascent microbiome, and starts its transition to bacterial population equilibrium. This early-in-life microbial population quite likely influences later-in-life host biology. However, we know little about the governance of community development: does the gut serve as a passive incubator where the first organisms randomly encountered gain entry and predominate, or is there an orderly progression of members joining the community of bacteria? We used fine interval enumeration of microbes in stools from multiple subjects to answer this question. We demonstrate via 16S rRNA gene pyrosequencing of 922 specimens from 58 subjects that the gut microbiota of premature infants residing in a tightly controlled microbial environment progresses through a choreographed succession of bacterial classes from Bacilli to Gammaproteobacteria to Clostridia, interrupted by abrupt population changes. As infants approach 33-36 wk postconceptional age (corresponding to the third to the twelfth weeks of life depending on gestational age at birth), the gut is well colonized by anaerobes. Antibiotics, vaginal vs. Caesarian birth, diet, and age of the infants when sampled influence the pace, but not the sequence, of progression. Our results suggest that in infants in a microbiologically constrained ecosphere of a neonatal intensive care unit, gut bacterial communities have an overall nonrandom assembly that is punctuated by microbial population abruptions. The possibility that the pace of this assembly depends more on host biology (chiefly gestational age at birth) than identifiable exogenous factors warrants further consideration.

Gut Colonization of Healthy Children and Their Mothers With Pathogenic Ciprofloxacin-Resistant Escherichia coli.

BACKGROUND: The reservoir of pathogenic ciprofloxacin-resistant Escherichia coli remains unknown. METHODS: We conducted a prospective cohort study of 80 healthy twins and their mothers to determine the frequency of excretion of ciprofloxacin-resistant, potentially pathogenic E. coli. Stool specimens were cultured selectively for ciprofloxacin-resistant gram-negative bacteria. Isolates were categorized on the basis of additional resistance and virulence profiles. We also prospectively collected clinical metadata. RESULTS: Fifteen children (19%) and 8 mothers (20%) excreted ciprofloxacin-resistant E. coli at least once. Overall, 33% of 40 families had at least 1 member whose stool specimen yielded ciprofloxacin-resistant E. coli on culture. Fifty-seven submitted stool specimens (2.8%) contained such organisms; clones ST131-H30 and ST405 accounted for 52 and 5 of the positive specimens, respectively. Length of hospital stay after birth (P = .002) and maternal colonization (P = .0001) were associated with subsequent childhood carriage of ciprofloxacin-resistant E. coli; antibiotic use, acid suppression, sex, mode of delivery, and maternal perinatal antibiotic use were not. Ciprofloxacin-resistant E. coli were usually resistant to additional antibiotic classes, and all had virulence genotypes typical of extraintestinal pathogenic E. coli. CONCLUSIONS: Healthy children and their mothers commonly harbor ciprofloxacin-resistant E. coli with pathogenic potential.

The mediating role of emotion dysregulation and depression on the relationship between childhood trauma exposure and emotional eating.

Exposure to childhood adversity is implicated in the etiology of adverse health outcomes, including depression, posttraumatic stress disorder (PTSD), and obesity. The relationship between childhood trauma and obesity may be related to the association of childhood trauma and risk for emotional eating. One pathway between trauma exposure, psychopathology, and emotional eating may be through emotion dysregulation and depression. The current study was undertaken to characterize demographic, environmental, and psychological risk factors for emotional eating in a primarily African American, low socioeconomic status (SES), inner-city population (N = 1110). Emotional eating was measured using the Dutch Eating Behavioral Questionnaire and the Emotional Dysregulation Scale was used to assess emotion regulation. The Beck Depression Inventory and the modified PTSD Symptom Scale were used to assess depression and PTSD, respectively. Higher levels of emotional eating were associated with body mass index, income, childhood and adulthood trauma exposure, depressive and PTSD symptoms, negative affect and emotion dysregulation. Childhood emotional abuse was the most associated with emotional eating in adulthood. Hierarchical linear regression and mediation analyses indicated that the association between childhood trauma exposure (and emotional abuse specifically) and emotional eating was fully mediated by depression symptoms and emotion dysregulation, with emotional dysregulation contributing more to the mediation effect. Together these findings support a model in which obesity and related adverse health outcomes in stress- and trauma-exposed populations may be directly related to self-regulatory coping strategies accompanying emotion dysregulation. Our data suggest that emotion dysregulation is a viable therapeutic target for emotional eating in at-risk populations.

