Mucus-degrading Bacteroides link carbapenems to aggravated graft-versus-host disease.

The intestinal microbiota is an important modulator of graft-versus-host disease (GVHD), which often complicates allogeneic hematopoietic stem cell transplantation (allo-HSCT). Broad-spectrum antibiotics such as carbapenems increase the risk for intestinal GVHD, but mechanisms are not well understood. In this study, we found that treatment with meropenem, a commonly used carbapenem, aggravates colonic GVHD in mice via the expansion of Bacteroides thetaiotaomicron (BT). BT has a broad ability to degrade dietary polysaccharides and host mucin glycans. BT in meropenem-treated allogeneic mice demonstrated upregulated expression of enzymes involved in the degradation of mucin glycans. These mice also had thinning of the colonic mucus layer and decreased levels of xylose in colonic luminal contents. Interestingly, oral xylose supplementation significantly prevented thinning of the colonic mucus layer in meropenem-treated mice. Specific nutritional supplementation strategies, including xylose supplementation, may combat antibiotic-mediated microbiome injury to reduce the risk for intestinal GVHD in allo-HSCT patients.

Wild Mouse Gut Microbiota Promotes Host Fitness and Improves Disease Resistance.

Laboratory mice, while paramount for understanding basic biological phenomena, are limited in modeling complex diseases of humans and other free-living mammals. Because the microbiome is a major factor in mammalian physiology, we aimed to identify a naturally evolved reference microbiome to better recapitulate physiological phenomena relevant in the natural world outside the laboratory. Among 21 distinct mouse populations worldwide, we identified a closely related wild relative to standard laboratory mouse strains. Its bacterial gut microbiome differed significantly from its laboratory mouse counterpart and was transferred to and maintained in laboratory mice over several generations. Laboratory mice reconstituted with natural microbiota exhibited reduced inflammation and increased survival following influenza virus infection and improved resistance against mutagen/inflammation-induced colorectal tumorigenesis. By demonstrating the host fitness-promoting traits of natural microbiota, our findings should enable the discovery of protective mechanisms relevant in the natural world and improve the modeling of complex diseases of free-living mammals. VIDEO ABSTRACT.

Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring.

Maternal obesity during pregnancy has been associated with increased risk of neurodevelopmental disorders, including autism spectrum disorder (ASD), in offspring. Here, we report that maternal high-fat diet (MHFD) induces a shift in microbial ecology that negatively impacts offspring social behavior. Social deficits and gut microbiota dysbiosis in MHFD offspring are prevented by co-housing with offspring of mothers on a regular diet (MRD) and transferable to germ-free mice. In addition, social interaction induces synaptic potentiation (LTP) in the ventral tegmental area (VTA) of MRD, but not MHFD offspring. Moreover, MHFD offspring had fewer oxytocin immunoreactive neurons in the hypothalamus. Using metagenomics and precision microbiota reconstitution, we identified a single commensal strain that corrects oxytocin levels, LTP, and social deficits in MHFD offspring. Our findings causally link maternal diet, gut microbial imbalance, VTA plasticity, and behavior and suggest that probiotic treatment may relieve specific behavioral abnormalities associated with neurodevelopmental disorders. VIDEO ABSTRACT.

TARO: tree-aggregated factor regression for microbiome data integration.

MOTIVATION: Although the human microbiome plays a key role in health and disease, the biological mechanisms underlying the interaction between the microbiome and its host are incompletely understood. Integration with other molecular profiling data offers an opportunity to characterize the role of the microbiome and elucidate therapeutic targets. However, this remains challenging to the high dimensionality, compositionality, and rare features found in microbiome profiling data. These challenges necessitate the use of methods that can achieve structured sparsity in learning cross-platform association patterns. RESULTS: We propose Tree-Aggregated factor RegressiOn (TARO) for the integration of microbiome and metabolomic data. We leverage information on the taxonomic tree structure to flexibly aggregate rare features. We demonstrate through simulation studies that TARO accurately recovers a low-rank coefficient matrix and identifies relevant features. We applied TARO to microbiome and metabolomic profiles gathered from subjects being screened for colorectal cancer to understand how gut microrganisms shape intestinal metabolite abundances. AVAILABILITY AND IMPLEMENTATION: The R package TARO implementing the proposed methods is available online at https://github.com/amishra-stats/taro-package.

Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases.

