Implications of microbe-derived ɣ-aminobutyric acid (GABA) in gut and brain barrier integrity and GABAergic signaling in Alzheimer's disease.

The gut microbial ecosystem communicates bidirectionally with the brain in what is known as the gut-microbiome-brain axis. Bidirectional signaling occurs through several pathways including signaling via the vagus nerve, circulation of microbial metabolites, and immune activation. Alterations in the gut microbiota are implicated in Alzheimer's disease (AD), a progressive neurodegenerative disease. Perturbations in gut microbial communities may affect pathways within the gut-microbiome-brain axis through altered production of microbial metabolites including ɣ-aminobutyric acid (GABA), the primary inhibitory mammalian neurotransmitter. GABA has been shown to act on gut integrity through modulation of gut mucins and tight junction proteins and may be involved in vagus nerve signal inhibition. The GABAergic signaling pathway has been shown to be dysregulated in AD, and may be responsive to interventions. Gut microbial production of GABA is of recent interest in neurological disorders, including AD. Bacteroides and Lactic Acid Bacteria (LAB), including Lactobacillus, are predominant producers of GABA. This review highlights how temporal alterations in gut microbial communities associated with AD may affect the GABAergic signaling pathway, intestinal barrier integrity, and AD-associated inflammation.

Environmental and structural factors associated with bacterial diversity in household dust across the Arizona-Sonora border.

We previously reported that asthma prevalence was higher in the United States (US) compared to Mexico (MX) (25.8% vs. 8.4%). This investigation assessed differences in microbial dust composition in relation to demographic and housing characteristics on both sides of the US-MX Border. Forty homes were recruited in the US and MX. Home visits collected floor dust and documented occupants' demographics, asthma prevalence, housing structure, and use characteristics. US households were more likely to have inhabitants who reported asthma when compared with MX households (30% vs. 5%) and had significantly different flooring types. The percentage of households on paved roads, with flushing toilets, with piped water and with air conditioning was higher in the US, while dust load was higher in MX. Significant differences exist between countries in the microbial composition of the floor dust. Dust from Mexican homes was enriched with Alishewanella, Paracoccus, Rheinheimera genera and Intrasporangiaceae family. A predictive metagenomics analysis identified 68 significantly differentially abundant functional pathways between US and MX. This study documented multiple structural, environmental, and demographic differences between homes in the US and MX that may contribute to significantly different microbial composition of dust observed in these two countries.

Morning exercise and pre-breakfast metformin interact to reduce glycaemia in people with type 2 diabetes: a randomized crossover trial.

Exercise is recommended in the treatment of type 2 diabetes and can improve insulin sensitivity. However, previous evidence suggests that exercise at different times of the day in people with type 2 diabetes may have opposing outcomes on glycaemia. Metformin is the most commonly prescribed initial pharmacological intervention in type 2 diabetes, and may alter adaptions to exercise. It is unknown if there is an interaction between metformin and diurnal exercise outcomes. We aimed to investigate glycaemic outcomes of moderate intensity morning vs. evening exercise in people with type 2 diabetes being prescribed metformin monotherapy. In this study, nine males and nine females with type 2 diabetes undergoing metformin monotherapy (age 61 ± 8.2 years, mean ± SD) completed a 16-week crossover trial including 2-week baseline recording, 6 weeks randomly assigned to a morning exercise (07.00-10.00 h) or evening exercise (16.00-19.00 h) and a 2-week wash-out period. Exercise arms consisted of 30 min of walking at 70% of estimated max heart rate every other day. Glucose levels were measured with continuous glucose monitors and activity measured by wrist-worn monitors. Food-intake was recorded by 4-day food diaries during baseline, first and last 2 weeks of each exercise arm. There was no difference in exercise intensity, total caloric intake or total physical activity between morning and evening arms. As primary outcomes, acute (24 h) glucose area under the curve (AUC), was lower (P = 0.02) after acute morning exercise (180.6 ± 68.4 mmol/l) compared to baseline (210.3 ± 76.7 mmol/l); and there were no differences identified for glucose (mmol/l) between baseline, morning and evening exercise at any specific time point when data were analysed with two-way ANOVA. As secondary outcomes, acute glucose AUC was significantly lower (P = 0.01) in participants taking metformin before breakfast (152.5 ± 29.95 mmol/l) compared with participants taking metformin after breakfast (227.2 ± 61.51 mmol/l) only during the morning exercise arm; and during weeks 5-6 of the exercise protocol, glucose AUC was significantly lower (P = 0.04) for participants taking metformin before breakfast (168.8 ± 15.8 mmol/l), rather than after breakfast (224.5 ± 52.0 mmol/l), only during morning exercise. Our data reveal morning moderate exercise acutely lowers glucose levels in people with type 2 diabetes being prescribed metformin. This difference appears to be driven by individuals that consumed metformin prior to breakfast rather than after breakfast. This beneficial effect upon glucose levels of combined morning exercise and pre-breakfast metformin persisted through the final 2 weeks of the trial. Our findings suggest that morning moderate intensity exercise combined with pre-breakfast metformin intake may benefit the management of glycaemia in people with type 2 diabetes. KEY POINTS: Morning moderate exercise acutely lowers glucose levels in people with type 2 diabetes being prescribed metformin. This difference appears to be driven by individuals that consumed metformin prior to breakfast rather than after breakfast. Morning exercise combined with pre-breakfast metformin persistently reduced glucose compared to morning exercise combined with post-breakfast metformin through the final week (week 6) of the intervention. Our study suggests it may be possible to make simple changes to the time that people with type 2 diabetes take metformin and perform exercise to improve their blood glucose.