Sepsis from the gut: the enteric habitat of bacteria that cause late-onset neonatal bloodstream infections.

BACKGROUND: Late-onset sepsis is a major problem in neonatology, but the habitat of the pathogens before bloodstream invasion occurs is not well established. METHODS: We examined prospectively collected stools from premature infants with sepsis to find pathogens that subsequently invaded their bloodstreams, and sought the same organisms in stools of infants without sepsis. Culture-based techniques were used to isolate stool bacteria that provisionally matched the bloodstream organisms, which were then genome sequenced to confirm or refute commonality. RESULTS: Of 11 children with late-onset neonatal bloodstream infections, 7 produced at least 1 stool that contained group B Streptococcus (GBS), Serratia marcescens, or Escherichia coli before their sepsis episode with provisionally matching organisms. Of 96 overlap comparison subjects without sepsis temporally associated with these cases, 4 were colonized with provisionally matching GBS or S. marcescens. Of 175 comparisons of stools from randomly selected infants without sepsis, 1 contained a GBS (this infant had also served as an overlap comparison subject and both specimens contained provisionally matching GBS). Genome sequencing confirmed common origin of provisionally matching fecal and blood isolates. The invasive E. coli were present in all presepticemic stools since birth, but gut colonization with GBS and S. marcescens occurred closer to time of bloodstream infection. CONCLUSIONS: The neonatal gut harbors sepsis-causing pathogens, but such organisms are not inevitable members of the normal microbiota. Surveillance microbiology, decolonization, and augmented hygiene might prevent dissemination of invasive bacteria between and within premature infants.

Understanding the control of ingestive behavior in primates.

This article is part of a Special Issue "Energy Balance". Ingestive behavior in free-ranging populations of nonhuman primates is influenced by resource availability and social group organization and provides valuable insight on the evolution of ecologically adaptive behaviors and physiological systems. As captive populations were established, questions regarding proximate mechanisms that regulate food intake in these animals could be more easily addressed. The availability of these captive populations has led to the use of selected species to understand appetite control or metabolic physiology in humans. Recognizing the difficulty of quantitating food intake in free-ranging groups, the use of captive, singly-housed animals provided a distinct advantage though, at the same time, produced a different social ecology from the animals' natural habitat. However, the recent application of novel technologies to quantitate caloric intake and energy expenditure in free-feeding, socially housed monkeys permits prospective studies that can accurately define how food intake changes in response to any number of interventions in the context of a social environment. This review provides an overview of studies examining food intake using captive nonhuman primates organized into three areas: a) neurochemical regulation of food intake in nonhuman primates; b) whether exposure to specific diets during key developmental periods programs differences in diet preferences or changes the expression of feeding related neuropeptides; and c) how psychosocial factors influence appetite regulation. Because feeding patterns are driven by more than just satiety and orexigenic signals, appreciating how the social context influences pattern of feeding in nonhuman primates may be quite informative for understanding the biological complexity of feeding in humans.

First-in-Human Assessment of Gut Permeability in Crohn's Disease Patients Using Fluorophore Technology.

Background and Aims: The dual sugar absorption test as a classic measure of human intestinal permeability has limited clinical utility due to lengthy and cumbersome urine collection, assay variability, and long turnaround. We aimed to determine if the orally administered fluorophore MB-102 (relmapirazin) (molecular weight [MW] = 372) compares to lactulose (L) (MW = 342) and rhamnose (R) (MW = 164)-based dual sugar absorption test as a measure of gut permeability in people with a spectrum of permeability including those with Crohn's disease (CD). Methods: We performed a single-center, randomized, open-label, crossover study comparing orally administered MB-102 (1.5 or 3.0 mg/kg) to L (1000 mg) and R (200 mg). Adults with active small bowel CD on magnetic resonance enterography (cases) and healthy adults (controls) were randomized to receive either MB-102 or L and R on study day 1, and the other tracer 3 to 7 days later. Urine was collected at baseline and 1, 2, 4, 6, 8, 10, and 12 hours after tracer ingestion to calculate the cumulative urinary percent excretion of MB-102 and L and R. Results: Nine cases and 10 controls completed the study without serious adverse events. Urinary recovery of administered MB-102 correlated with recovery of lactulose (r-squared = 0.83) for all participants. MB-102 urine recovery was also tracked with the L:R ratio urine recovery (r-squared = 0.57). In controls, the percentages of L and MB-102 recovered were similar within a narrow range, unlike in CD patients. Conclusion: This first-in-human study of an orally administered fluorophore to quantify gastrointestinal permeability in adults with CD demonstrates that MB-102 is well tolerated, and its recovery in urine mirrors that of percent L and the L:R ratio.

