Fecal microbiota is associated with extraintestinal manifestations in inflammatory bowel disease.

INTRODUCTION: A large proportion of patients with inflammatory bowel disease (IBD) experience IBD-related inflammatory conditions outside of the gastrointestinal tract, termed extraintestinal manifestations (EIMs) which further decreases quality of life and, in extreme cases, can be life threatening. The pathogenesis of EIMs remains unknown, and although gut microbiota alterations are a well-known characteristic of patients with IBD, its relationship with EIMs remains sparsely investigated. This study aimed to compare the gut microbiota of patients with IBD with and without EIMs. METHODS: A total of 131 Danish patients with IBD were included in the study, of whom 86 had a history of EIMs (IBD-EIM) and 45 did not (IBD-C). Stool samples underwent 16S rRNA sequencing. Amplicon sequence variants (ASVs) were mapped to the Silva database. Diversity indices and distance matrices were compared between IBD-EIM and IBD-C. Differentially abundant ASVs were identified using a custom multiple model statistical analysis approach, and modules of co-associated bacteria were identified using sparse correlations for compositional data (SparCC) and related to patient EIM status. RESULTS: Patients with IBD and EIMs exhibited increased disease activity, body mass index, increased fecal calprotectin levels and circulating monocytes and neutrophils. Microbiologically, IBD-EIM exhibited lower fecal microbial diversity than IBD-C (Mann-Whitney's test, p = .01) and distinct fecal microbiota composition (permutational multivariate analysis of variance; weighted UniFrac, R2 = 0.018, p = .01). A total of 26 ASVs exhibited differential relative abundances between IBD-EIM and IBD-C, including decreased Agathobacter and Blautia and increased Eggerthella lenta in the IBD-EIM group. SparCC analysis identified 27 bacterial co-association modules, three of which were negatively related to EIM (logistic regression, p < .05) and included important health-associated bacteria, such as Agathobacter and Faecalibacterium. CONCLUSIONS: The fecal microbiota in IBD patients with EIMs is distinct from that in IBD patients without EIM and could be important for EIM pathogenesis.

Alteration in the gut microbiome is associated with changes in bone metabolism after laparoscopic sleeve gastrectomy.

Laparoscopic sleeve gastrectomy (LSG), the most common bariatric surgical procedure, leads to durable weight loss and improves obesity-related comorbidities. However, it induces abnormalities in bone metabolism. One unexplored potential contributor is the gut microbiome, which influences bone metabolism and is altered after surgery. We characterized the relationship between the gut microbiome and skeletal health in severe obesity and after LSG. In a prospective cohort study, 23 adults with severe obesity underwent skeletal health assessment and stool collection preoperatively and 6 mo after LSG. Gut microbial diversity and composition were characterized using 16S rRNA gene sequencing, and fecal concentrations of short-chain fatty acids (SCFA) were measured with LC-MS/MS. Spearman's correlations and PERMANOVA analyses were applied to assess relationships between the gut microbiome and bone health measures including serum bone turnover markers (C-terminal telopeptide of type 1 collagen [CTx] and procollagen type 1 N-terminal propeptide [P1NP]), areal BMD, intestinal calcium absorption, and calciotropic hormones. Six months after LSG, CTx and P1NP increased (by median 188% and 61%, P < .01) and femoral neck BMD decreased (mean -3.3%, P < .01). Concurrently, there was a decrease in relative abundance of the phylum Firmicutes. Although there were no change in overall microbial diversity or fecal SCFA concentrations after LSG, those with greater within-subject change in gut community microbial composition (ß-diversity) postoperatively had greater increases in P1NP level (ρ = 0.48, P = .02) and greater bone loss at the femoral neck (ρ = -0.43, P = .04). In addition, within-participant shifts in microbial richness/evenness (α-diversity) were associated with changes in IGF-1 levels (ρ = 0.56, P < .01). The lower the postoperative fecal butyrate concentration, the lower the IGF-1 level (ρ = 0.43, P = .04). Meanwhile, the larger the decrease in butyrate concentration, the higher the postoperative CTx (ρ = -0.43, P = .04). These findings suggest that LSG-induced gut microbiome alteration may influence skeletal outcomes postoperatively, and microbial influences on butyrate formation and IGF-1 are possible mechanisms.