Inflammatory bowel diseases, which include Crohn's disease and ulcerative colitis, affect several million individuals worldwide. Crohn's disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study's infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi'omics Database ( http://ibdmdb.org ), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases.

The human gut microbiome in early-onset type 1 diabetes from the TEDDY study.

Type 1 diabetes (T1D) is an autoimmune disease that targets pancreatic islet beta cells and incorporates genetic and environmental factors1, including complex genetic elements2, patient exposures3 and the gut microbiome4. Viral infections5 and broader gut dysbioses6 have been identified as potential causes or contributing factors; however, human studies have not yet identified microbial compositional or functional triggers that are predictive of islet autoimmunity or T1D. Here we analyse 10,913 metagenomes in stool samples from 783 mostly white, non-Hispanic children. The samples were collected monthly from three months of age until the clinical end point (islet autoimmunity or T1D) in the The Environmental Determinants of Diabetes in the Young (TEDDY) study, to characterize the natural history of the early gut microbiome in connection to islet autoimmunity, T1D diagnosis, and other common early life events such as antibiotic treatments and probiotics. The microbiomes of control children contained more genes that were related to fermentation and the biosynthesis of short-chain fatty acids, but these were not consistently associated with particular taxa across geographically diverse clinical centres, suggesting that microbial factors associated with T1D are taxonomically diffuse but functionally more coherent. When we investigated the broader establishment and development of the infant microbiome, both taxonomic and functional profiles were dynamic and highly individualized, and dominated in the first year of life by one of three largely exclusive Bifidobacterium species (B. bifidum, B. breve or B. longum) or by the phylum Proteobacteria. In particular, the strain-specific carriage of genes for the utilization of human milk oligosaccharide within a subset of B. longum was present specifically in breast-fed infants. These analyses of TEDDY gut metagenomes provide, to our knowledge, the largest and most detailed longitudinal functional profile of the developing gut microbiome in relation to islet autoimmunity, T1D and other early childhood events. Together with existing evidence from human cohorts7,8 and a T1D mouse model9, these data support the protective effects of short-chain fatty acids in early-onset human T1D.

Temporal development of the gut microbiome in early childhood from the TEDDY study.

The development of the microbiome from infancy to childhood is dependent on a range of factors, with microbial-immune crosstalk during this time thought to be involved in the pathobiology of later life diseases1-9 such as persistent islet autoimmunity and type 1 diabetes10-12. However, to our knowledge, no studies have performed extensive characterization of the microbiome in early life in a large, multi-centre population. Here we analyse longitudinal stool samples from 903 children between 3 and 46 months of age by 16S rRNA gene sequencing (n = 12,005) and metagenomic sequencing (n = 10,867), as part of the The Environmental Determinants of Diabetes in the Young (TEDDY) study. We show that the developing gut microbiome undergoes three distinct phases of microbiome progression: a developmental phase (months 3-14), a transitional phase (months 15-30), and a stable phase (months 31-46). Receipt of breast milk, either exclusive or partial, was the most significant factor associated with the microbiome structure. Breastfeeding was associated with higher levels of Bifidobacterium species (B. breve and B. bifidum), and the cessation of breast milk resulted in faster maturation of the gut microbiome, as marked by the phylum Firmicutes. Birth mode was also significantly associated with the microbiome during the developmental phase, driven by higher levels of Bacteroides species (particularly B. fragilis) in infants delivered vaginally. Bacteroides was also associated with increased gut diversity and faster maturation, regardless of the birth mode. Environmental factors including geographical location and household exposures (such as siblings and furry pets) also represented important covariates. A nested case-control analysis revealed subtle associations between microbial taxonomy and the development of islet autoimmunity or type 1 diabetes. These data determine the structural and functional assembly of the microbiome in early life and provide a foundation for targeted mechanistic investigation into the consequences of microbial-immune crosstalk for long-term health.

Young-onset Rectal Cancer: Unique Tumoral Microbiome and Correlation With Response to Neoadjuvant Therapy.