Small changes in meal patterns lead to significant changes in total caloric intake. Effects of diet and social status on food intake in female rhesus monkeys.

Social subordination in macaques is a well-established model to study the adverse effects of psychosocial stress on a number of health outcomes, including stress-induced eating. The present analysis was conducted to empirically define a meal among free-feeding female rhesus monkeys and to examine the roles of meal patterning (e.g., meal size, meal frequency, and snacking patterns) in findings from a previous study demonstrating that psychosocial stress increases overall caloric intake among subordinate animals with access to a highly palatable diet. Results indicate that all animals, regardless of social status, consumed more frequent meals, larger meals, and more calories in the form of snacks when a highly palatable diet was available. Additional findings suggest that subordinate animals consumed significantly larger meals compared to their dominant counterparts regardless of the dietary environment. Additionally, subordinate females with a history of exposure to the palatable diet consumed significantly more snack calories than both dominant and subordinate animals without previous exposure to the palatable diet when these females were returned to a standard laboratory diet. These findings illustrate how small changes in meal patterns can lead to significant increases in total caloric intake, which if prolonged, could promote the emergence of an obese phenotype.

Gut pathogen colonization precedes bloodstream infection in the neonatal intensive care unit.

Bacterial bloodstream infections (BSIs) resulting in late-onset sepsis affect up to half of extremely preterm infants and have substantial morbidity and mortality. Bacterial species associated with BSIs in neonatal intensive care units (NICUs) commonly colonize the preterm infant gut microbiome. Accordingly, we hypothesized that the gut microbiome is a reservoir of BSI-causing pathogenic strains that increase in abundance before BSI onset. We analyzed 550 previously published fecal metagenomes from 115 hospitalized neonates and found that recent ampicillin, gentamicin, or vancomycin exposure was associated with increased abundance of Enterobacteriaceae and Enterococcaceae in infant guts. We then performed shotgun metagenomic sequencing on 462 longitudinal fecal samples from 19 preterm infants (cases) with BSI and 37 non-BSI controls, along with whole-genome sequencing of the BSI isolates. Infants with BSI caused by Enterobacteriaceae were more likely than infants with BSI caused by other organisms to have had ampicillin, gentamicin, or vancomycin exposure in the 10 days before BSI. Relative to controls, gut microbiomes of cases had increased relative abundance of the BSI-causing species and clustered by Bray-Curtis dissimilarity according to BSI pathogen. We demonstrated that 11 of 19 (58%) of gut microbiomes before BSI, and 15 of 19 (79%) of gut microbiomes at any time, harbored the BSI isolate with fewer than 20 genomic substitutions. Last, BSI strains from the Enterobacteriaceae and Enterococcaceae families were detected in multiple infants, indicating BSI-strain transmission. Our findings support future studies to evaluate BSI risk prediction strategies based on gut microbiome abundance in hospitalized preterm infants.

Gut microbiome composition may be an indicator of preclinical Alzheimer's disease.

Alzheimer's disease (AD) pathology is thought to progress from normal cognition through preclinical disease and ultimately to symptomatic AD with cognitive impairment. Recent work suggests that the gut microbiome of symptomatic patients with AD has an altered taxonomic composition compared with that of healthy, cognitively normal control individuals. However, knowledge about changes in the gut microbiome before the onset of symptomatic AD is limited. In this cross-sectional study that accounted for clinical covariates and dietary intake, we compared the taxonomic composition and gut microbial function in a cohort of 164 cognitively normal individuals, 49 of whom showed biomarker evidence of early preclinical AD. Gut microbial taxonomic profiles of individuals with preclinical AD were distinct from those of individuals without evidence of preclinical AD. The change in gut microbiome composition correlated with ß-amyloid (Aß) and tau pathological biomarkers but not with biomarkers of neurodegeneration, suggesting that the gut microbiome may change early in the disease process. We identified specific gut bacterial taxa associated with preclinical AD. Inclusion of these microbiome features improved the accuracy, sensitivity, and specificity of machine learning classifiers for predicting preclinical AD status when tested on a subset of the cohort (65 of the 164 participants). Gut microbiome correlates of preclinical AD neuropathology may improve our understanding of AD etiology and may help to identify gut-derived markers of AD risk.

Social and psychological adversity are associated with distinct mother and infant gut microbiome variations.