Key results from the salt lake regional smoke, ozone, and aerosol study (SAMOZA).

The Northern Wasatch Front area is one of ~ 50 metropolitan regions in the U.S. that do not meet the 2015 O3 standard. To better understand the causes of high O3 days in this region we conducted the Salt Lake regional Smoke, Ozone and Aerosol Study (SAMOZA) in the summer of 2022. The primary goals of SAMOZA were: Measure a suite of VOCs, by Proton Transfer Reaction Mass Spectrometry (PTR-MS) and the 2,4-dinitrophenylhydrazine (DNPH) cartridge method.Evaluate whether the standard UV O3 measurements made in SLC show a positive bias during smoke events, as has been suggested in some recent studies.Use the observations to conduct photochemical modeling and statistical/machine learning analyses to understand photochemistry on both smoke-influenced and non-smoke days.Implications: The Northern Wasatch Front area is one of ~50 metropolitan regions in the U.S. that do not meet the 2015 O3 standard. To better understand the causes of high O3 days in this region we conducted the Salt Lake regional Smoke, Ozone and Aerosol Study (SAMOZA) in the summer of 2022. A number of policy relevant findings are identified in the manuscript including role of smoke and NOx vs VOC sensitivity.

We found no significant difference in the O₃ measurements using a "scrubber-less" UV instrument compared to the standard O₃ measurements at PM_2.5 concentrations up to 60 µg m⁻³.On days with smoke, we found that PM_2.5, CO, O₃ and nearly all VOCs were significantly enhanced. On average, NO_x was also enhanced on days with smoke, but this was complicated by day of week effects.Photochemical modeling of O₃ production rates at the Utah Tech Center demonstrates a strong sensitivity to VOC concentrations and less sensitivity to NOx. For non-smoke days, achieving the current O₃ standard would require regional reductions in VOCs of ~40% or reductions in NO_x ~ 60%.The photochemical modeling shows that formaldehyde and other OVOCs, along with alkenes, were the most important O₃ precursors.Generalized Additive Modeling (GAM) gave similar MDA8 O₃ enhancements on smoky days as the photochemical modeling. Analysis of the GAM results show that 23% of the smoke days have GAM residuals that exceed the U.S. EPA's criteria for inclusion as exceptional event documentation.

Investigation of Ozone Formation Chemistry during the Salt Lake Regional Smoke, Ozone, and Aerosol Study (SAMOZA).