Laparoscopic sleeve gastrectomy (LSG), the most common bariatric surgical procedure, is a highly effective treatment for obesity because it produces dramatic weight loss and improves obesity-related medical conditions. However, it also results in abnormalities in bone metabolism. It is important to understand how LSG affects the skeleton, so that bone loss after surgery might be prevented. We studied adult men and women before and 6 mo after LSG, and we explored the relationship between the altered gut bacteria and bone metabolism changes. We found that: Those with greater shifts in their gut bacterial composition had more bone loss.Butyrate, a metabolite produced by gut bacteria from fermentation of dietary fiber, was associated with less bone breakdown and higher IGF-1 level (a bone-building hormone). We conclude that changes in the gut bacteria may contribute to the negative skeletal impact of LSG and reduced butyrate production by the gut bacteria leading to lower IGF-1 levels is a possible mechanism.

Early-life nasal microbiota dynamics relate to longitudinal respiratory phenotypes in urban children.

BACKGROUND: Five distinct respiratory phenotypes based on latent classes of longitudinal patterns of wheezing, allergic sensitization. and pulmonary function measured in urban children from ages from 0 to 7 years have previously been described. OBJECTIVE: Our aim was to determine whether distinct respiratory phenotypes are associated with early-life upper respiratory microbiota development and environmental microbial exposures. METHODS: Microbiota profiling was performed using 16S ribosomal RNA-based sequencing of nasal samples collected at age 12 months (n = 120) or age 36 months (n = 142) and paired house dust samples collected at 3 months (12-month, n = 73; 36-month, n = 90) from all 4 centers in the Urban Environment and Childhood Asthma (URECA) cohort. RESULTS: In these high-risk urban children, nasal microbiota increased in diversity between ages 12 and 36 months (ß = 2.04; P = .006). Age-related changes in microbiota evenness differed significantly by respiratory phenotypes (interaction P = .0007), increasing most in the transient wheeze group. At age 12 months, respiratory illness (R2 = 0.055; P = .0001) and dominant bacterial genus (R2 = 0.59; P = .0001) explained variance in nasal microbiota composition, and enrichment of Moraxella and Haemophilus members was associated with both transient and high-wheeze respiratory phenotypes. By age 36 months, nasal microbiota was significantly associated with respiratory phenotypes (R2 = 0.019; P = .0376), and Moraxella-dominated microbiota was associated specifically with atopy-associated phenotypes. Analysis of paired house dust and nasal samples indicated that 12 month olds with low wheeze and atopy incidence exhibited the largest number of shared bacterial taxa with their environment. CONCLUSION: Nasal microbiota development over the course of early childhood and composition at age 3 years are associated with longitudinal respiratory phenotypes. These data provide evidence supporting an early-life window of airway microbiota development that is influenced by environmental microbial exposures in infancy and associates with wheeze- and atopy-associated respiratory phenotypes through age 7 years.

Short-chain fatty acid producers in the gut are associated with pediatric multiple sclerosis onset.

OBJECTIVE: The relationship between multiple sclerosis and the gut microbiome has been supported by animal models in which commensal microbes are required for the development of experimental autoimmune encephalomyelitis. However, observational study findings in humans have only occasionally converged when comparing multiple sclerosis cases and controls which may in part reflect confounding by comorbidities and disease duration. The study of microbiome in pediatric-onset multiple sclerosis offers unique opportunities as it is closer to biological disease onset and minimizes confounding by comorbidities and environmental exposures. METHODS: A multicenter case-control study in which 35 pediatric-onset multiple sclerosis cases were 1:1 matched to healthy controls on age, sex, self-reported race, ethnicity, and recruiting site. Linear mixed effects models, weighted correlation network analyses, and PICRUSt2 were used to identify microbial co-occurrence networks and for predicting functional abundances based on marker gene sequences. RESULTS: Two microbial co-occurrence networks (one reaching significance after adjustment for multiple comparisons; q < 0.2) were identified, suggesting interdependent bacterial taxa that exhibited association with disease status. Both networks indicated a potentially protective effect of higher relative abundance of bacteria observed in these clusters. Functional predictions from the significant network suggested a contribution of short-chain fatty acid producers through anaerobic fermentation pathways in healthy controls. Consistent family-level findings from an independent Canadian-US study (19 case/control pairs) included Ruminococaccaeae and Lachnospiraceae (p < 0.05). Macronutrient intake was not significantly different between cases and controls, minimizing the potential for dietary confounding. INTERPRETATION: Our results suggest that short-chain fatty acid producers may be important contributors to multiple sclerosis onset.