Health disparities are driven by underlying social disadvantage and psychosocial stressors. However, how social disadvantage and psychosocial stressors lead to adverse health outcomes is unclear, particularly when exposure begins prenatally. Variations in the gut microbiome and circulating proinflammatory cytokines offer potential mechanistic pathways. Here, we interrogate the gut microbiome of mother-child dyads to compare high-versus-low prenatal social disadvantage, psychosocial stressors and maternal circulating cytokine cohorts (prospective case-control study design using gut microbiomes from 121 dyads profiled with 16 S rRNA sequencing and 89 dyads with shotgun metagenomic sequencing). Gut microbiome characteristics significantly predictive of social disadvantage and psychosocial stressors in the mothers and children indicate that different discriminatory taxa and related pathways are involved, including many species of Bifidobacterium and related pathways across several comparisons. The lowest inter-individual gut microbiome similarity was observed among high-social disadvantage/high-psychosocial stressors mothers, suggesting distinct environmental exposures driving a diverging gut microbiome assembly compared to low-social disadvantage/low-psychosocial stressors controls (P = 3.5 × 10-5 for social disadvantage, P = 2.7 × 10-15 for psychosocial stressors). Children's gut metagenome profiles at 4 months also significantly predicted high/low maternal prenatal IL-6 (P = 0.029), with many bacterial species overlapping those identified by social disadvantage and psychosocial stressors. These differences, based on maternal social and psychological status during a critical developmental window early in life, offer potentially modifiable targets to mitigate health inequities.

The role of matrix metalloproteinase-9 in cigarette smoke-induced emphysema.

RATIONALE: Matrix metalloprotease (MMP)-9 is an elastolytic endopeptidase produced by activated macrophages that may be involved in the development of human pulmonary emphysema and could be inhibited with existing compounds. Mouse models have demonstrated that excess MMP-9 production can result in permanent alveolar destruction. OBJECTIVES: To determine if MMP-9 causes cigarette smoke-induced emphysema using MMP-9 knockout mice and human samples. METHODS: Mouse lungs were analyzed for inflammation and airspace enlargement using a mainstream smoke-exposure model. Human macrophage mRNA was isolated from subjects with emphysema by laser capture microdissection. Human blood monocyte mRNA was isolated from subjects with greater than 30 pack-year smoking history. Human gene expression was determined by quantitative polymerase chain reaction and compared with emphysema severity determined by automated computed tomography analysis. Plasma Clara cell secretory protein and surfactant protein-D were quantified to measure ongoing lung injury. MEASUREMENTS AND MAIN RESULTS: Mice deficient in MMP-9 develop the same degree of cigarette smoke-induced inflammation and airspace enlargement as strain-matched controls. Macrophages are the predominant source of MMP-9 production in human emphysema specimens and similar quantities of macrophage MMP-9 mRNA is present in areas of lung with and without emphysema. Circulating monocytes produce more MMP-9 in individuals with advanced emphysema severity despite no correlation of MMP-9 with markers of ongoing lung damage. CONCLUSIONS: These results suggest that MMP-9 in humans who smoke is similar to smoke-exposed mice, where MMP-9 is present in emphysematous lung but not correlated with the emphysema. To the degree that the mechanisms of emphysema in humans who smoke resemble the mouse model, these data suggest specific inhibition of MMP-9 is unlikely to be an effective therapy for cigarette smoke-induced emphysema. Clinical trial registered with www.clinicaltrials.gov (NCT 00757120).

Longitudinal gut virome analysis identifies specific viral signatures that precede necrotizing enterocolitis onset in preterm infants.

Necrotizing enterocolitis (NEC) is a serious consequence of preterm birth and is often associated with gut bacterial microbiome alterations. However, little is known about the development of the gut virome in preterm infants, or its role in NEC. Here, using metagenomic sequencing, we characterized the DNA gut virome of 9 preterm infants who developed NEC and 14 gestational age-matched preterm infants who did not. Infants were sampled longitudinally before NEC onset over the first 11 weeks of life. We observed substantial interindividual variation in the gut virome between unrelated preterm infants, while intraindividual variation over time was significantly less. We identified viral and bacterial signatures in the gut that preceded NEC onset. Specifically, we observed a convergence towards reduced viral beta diversity over the 10 d before NEC onset, which was driven by specific viral signatures and accompanied by specific viral-bacterial interactions. Our results indicate that bacterial and viral perturbations precede the sudden onset of NEC. These findings suggest that early life virome signatures in preterm infants may be implicated in NEC.