Salt Lake City (SLC), UT, is an urban area where ozone (O3) concentrations frequently exceed health standards. This study uses an observationally constrained photochemical box model to investigate the drivers of O3 production during the Salt Lake Regional Smoke, Ozone, and Aerosol Study (SAMOZA), which took place from August to September 2022 in SLC. During SAMOZA, a suite of volatile organic compounds (VOCs), oxides of nitrogen (NOx), and other parameters were measured at the Utah Technical Center, a high-NOx site in the urban core. We examined four high-O3 cases: 4 August and 3, 11, and 12 September, which were classified as a nonsmoky weekday, a weekend day with minimal smoke influence, a smoky weekend day, and a smoky weekday, respectively. The modeled O3 production on 4 August and 3 September was highly sensitive to VOCs and insensitive to NOx reductions of ≤50%. Box model results suggest that the directly emitted formaldehyde contributed to the rapid increase in morning O3 concentrations on 3 September. Model sensitivity tests for September 11-12 indicated that smoke-emitted VOCs, especially aldehydes, had a much larger impact on O3 production than NOx and/or anthropogenic VOCs. On 11 and 12 September, smoke-emitted VOCs enhanced model-predicted maximum daily 8 h average O3 concentrations by 21 and 13 parts per billion (ppb), respectively. Overall, our results suggest that regionwide VOC reductions of at least 30-50% or NOx reductions of at least 60% are needed to bring SLC into compliance with the national O3 standard of 70 ppb.

Environmental and Structural Factors Associated with Bacterial Diversity in Household Dust Across the Arizona-Sonora Border.

We previously reported that asthma prevalence was higher in the United States (US) compared to Mexico (MX) (25.8% vs 8.4%). This investigation assessed differences in microbial dust composition in relation to demographic and housing characteristics on both sides of the US-MX Border. Forty homes were recruited in the US and MX. Home visits collected floor dust and documented occupants' demographics, asthma prevalence, and housing structure and use characteristics. US households were more likely to have inhabitants who reported asthma when compared with MX households (30% vs 5%) and had significantly different flooring types. The percentage of households on paved roads, with flushing toilets, with piped water and with air conditioning was higher in the US, while dust load was higher in MX. Significant differences exist between countries in the microbial composition of the floor dust. Dust from US homes was enriched with Geodermatophilus, whereas dust from Mexican homes was enriched with Alishewanella and Chryseomicrobium. A predictive metagenomics analysis identified 68 significantly differentially abundant functional pathways between US and MX. This study documented multiple structural, environmental, and demographic differences between homes in the US and MX that may contribute to significantly different microbial composition of dust observed in these two countries.

Oligofructose improves small intestinal lipid-sensing mechanisms via alterations to the small intestinal microbiota.

BACKGROUND: Upper small intestinal dietary lipids activate a gut-brain axis regulating energy homeostasis. The prebiotic, oligofructose (OFS) improves body weight and adiposity during metabolic dysregulation but the exact mechanisms remain unknown. This study examines whether alterations to the small intestinal microbiota following OFS treatment improve small intestinal lipid-sensing to regulate food intake in high fat (HF)-fed rats. RESULTS: In rats fed a HF diet for 4 weeks, OFS supplementation decreased food intake and meal size within 2 days, and reduced body weight and adiposity after 6 weeks. Acute (3 day) OFS treatment restored small intestinal lipid-induced satiation during HF-feeding, and was associated with increased small intestinal CD36 expression, portal GLP-1 levels and hindbrain neuronal activation following a small intestinal lipid infusion. Transplant of the small intestinal microbiota from acute OFS treated donors into HF-fed rats also restored lipid-sensing mechanisms to lower food intake. 16S rRNA gene sequencing revealed that both long and short-term OFS altered the small intestinal microbiota, increasing Bifidobacterium relative abundance. Small intestinal administration of Bifidobacterium pseudolongum to HF-fed rats improved small intestinal lipid-sensing to decrease food intake. CONCLUSION: OFS supplementation rapidly modulates the small intestinal gut microbiota, which mediates improvements in small intestinal lipid sensing mechanisms that control food intake to improve energy homeostasis. Video Abstract.

Predicting Neurodegenerative Disease Using Prepathology Gut Microbiota Composition: a Longitudinal Study in Mice Modeling Alzheimer's Disease Pathologies.