OBJECTIVE: External exposures, the host, and the microbiome interact in oncology. We aimed to investigate tumoral microbiomes in young-onset rectal cancers (YORCs) for profiles potentially correlative with disease etiology and biology. BACKGROUND: YORC is rapidly increasing, with 1 in 4 new rectal cancer cases occurring under the age of 50 years. Its etiology is unknown. METHODS: YORC (<50 y old) or later-onset rectal cancer (LORC, ≥50 y old) patients underwent pretreatment biopsied of tumor and tumor-adjacent normal (TAN) tissue. After whole genome sequencing, metagenomic analysis quantified microbial communities comparing tumors versus TANs and YORCs versus LORCs, controlling for multiple testing. Response to neoadjuvant therapy (NT) was categorized as major pathological response (MPR, ≤10% residual viable tumor) versus non-MPR. RESULTS: Our 107 tumors, 75 TANs from 37 (35%) YORCs, and 70 (65%) LORCs recapitulated bacterial species were previously associated with colorectal cancers (all P <0.0001). YORC and LORC tumoral microbiome signatures were distinct. After NT, 13 patients (12.4%) achieved complete pathologic response, whereas MPR occurred in 47 patients (44%). Among YORCs, MPR was associated with Fusobacterium nucleaum , Bacteroides dorei, and Ruminococcus bromii (all P <0.001), but MPR in LORC was associated with R. bromii ( P <0.001). Network analysis of non-MPR tumors demonstrated a preponderance of oral bacteria not observed in MPR tumors. CONCLUSIONS: Microbial signatures were distinct between YORC and LORC. Failure to achieve an MPR was associated with oral bacteria in tumors. These findings urge further studies to decipher correlative versus mechanistic associations but suggest a potential for microbial modulation to augment current treatments.

Spatial Characteristics of Colonic Mucosa-Associated Gut Microbiota in Humans.

Limited data exist on the spatial distribution of the colonic bacteria in humans. We collected the colonic biopsies from five segments of 27 polyp-free adults and collected feces from 13 of them. We sequenced the V4 region of the bacterial 16S rRNA gene using the MiSeq platform. The sequencing data were assigned to the amplicon sequence variant (ASV) using SILVA. Biodiversity and the relative abundance of the ASV were compared across the colonic segments and between the rectal and fecal samples. Bacterial functional capacity was assessed using Tax4fun. Each individual had a unique bacterial community composition (Weighted Bray-Curtis P value = 0.001). There were no significant differences in richness, evenness, community composition, and the taxonomic structure across the colon segments in all the samples. Firmicutes (47%), Bacteroidetes (39%), and Proteobacteria (6%) were the major phyla in all segments, followed by Verrucomicrobia, Fusobacteria, Desulfobacterota, and Actinobacteria. There were 15 genera with relative abundance > 1%, including Bacteroides, Faecalibacterium, Escherichia/Shigella, Sutterella, Akkermansia, Parabacteroides, Prevotella, Lachnoclostridium, Alistipes, Fusobacterium, Erysipelatoclostridium, and four Lachnospiraceae family members. Intra-individually, the community compositional dissimilarity was the greatest between the cecum and the rectum. There were significant differences in biodiversity and the taxonomic structure between the rectal and fecal bacteria. The bacterial community composition and structure were homogeneous across the large intestine in adults. The inter-individual variability of the bacteria was greater than inter-segment variability. The rectal and fecal bacteria differed in the community composition and structure.

The Microbiome: the Link to Colorectal Cancer and Research Opportunities.

OPINION STATEMENT: In recent years, we have seen an increase in the study and interest of the role of the microbiome in the development of malignancies, their progression, and evasion of therapies. This has been particularly fruitful in the case of colorectal cancer; multiple investigators have described correlative observations as well as hypotheses strengthened in preclinical studies that have begun to elucidate the critical role the gut and tumoral microbiome plays in carcinogenesis. Furthermore, these landmark studies lay the groundwork in describing the microbiome's role in carcinogenesis and provide a rich field of future study. Here, we review contemporary understandings of these observations and proposed mechanisms behind them.

Alterations of the Oral Microbiome and Cumulative Carbapenem Exposure Are Associated With Stenotrophomonas maltophilia Infection in Patients With Acute Myeloid Leukemia Receiving Chemotherapy.