Precocious infant fecal microbiome promotes enterocyte barrier dysfuction, altered neuroendocrine signaling and associates with increased childhood obesity risk.

Early life gut microbiome composition has been correlated with childhood obesity, though microbial functional contributions to disease origins remain unclear. Here, using an infant birth cohort (n = 349) we identify a distinct fecal microbiota composition in 1-month-old infants with the lowest rate of exclusive breastfeeding, that relates with higher relative risk for obesity and overweight phenotypes at two years. Higher-risk infant fecal microbiomes exhibited accelerated taxonomic and functional maturation and broad-ranging metabolic reprogramming, including reduced concentrations of neuro-endocrine signals. In vitro, exposure of enterocytes to fecal extracts from higher-risk infants led to upregulation of genes associated with obesity and with expansion of nutrient sensing enteroendocrine progenitor cells. Fecal extracts from higher-risk infants also promoted enterocyte barrier dysfunction. These data implicate dysregulation of infant microbiome functional development, and more specifically promotion of enteroendocrine signaling and epithelial barrier impairment in the early-life developmental origins of childhood obesity.

Microbiome preterm birth DREAM challenge: Crowdsourcing machine learning approaches to advance preterm birth research.

Every year, 11% of infants are born preterm with significant health consequences, with the vaginal microbiome a risk factor for preterm birth. We crowdsource models to predict (1) preterm birth (PTB; <37 weeks) or (2) early preterm birth (ePTB; <32 weeks) from 9 vaginal microbiome studies representing 3,578 samples from 1,268 pregnant individuals, aggregated from public raw data via phylogenetic harmonization. The predictive models are validated on two independent unpublished datasets representing 331 samples from 148 pregnant individuals. The top-performing models (among 148 and 121 submissions from 318 teams) achieve area under the receiver operator characteristic (AUROC) curve scores of 0.69 and 0.87 predicting PTB and ePTB, respectively. Alpha diversity, VALENCIA community state types, and composition are important features in the top-performing models, most of which are tree-based methods. This work is a model for translation of microbiome data into clinically relevant predictive models and to better understand preterm birth.

Robust airway microbiome signatures in acute respiratory failure and hospital-acquired pneumonia.

Respiratory microbial dysbiosis is associated with acute respiratory distress syndrome (ARDS) and hospital-acquired pneumonia (HAP) in critically ill patients. However, we lack reproducible respiratory microbiome signatures that can increase our understanding of these conditions and potential treatments. Here, we analyze 16S rRNA sequencing data from 2,177 respiratory samples collected from 1,029 critically ill patients (21.7% with ARDS and 26.3% with HAP) and 327 healthy controls, sourced from 17 published studies. After data harmonization and pooling of individual patient data, we identified microbiota signatures associated with ARDS, HAP and prolonged mechanical ventilation. Microbiota signatures for HAP and prolonged mechanical ventilation were characterized by depletion of a core group of microbes typical of healthy respiratory samples, and the ARDS microbiota signature was distinguished by enrichment of potentially pathogenic respiratory microbes, including Pseudomonas and Staphylococcus. Using machine learning models, we identified clinically informative, three- and four-factor signatures that predicted ARDS, HAP and prolonged mechanical ventilation with relatively high accuracy (area under the curve of 0.751, 0.72 and 0.727, respectively). We validated the signatures in an independent prospective cohort of 136 patients on mechanical ventillation and found that patients with microbiome signatures associated with ARDS, HAP or prolonged mechanical ventilation had longer times to successful extubation than patients lacking these signatures (hazard ratios of 1.56 (95% confidence interval (CI) 1.07-2.27), 1.51 (95% CI 1.02-2.23) and 1.50 (95% CI 1.03-2.18), respectively). Thus, we defined and validated robust respiratory microbiome signatures associated with ARDS and HAP that may help to identify promising targets for microbiome therapeutic modulation in critically ill patients.

Mild SARS-CoV-2 infection results in long-lasting microbiota instability.