The gut microbiota-brain axis is suspected to contribute to the development of Alzheimer's disease (AD), a neurodegenerative disease characterized by amyloid-ß plaque deposition, neurofibrillary tangles, and neuroinflammation. To evaluate the role of the gut microbiota-brain axis in AD, we characterized the gut microbiota of female 3xTg-AD mice modeling amyloidosis and tauopathy and wild-type (WT) genetic controls. Fecal samples were collected fortnightly from 4 to 52 weeks, and the V4 region of the 16S rRNA gene was amplified and sequenced on an Illumina MiSeq. RNA was extracted from the colon and hippocampus, converted to cDNA, and used to measure immune gene expression using reverse transcriptase quantitative PCR (RT-qPCR). Diversity metrics were calculated using QIIME2, and a random forest classifier was applied to predict bacterial features that are important in predicting mouse genotype. Gene expression of glial fibrillary acidic protein (GFAP; indicating astrocytosis) was elevated in the colon at 24 weeks. Markers of Th1 inflammation (il6) and microgliosis (mrc1) were elevated in the hippocampus. Gut microbiota were compositionally distinct early in life between 3xTg-AD mice and WT mice (permutational multivariate analysis of variance [PERMANOVA], 8 weeks, P = 0.001, 24 weeks, P = 0.039, and 52 weeks, P = 0.058). Mouse genotypes were correctly predicted 90 to 100% of the time using fecal microbiome composition. Finally, we show that the relative abundance of Bacteroides species increased over time in 3xTg-AD mice. Taken together, we demonstrate that changes in bacterial gut microbiota composition at prepathology time points are predictive of the development of AD pathologies. IMPORTANCE Recent studies have demonstrated alterations in the gut microbiota composition in mice modeling Alzheimer's disease (AD) pathologies; however, these studies have only included up to 4 time points. Our study is the first of its kind to characterize the gut microbiota of a transgenic AD mouse model, fortnightly, from 4 weeks of age to 52 weeks of age, to quantify the temporal dynamics in the microbial composition that correlate with the development of disease pathologies and host immune gene expression. In this study, we observed temporal changes in the relative abundances of specific microbial taxa, including the genus Bacteroides, that may play a central role in disease progression and the severity of pathologies. The ability to use features of the microbiota to discriminate between mice modeling AD and wild-type mice at prepathology time points indicates a potential role of the gut microbiota as a risk or protective factor in AD.

IL-13-associated epithelial remodeling correlates with clinical severity in nasal polyposis.

BACKGROUND: Epithelial remodeling is a histopathologic feature of chronic inflammatory airway diseases including chronic rhinosinusitis (CRS). Cell-type shifts and their relationship to CRS endotypes and severity are incompletely described. OBJECTIVE: We sought to understand the relationship of epithelial cell remodeling to inflammatory endotypes and disease outcomes in CRS. METHODS: Using cell-type transcriptional signatures derived from epithelial single-cell sequencing, we analyzed bulk RNA-sequencing data from sinus epithelial brushings obtained from patients with CRS with and without nasal polyps in comparison to healthy controls. RESULTS: The airway epithelium in nasal polyposis displayed increased tuft cell transcripts and decreased ciliated cell transcripts along with an IL-13 activation signature. In contrast, CRS without polyps showed an IL-17 activation signature. IL-13 activation scores were associated with increased tuft cell, goblet cell, and mast cell scores and decreased ciliated cell scores. Furthermore, the IL-13 score was strongly associated with a previously reported activated ("polyp") tuft cell score and a prostaglandin E2 activation signature. The Lund-Mackay score, a computed tomographic metric of sinus opacification, correlated positively with activated tuft cell, mast cell, prostaglandin E2, and IL-13 signatures and negatively with ciliated cell transcriptional signatures. CONCLUSIONS: These results demonstrate that cell-type alterations and prostaglandin E2 stimulation are key components of IL-13-induced epithelial remodeling in nasal polyposis, whereas IL-17 signaling is more prominent in CRS without polyps, and that clinical severity correlates with the degree of IL-13-driven epithelial remodeling.

Antibody responses to the host microbiome in chronic rhinosinusitis.