BACKGROUND: Stenotrophomonas maltophilia is increasingly common in patients with acute myeloid leukemia (AML). Little is known about factors that drive S. maltophilia infection. We evaluated the microbiome and cumulative antibiotic use as predictors of S. maltophilia infection in AML patients receiving remission induction chemotherapy (RIC). METHODS: Subanalysis of a prospective, observational cohort of patients with AML receiving RIC between September 2013 and August 2015 was performed. Fecal and oral microbiome samples collected from initiation of RIC until neutrophil recovery were assessed for the relative abundance of Stenotrophomonas via 16S rRNA gene quantitation. The primary outcome, microbiologically proven S. maltophilia infection, was analyzed using a time-varying Cox proportional hazards model. RESULTS: Of 90 included patients, 8 (9%) developed S. maltophilia infection (pneumonia, n = 6; skin-soft tissue, n = 2); 4/8 (50%) patients were bacteremic; and 7/8 (88%) patients with S. maltophilia infection had detectable levels of Stenotrophomonas vs 22/82 (27%) without infection (P < .01). An oral Stenotrophomonas relative abundance of 36% predicted infection (sensitivity, 96%; specificity, 93%). No association of S. maltophilia infection with fecal relative abundance was found. Cumulative meropenem exposure was associated with increased infection risk (hazard ratio, 1.17; 95% confidence interval, 1.01-1.35; P = .03). CONCLUSIONS: Here, we identify the oral microbiome as a potential source for S. maltophilia infection and highlight cumulative carbapenem use as a risk factor for S. maltophilia in leukemia patients. These data suggest that real-time monitoring of the oral cavity might identify patients at risk for S. maltophilia infection.

Genomic Epidemiology of Severe Acute Respiratory Syndrome Coronavirus 2, Colombia.

Coronavirus disease (COVID-19) in Colombia was first diagnosed in a traveler arriving from Italy on February 26, 2020. However, limited data are available on the origins and number of introductions of COVID-19 into the country. We sequenced the causative agent of COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), from 43 clinical samples we collected, along with another 79 genome sequences available from Colombia. We investigated the emergence and importation routes for SARS-CoV-2 into Colombia by using epidemiologic, historical air travel, and phylogenetic observations. Our study provides evidence of multiple introductions, mostly from Europe, and documents >12 lineages. Phylogenetic findings validate the lineage diversity, support multiple importation events, and demonstrate the evolutionary relationship of epidemiologically linked transmission chains. Our results reconstruct the early evolutionary history of SARS-CoV-2 in Colombia and highlight the advantages of genome sequencing to complement COVID-19 outbreak investigations.

PPARD and Interferon Gamma Promote Transformation of Gastric Progenitor Cells and Tumorigenesis in Mice.

BACKGROUND & AIMS: The peroxisome proliferator-activated receptor delta (PPARD) regulates cell metabolism, proliferation, and inflammation and has been associated with gastric and other cancers. Villin-positive epithelial cells are a small population of quiescent gastric progenitor cells. We expressed PPARD from a villin promoter to investigate the role of these cells and PPARD in development of gastric cancer. METHODS: We analyzed gastric tissues from mice that express the Ppard (PPARD1 and PPARD2 mice) from a villin promoter, and mice that did not carry this transgene (controls), by histology and immunohistochemistry. We performed cell lineage-tracing experiments and analyzed the microbiomes, chemokine and cytokine production, and immune cells and transcriptomes of stomachs of these mice. We also performed immunohistochemical analysis of PPARD levels in 2 sets of human gastric tissue microarrays. RESULTS: Thirty-eight percent of PPARD mice developed spontaneous, invasive gastric adenocarcinomas, with severe chronic inflammation. Levels of PPARD were increased in human gastric cancer tissues, compared with nontumor tissues, and associated with gastric cancer stage and grade. We found an inverse correlation between level of PPARD in tumor tissue and patient survival time. Gastric microbiomes from PPARD and control mice did not differ significantly. Lineage-tracing experiments identified villin-expressing gastric progenitor cells (VGPCs) as the origin of gastric tumors in PPARD mice. In these mice, PPARD up-regulated CCL20 and CXCL1, which increased infiltration of the gastric mucosa by immune cells. Immune cell production of inflammatory cytokines promoted chronic gastric inflammation and expansion and transformation of VGPCs, leading to tumorigenesis. We identified a positive-feedback loop between PPARD and interferon gamma signaling that sustained gastric inflammation to induce VGPC transformation and gastric carcinogenesis. CONCLUSIONS: We found PPARD overexpression in VPGCs to result in inflammation, dysplasia, and tumor formation. PPARD and VGPCs might be therapeutic targets for stomach cancer.

Gastric microbiota and Helicobacter pylori in Indonesian population.