Viruses targeting mammalian cells can indirectly alter the gut microbiota, potentially compounding their phenotypic effects. Multiple studies have observed a disrupted gut microbiota in severe cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that require hospitalization. Yet, despite demographic shifts in disease severity resulting in a large and continuing burden of non-hospitalized infections, we still know very little about the impact of mild SARS-CoV-2 infection on the gut microbiota in the outpatient setting. To address this knowledge gap, we longitudinally sampled 14 SARS-CoV-2-positive subjects who remained outpatient and 4 household controls. SARS-CoV-2 cases exhibited a significantly less stable gut microbiota relative to controls. These results were confirmed and extended in the K18-humanized angiotensin-converting enzyme 2 mouse model, which is susceptible to SARS-CoV-2 infection. All of the tested SARS-CoV-2 variants significantly disrupted the mouse gut microbiota, including USA-WA1/2020 (the original variant detected in the USA), Delta, and Omicron. Surprisingly, despite the fact that the Omicron variant caused the least severe symptoms in mice, it destabilized the gut microbiota and led to a significant depletion in Akkermansia muciniphila. Furthermore, exposure of wild-type C57BL/6J mice to SARS-CoV-2 disrupted the gut microbiota in the absence of severe lung pathology. IMPORTANCE Taken together, our results demonstrate that even mild cases of SARS-CoV-2 can disrupt gut microbial ecology. Our findings in non-hospitalized individuals are consistent with studies of hospitalized patients, in that reproducible shifts in gut microbial taxonomic abundance in response to SARS-CoV-2 have been difficult to identify. Instead, we report a long-lasting instability in the gut microbiota. Surprisingly, our mouse experiments revealed an impact of the Omicron variant, despite producing the least severe symptoms in genetically susceptible mice, suggesting that despite the continued evolution of SARS-CoV-2, it has retained its ability to perturb the intestinal mucosa. These results will hopefully renew efforts to study the mechanisms through which Omicron and future SARS-CoV-2 variants alter gastrointestinal physiology, while also considering the potentially broad consequences of SARS-CoV-2-induced microbiota instability for host health and disease.

Progression of C-reactive protein from birth through preadolescence varies by mode of delivery.

Introduction: Delivery via caesarean section (C-section) has been associated with an increased risk of childhood chronic diseases such as obesity and asthma, which may be due to underlying systemic inflammation. However, the impact of specific C-section types may be differential, as emergency C-sections typically involve partial labor and/or membrane rupture. Our objectives were to determine if mode of delivery associates with longitudinal profiles of high sensitivity CRP (hs-CRP) -a marker of systemic inflammation-from birth through preadolescence, and to examine if CRP mediates the association between mode of delivery and preadolescent body mass index (BMI). Methods: Data from the WHEALS birth cohort (N = 1,258) were analyzed; 564 of the 1,258 children in the cohort had data available for analysis. Longitudinal plasma samples (birth through 10-years of age) from 564 children from were assayed for hs-CRP levels. Maternal medical records were abstracted to obtain mode of delivery. Growth mixture models (GMMs) were used to determine classes of hs-CRP trajectories. Poisson regression with robust error variance was used to calculate risk ratios (RRs). Results: Two hs-CRP trajectory classes were identified: class 1 (76% of children) was characterized by low hs-CRP, while class 2 (24% of children) was characterized by high and steadily increasing hs-CRP. In multivariable models, children delivered via planned C-section had 1.15 times higher risk of being in hs-CRP class 2, compared to vaginal deliveries (p = 0.028), while no association was found for unplanned C-section deliveries [RR (95% CI) = 0.96 (0.84, 1.09); p = 0.49]. Further, the effect of planned C-section on BMI z-score at age 10 was significantly mediated by hs-CRP class (percent mediated = 43.4%). Conclusions: These findings suggest potentially beneficial effects of experiencing partial or full labor, leading to a lower trajectory of systemic inflammation throughout childhood and decreased BMI during preadolescence. These findings may have implications for chronic disease development later in life.

Contributions of the early-life microbiome to childhood atopy and asthma development.