BACKGROUND: The profile of gastric mucosal microbiota has not yet been described in the Indonesian population where the prevalence of Helicobacter pylori is low. METHODS: This is a cross-sectional study analyzing 16S rRNA of 137 gastric biopsy specimens. We analyzed the association between gastric microbiota, H. pylori infection, and gastric mucosal damage. RESULT: Among 137 analyzed samples, 27 were H. pylori-positive and 110 were H. pylori -negative based on culture, histology, and 16S rRNA gene analysis. Significantly lower α-diversity parameters, including Pielou's index, was observed in H. pylori-infected individuals compared with noninfected individuals (all P < .001). Among H. pylori-negative individuals, the permutational analysis of variance of Bray-Curtis dissimilarity distances showed a significant association with different ethnicities, suggesting some ethnic groups had specific microbiota profiles based on the presence of different operational taxonomic units. The linear discriminant analysis effect size (LEfSe) of the H. pylori-negative group showed significant associations between the presence of Micrococcus luteus and Sphingomonas yabuuchiae with Timor and Papuan ethnicities, respectively. The presence of Bulledia sp and Atopobium sp was associated with the Javanese ethnicity. We observed lower α-diversity scores in individuals with gastric mucosal damage and profiles with high abundances of Paludibacter sp and Dialister sp based on LEfSe analysis. CONCLUSION: Our findings suggest the presence of H. pylori is more correlated with a distinct microbiome profile than ethnic precedence.

A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection.

The intestinal epithelium can limit enteric pathogens by producing antiviral cytokines, such as IFNs. Type I IFN (IFN-α/ß) and type III IFN (IFN-λ) function at the epithelial level, and their respective efficacies depend on the specific pathogen and site of infection. However, the roles of type I and type III IFN in restricting human enteric viruses are poorly characterized as a result of the difficulties in cultivating these viruses in vitro and directly obtaining control and infected small intestinal human tissue. We infected nontransformed human intestinal enteroid cultures from multiple individuals with human rotavirus (HRV) and assessed the host epithelial response by using RNA-sequencing and functional assays. The dominant transcriptional pathway induced by HRV infection is a type III IFN-regulated response. Early after HRV infection, low levels of type III IFN protein activate IFN-stimulated genes. However, this endogenous response does not restrict HRV replication because replication-competent HRV antagonizes the type III IFN response at pre- and posttranscriptional levels. In contrast, exogenous IFN treatment restricts HRV replication, with type I IFN being more potent than type III IFN, suggesting that extraepithelial sources of type I IFN may be the critical IFN for limiting enteric virus replication in the human intestine.

Exploration of the Vaginal and Gut Microbiome in African American Women by Body Mass Index, Class of Obesity, and Gestational Weight Gain: A Pilot Study.

OBJECTIVE: This study determines the differences in the distal gut and vaginal microbiome in African American (AA) women by prepregnancy body mass index and gestational weight gain (GWG) comparing women with and without obesity and by obesity class. STUDY DESIGN: We prospectively sampled the vaginal and distal gut microbiome in pregnant AA women at two time points during pregnancy. Samples were analyzed using high-throughput sequencing of the V4 region of the 16S ribosomal ribonucleic acid gene. RESULTS: Distinct differences in vaginal and distal gut α-diversity were observed at time point 1 between women with and without obesity by total GWG. Significant differences in distal gut ß-diversity were also found at time point 1 in obese women by GWG. Within the Bacteroides genus, a significant association was observed by total GWG among obese women which was absent in nonobese women. Women with class III obesity who experienced low GWG had the lowest abundance of distal gut Bacteroides and appreciably higher relative abundance of a consortia of vaginal taxa including Atopobium, Gardnerella, Prevotella, and Sneathia. CONCLUSION: These results contribute new evidence showing that GWG in combination with obesity and obesity class is associated with an altered distal gut and vaginal composition early in pregnancy among AA women.

Serum Metabolome Is Associated With the Nasopharyngeal Microbiota and Disease Severity Among Infants With Bronchiolitis.