The rapid rise in atopy and asthma in industrialized nations has led to the identification of early life environmental factors that promote these conditions and spurred research into how such exposures may mediate the trajectory to childhood disease development. Over the past decade, the human microbiome has emerged as a key determinant of human health. This is largely due to the increasing appreciation for the myriad of non-mutually exclusive mechanisms by which microbes tune and train host immunity. Microbiomes, particularly those in early life, are shaped by extrinsic and intrinsic factors, including many of the exposures known to influence allergy and asthma risk. This has led to the over-arching hypothesis that such exposures mediate their effect on childhood atopy and asthma by altering the functions and metabolic productivity of microbiomes that shape immune function during this critical developmental period. The capacity to study microbiomes at the genetic and molecular level in humans from the pre-natal period into childhood with well-defined clinical outcomes, offers an unprecedented opportunity to identify early-life and inter-generational determinants of atopy and asthma outcomes. Moreover, such studies provide an integrative microbiome research framework that can be applied to other chronic inflammatory conditions. This review attempts to capture key studies in the field that offer insights into the developmental origins of childhood atopy and asthma, providing novel insights into microbial mediators of maladaptive immunity and chronic inflammatory disease in childhood.

The Associations of Maternal Health Characteristics, Newborn Metabolite Concentrations, and Child Body Mass Index among US Children in the ECHO Program.

We aimed first to assess associations between maternal health characteristics and newborn metabolite concentrations and second to assess associations between metabolites associated with maternal health characteristics and child body mass index (BMI). This study included 3492 infants enrolled in three birth cohorts with linked newborn screening metabolic data. Maternal health characteristics were ascertained from questionnaires, birth certificates, and medical records. Child BMI was ascertained from medical records and study visits. We used multivariate analysis of variance, followed by multivariable linear/proportional odds regression, to determine maternal health characteristic-newborn metabolite associations. Significant associations were found in discovery and replication cohorts of higher pre-pregnancy BMI with increased C0 and higher maternal age at delivery with increased C2 (C0: discovery: aß 0.05 [95% CI 0.03, 0.07]; replication: aß 0.04 [95% CI 0.006, 0.06]; C2: discovery: aß 0.04 [95% CI 0.003, 0.08]; replication: aß 0.04 [95% CI 0.02, 0.07]). Social Vulnerability Index, insurance, and residence were also associated with metabolite concentrations in a discovery cohort. Associations between metabolites associated with maternal health characteristics and child BMI were modified from 1-3 years (interaction: p < 0.05). These findings may provide insights on potential biologic pathways through which maternal health characteristics may impact fetal metabolic programming and child growth patterns.

The impact of prenatal dog keeping on infant gut microbiota development.

INTRODUCTION: Prenatal and early-life dog exposure has been linked to reduced childhood allergy and asthma. A potential mechanism includes altered early immune development in response to changes in the gut microbiome among dog-exposed infants. We thus sought to determine whether infants born into homes with indoor dog(s) exhibit altered gut microbiome development. METHODS: Pregnant women living in homes with dogs or in pet-free homes were recruited in southeast Michigan. Infant stool samples were collected at intervals between 1 week and 18 months after birth and microbiome was assessed using 16S ribosomal sequencing. Perinatal maternal vaginal/rectal swabs and stool samples were sequenced from a limited number of mothers. Mixed effect adjusted models were used to assess stool microbial community trajectories comparing infants from dog-keeping versus pet-free homes with adjustment for relevant covariates. RESULTS: Infant gut microbial composition among vaginally born babies became less similar to the maternal vaginal/rectal microbiota and more similar to the maternal gut microbiota with age-related accumulation of bacterial species with advancing age. Stool samples from dog-exposed infants were microbially more diverse (p = .041) through age 18 months with enhanced diversity most apparent between 3 and 6 months of age. Statistically significant effects of dog exposure on ß-diversity metrics were restricted to formula-fed children. Across the sample collection period, dog exposure was associated with Fusobacterium genera enrichment, as well as enrichment of Collinsella, Ruminococcus, Clostridaceae and Lachnospiraceae OTUs. CONCLUSION: Prenatal/early-life dog exposure is associated with an altered gut microbiome during infancy and supports a potential mechanism explaining lessened atopy and asthma risk. Further research directly linking specific dog-attributable changes in the infant gut microbiome to the risk of allergic disorders is needed.

VMAP: Vaginal Microbiome Atlas During Pregnancy.

The vaginal microbiome has been shown to be associated with pregnancy outcomes including preterm birth (PTB) risk. Here we present VMAP: Vaginal Microbiome Atlas during Pregnancy (http://vmapapp.org), an application to visualize features of 3,909 vaginal microbiome samples of 1,416 pregnant individuals from 11 studies, aggregated from raw public and newly generated sequences via an open-source tool, MaLiAmPi. Our visualization tool (http://vmapapp.org) includes microbial features such as various measures of diversity, VALENCIA community state types (CST), and composition (via phylotypes and taxonomy). This work serves as a resource for the research community to further analyze and visualize vaginal microbiome data in order to better understand both healthy term pregnancies and those associated with adverse outcomes.