BACKGROUND: Emerging evidence suggests relationships between the nasopharyngeal metabolome and both the microbiota and severity of bronchiolitis. However, the influence of host systemic metabolism on disease pathobiology remains unclear. We aimed to examine metabolome profiles and their association with more-severe disease, defined by use of positive pressure ventilation (PPV), in infants hospitalized for bronchiolitis. METHODS: In 140 infants with bronchiolitis, metabolomic profiling was performed on serum; samples from 70 were in a training data set, and samples from 70 were in an independent test data set. We also profiled the nasopharyngeal airway microbiota and examined its association with the serum metabolites. RESULTS: Serum metabolome profiles differed by bronchiolitis severity (P < .001). In total, 20 metabolites in the training data set were significantly associated with the risk of PPV, of which 18 remained significant following adjustment for confounders (false-discovery rate [FDR], < 0.10). Phosphatidylcholine metabolites were associated with higher risks of PPV use, while metabolites from the plasmalogen subpathway were associated with lower risks. The test data set validated these findings (FDR < 0.05). Streptococcus abundance was positively associated with metabolites that are associated with higher risks of PPV. CONCLUSIONS: Serum metabolomic signatures were associated with both the nasopharyngeal microbiota and the severity of bronchiolitis. Our findings advance research into the complex interrelations between the airway microbiome, host systemic response, and pathobiology of bronchiolitis.

Early nasal microbiota and acute respiratory infections during the first years of life.

BACKGROUND: Emerging evidence shows that airway microbiota may modulate local immune responses, thereby contributing to the susceptibility and severity of acute respiratory infections (ARIs). However, there are little data on the longitudinal relationships between airway microbiota and susceptibility to ARIs in children. OBJECTIVE: We aimed to investigate the association of early nasal microbiota and the subsequent risk of ARIs during the first years of life. METHODS: In this prospective population-based birth-cohort study in Finland, we followed 839 healthy infants for ARIs from birth to age 24 months. Nasal microbiota was tested using 16S rRNA gene sequencing at age 2 months. We applied an unsupervised clustering approach to identify early nasal microbiota profiles, and examined the association of profiles with the rate of ARIs during age 2-24 months. RESULTS: We identified five nasal microbiota profiles dominated by Moraxella, Streptococcus, Dolosigranulum, Staphylococcus and Corynebacteriaceae, respectively. Incidence rate of ARIs was highest in children with an early Moraxella-dominant profile and lowest in those with a Corynebacteriaceae-dominant profile (738 vs 552/100 children years; unadjusted incidence rate ratio (IRR), 1.34; 95% CI 1.16 to 1.54; p < 0.001). After adjusting for nine potential confounders, the Moraxella-dominant profile-ARI association persisted (adjusted IRR (aIRR), 1.19; 95% CI 1.04 to 1.37; p = 0.01). Similarly, the incidence rate of lower respiratory tract infections (a subset of all ARIs) was significantly higher in children with an early Moraxella-dominant profile (aIRR, 2.79; 95% CI 1.04 to 8.09; p = 0.04). CONCLUSION: Moraxella-dominant nasal microbiota profile in early infancy was associated with an increased rate of ARIs during the first 2 years of life.

Age-related changes in the gut microbiota influence systemic inflammation and stroke outcome.

OBJECTIVE: Chronic systemic inflammation contributes to the pathogenesis of many age-related diseases. Although not well understood, alterations in the gut microbiota, or dysbiosis, may be responsible for age-related inflammation. METHODS: Using stroke as a disease model, we tested the hypothesis that a youthful microbiota, when established in aged mice, produces positive outcomes following ischemic stroke. Conversely, an aged microbiota, when established in young mice, produces negative outcomes after stroke. Young and aged male mice had either a young or an aged microbiota established by fecal transplant gavage (FTG). Mice were subjected to ischemic stroke (middle cerebral artery occlusion; MCAO) or sham surgery. During the subsequent weeks, mice underwent behavioral testing and fecal samples were collected for 16S ribosomal RNA analysis of bacterial content. RESULTS: We found that the microbiota is altered after experimental stroke in young mice and resembles the biome of uninjured aged mice. In aged mice, the ratio of Firmicutes to Bacteroidetes (F:B), two main bacterial phyla in gut microbiota, increased ∼9-fold (p < 0.001) compared to young. This increased F:B ratio in aged mice is indicative of dysbiosis. Altering the microbiota in young by fecal gavage to resemble that of aged mice (∼6-fold increase in F:B ratio, p < 0.001) increased mortality following MCAO, decreased performance in behavioral testing, and increased cytokine levels. Conversely, altering the microbiota in aged to resemble that of young (∼9-fold decrease in F:B ratio, p < 0.001) increased survival and improved recovery following MCAO. INTERPRETATION: Aged biome increased the levels of systemic proinflammatory cytokines. We conclude that the gut microbiota can be modified to positively impact outcomes from age-related diseases. Ann Neurol 2018;83:23-36.