Microbiome Preterm Birth DREAM Challenge: Crowdsourcing Machine Learning Approaches to Advance Preterm Birth Research.

Globally, every year about 11% of infants are born preterm, defined as a birth prior to 37 weeks of gestation, with significant and lingering health consequences. Multiple studies have related the vaginal microbiome to preterm birth. We present a crowdsourcing approach to predict: (a) preterm or (b) early preterm birth from 9 publicly available vaginal microbiome studies representing 3,578 samples from 1,268 pregnant individuals, aggregated from raw sequences via an open-source tool, MaLiAmPi. We validated the crowdsourced models on novel datasets representing 331 samples from 148 pregnant individuals. From 318 DREAM challenge participants we received 148 and 121 submissions for our two separate prediction sub-challenges with top-ranking submissions achieving bootstrapped AUROC scores of 0.69 and 0.87, respectively. Alpha diversity, VALENCIA community state types, and composition (via phylotype relative abundance) were important features in the top performing models, most of which were tree based methods. This work serves as the foundation for subsequent efforts to translate predictive tests into clinical practice, and to better understand and prevent preterm birth.

Complete Genome Sequence of Lactobacillus johnsonii MR1, Isolated from a BALB/c Mouse Cecum.

Lactobacillus johnsonii strain MR1, which was isolated from the cecum of a BALB/cJ mouse in an airway allergy model, can decrease allergic airway inflammation in the model upon oral administration. Long-read sequencing of this isolate, which was performed using a MinION sequencer, yielded a single, closed genome of 1,953,837 bp, with a GC content of 34.67%.

Early-life gut microbiota and attention deficit hyperactivity disorder in preadolescents.

BACKGROUND: Gut microbiota maturation coincides with nervous system development. Cross-sectional data suggest gut microbiota of individuals with and without attention deficit hyperactivity disorder (ADHD) differs. We hypothesized that infant gut microbiota composition is associated with later ADHD development in our on-going birth cohort study, WHEALS. METHODS: Gut microbiota was profiled using 16S ribosomal RNA and the internal transcribed spacer region 2 (ITS2) sequencing in stool samples from 1 month and 6 months of age. ADHD was defined by parent-reported or medical record doctor diagnosis at age 10. RESULTS: A total of 314 children had gut microbiota and ADHD data; 59 (18.8%) had ADHD. After covariate adjustment, bacterial phylogenetic diversity (p = 0.017) and bacterial composition (unweighted UniFrac p = 0.006, R2 = 0.9%) at age 6 months were associated with development of ADHD. At 1 month of age, 18 bacterial and 3 fungal OTUs were associated with ADHD development. At 6 months of age, 51 bacterial OTUs were associated with ADHD; 14 of the order Lactobacillales. Three fungal OTUs at 6 months of age were associated with ADHD development. CONCLUSIONS: Infant gut microbiota is associated with ADHD development in pre-adolescents. Further studies replicating these findings and evaluating potential mechanisms of the association are needed. IMPACT: Cross-sectional studies suggest that the gut microbiota of individuals with and without ADHD differs. We found evidence that the bacterial gut microbiota of infants at 1 month and 6 months of age is associated with ADHD at age 10 years. We also found novel evidence that the fungal gut microbiota in infancy (ages 1 month and 6 months) is associated with ADHD at age 10 years. This study addresses a gap in the literature in providing longitudinal evidence for an association of the infant gut microbiota with later ADHD development.

Mild SARS-CoV-2 infection results in long-lasting microbiota instability.

Viruses targeting mammalian cells can indirectly alter the gut microbiota, potentially compounding their phenotypic effects. Multiple studies have observed a disrupted gut microbiota in severe cases of SARS-CoV-2 infection that require hospitalization. Yet, despite demographic shifts in disease severity resulting in a large and continuing burden of non-hospitalized infections, we still know very little about the impact of mild SARS-CoV-2 infection on the gut microbiota in the outpatient setting. To address this knowledge gap, we longitudinally sampled 14 SARS-CoV-2 positive subjects who remained outpatient and 4 household controls. SARS-CoV-2 cases exhibited a significantly less stable gut microbiota relative to controls, as long as 154 days after their positive test. These results were confirmed and extended in the K18-hACE2 mouse model, which is susceptible to SARS-CoV-2 infection. All of the tested SARS-CoV-2 variants significantly disrupted the mouse gut microbiota, including USA-WA1/2020 (the original variant detected in the United States), Delta, and Omicron. Surprisingly, despite the fact that the Omicron variant caused the least severe symptoms in mice, it destabilized the gut microbiota and led to a significant depletion in Akkermansia muciniphila . Furthermore, exposure of wild-type C57BL/6J mice to SARS-CoV-2 disrupted the gut microbiota in the absence of severe lung pathology. IMPORTANCE: Taken together, our results demonstrate that even mild cases of SARS-CoV-2 can disrupt gut microbial ecology. Our findings in non-hospitalized individuals are consistent with studies of hospitalized patients, in that reproducible shifts in gut microbial taxonomic abundance in response to SARS-CoV-2 have been difficult to identify. Instead, we report a long-lasting instability in the gut microbiota. Surprisingly, our mouse experiments revealed an impact of the Omicron variant, despite producing the least severe symptoms in genetically susceptible mice, suggesting that despite the continued evolution of SARS-CoV-2 it has retained its ability to perturb the intestinal mucosa. These results will hopefully renew efforts to study the mechanisms through which Omicron and future SARS-CoV-2 variants alter gastrointestinal physiology, while also considering the potentially broad consequences of SARS-CoV-2-induced microbiota instability for host health and disease.

Topical Glaucoma Therapy Is Associated With Alterations of the Ocular Surface Microbiome.

Purpose: To investigate the ocular surface microbiome of patients with unilateral or asymmetric glaucoma being treated with topical ophthalmic medications in one eye and to determine whether microbial community changes were related to measures of ocular surface disease. Methods: V3-V4 16S rRNA sequencing was conducted on ocular surface swabs collected from both eyes of 17 subjects: 10 patients with asymmetric/unilateral glaucoma using topical glaucoma therapy on only one eye and seven age-matched, healthy controls with no history of ocular disease or eyedrop use. Samples were categorized into three groups: patients' glaucomatous eye treated with eyedrops, patients' contralateral eye without eyedrops, and healthy control eyes. Comparisons were made for microbial diversity and composition, with differences in composition tested for association with ocular surface disease measures including tear meniscus height, tear break-up time, and Dry Eye Questionnaire. Results: Samples obtained from the patients' treated and untreated eyes both had significantly greater alpha-diversity and relative abundance of gram-negative organisms compared to healthy controls. The microbial composition of patient eyes was associated with decreased tear meniscus height and tear break-up time, whereas metagenomic predictions, based on 16S rRNA data, suggested increased synthesis of lipopolysaccharide. Conclusions: The ocular surface microbiome of patients taking unilateral preserved glaucoma drops is characterized by a highly diverse array of gram-negative bacteria that is significantly different from the predominantly gram-positive microbes detected on healthy control eyes. These compositional differences were associated with decreased tear film measures and distinct inferred protein synthesis pathways, suggesting a potential link between microbial alterations and ocular surface inflammation.

Heritable vaginal bacteria influence immune tolerance and relate to early-life markers of allergic sensitization in infancy.

Maternal asthma status, prenatal exposures, and infant gut microbiota perturbation are associated with heightened risk of atopy and asthma risk in childhood, observations hypothetically linked by intergenerational microbial transmission. Using maternal vaginal (n = 184) and paired infant stool (n = 172) samples, we identify four compositionally and functionally distinct Lactobacillus-dominated vaginal microbiota clusters (VCs) that relate to prenatal maternal health and exposures and infant serum immunoglobulin E (IgE) status at 1 year. Variance in bacteria shared between mother and infant pairs relate to VCs, maternal allergy/asthma status, and infant IgE levels. Heritable bacterial gene pathways associated with infant IgE include fatty acid synthesis and histamine and tryptophan degradation. In vitro, vertically transmitted Lactobacillus jensenii strains induce immunosuppressive phenotypes on human antigen-presenting cells. Murine supplementation with L. jensenii reduces lung eosinophils, neutrophilic expansion, and the proportion of interleukin-4 (IL-4)+ CD4+ T cells. Thus, bacterial and atopy heritability are intimately linked, suggesting a microbial component of intergenerational disease transmission.