BACKGROUND: The role of microbes in chronic rhinosinusitis (CRS) is poorly understood. We hypothesize that analyzing prior microbial exposures via assessing microbial protein serological reactivity in CRS versus controls may offer insights for CRS etiopathogenesis. METHODS: We profiled IgG and IgA antibodies to individual microbial proteins in serum samples of CRS patients and controls using a novel high-throughput microarray protein technology, Nucleic Acid Programmable Protein Array (NAPPA). The study was conducted on 118 subjects (39 CRS, 79 controls). A CRS-focused NAPPA array, with 1557 potentially sero-reactive microbial proteins elected from a pre-screening of 6500 genes of interest was constructed. It included membrane-associated proteins from 47 bacterial species and all proteins from 43 viral strains. Differences between CRS and controls were compared across individual antimicrobial antibodies and the species. RESULTS: Chronic rhinosinusitis patients had significantly elevated antimicrobial antibodies compared with controls. One bacterium (Staphylococcus aureus) and three viral strains (human metapneumovirus, human herpesvirus 5, and human herpesvirus 4) were identified as sources of the proteins that showed significantly elevated sero-reactivity in CRS patients. Within CRS, patients with polyps had elevated antibodies against S. aureus, influenza A virus (H1N1, H3N2), and rhinovirus B14. CRS patients without polyps showed more antibodies against human herpesvirus 1 and vaccinia virus WR. CONCLUSIONS: Compared with healthy controls, CRS patients' serum samples showed significantly increased sero-reactivity to both bacterial and viral proteins, reflecting recent or current infection or active colonization. Significantly higher antibodies against S. aureus, human metapneumovirus, human herpesvirus 5, and human herpesvirus 4 in CRS need further study.

IL-13-programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function.

Chronic type 2 (T2) inflammatory diseases of the respiratory tract are characterized by mucus overproduction and disordered mucociliary function, which are largely attributed to the effects of IL-13 on common epithelial cell types (mucus secretory and ciliated cells). The role of rare cells in airway T2 inflammation is less clear, though tuft cells have been shown to be critical in the initiation of T2 immunity in the intestine. Using bulk and single-cell RNA sequencing of airway epithelium and mouse modeling, we found that IL-13 expanded and programmed airway tuft cells toward eicosanoid metabolism and that tuft cell deficiency led to a reduction in airway prostaglandin E2 (PGE2) concentration. Allergic airway epithelia bore a signature of PGE2 activation, and PGE2 activation led to cystic fibrosis transmembrane receptor-dependent ion and fluid secretion and accelerated mucociliary transport. These data reveal a role for tuft cells in regulating epithelial mucociliary function in the allergic airway.

Unraveling the role of the microbiome in chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is a complex, heterogenous condition that is likely associated with infectious and inflammatory causative factors. Renewed interest in the role that microbes play in this condition has stemmed from advancements in microbe identification and parallel research implicating the microbiome as having a role in other chronic inflammatory conditions. This clinical commentary provides a review of the current literature relevant to chronic rhinosinusitis. Particular focus is placed on factors specific to investigation of the sinonasal microbiome, evidence for the role of dysbiosis in the disease state, and influences that may affect the microbiome. Possible mechanisms of disease and therapeutic implications through microbial manipulation are also reviewed, as are deficiencies and limitations of the current body of research.

Experiences and lessons learned from two virtual, hands-on microbiome bioinformatics workshops.

In October of 2020, in response to the Coronavirus Disease 2019 (COVID-19) pandemic, our team hosted our first fully online workshop teaching the QIIME 2 microbiome bioinformatics platform. We had 75 enrolled participants who joined from at least 25 different countries on 6 continents, and we had 22 instructors on 4 continents. In the 5-day workshop, participants worked hands-on with a cloud-based shared compute cluster that we deployed for this course. The event was well received, and participants provided feedback and suggestions in a postworkshop questionnaire. In January of 2021, we followed this workshop with a second fully online workshop, incorporating lessons from the first. Here, we present details on the technology and protocols that we used to run these workshops, focusing on the first workshop and then introducing changes made for the second workshop. We discuss what worked well, what didn't work well, and what we plan to do differently in future workshops.

The microbiome in obstructive sleep apnea.

Recent evidence has highlighted important associations between obstructive sleep apnea and the microbiome. Although the intricacies of the pathophysiologic mechanisms are not well understood, available evidence suggests a bidirectional relationship between obstructive sleep apnea and microbiota composition. Sleep fragmentation, intermittent hypoxia, and intermittent hypercapnia all play significant roles in altering the microbiome, and initial evidence has shown that alterations of the microbiota affect sleep patterns. Animal model evidence strongly supports the idea that the microbiome mediates disease states associated with obstructive sleep apnea including hypertension, atherosclerosis, and obesity. While evidence is limited, several studies suggest there may be a role for treatment of obstructive sleep apnea and obstructive sleep apnea-related comorbidities through alteration of the microbiome with probiotics, prebiotics, and microbiota transplantation.

Impact of Different Exercise Modalities on the Human Gut Microbiome.

In this study we examined changes to the human gut microbiome resulting from an eight-week intervention of either cardiorespiratory exercise (CRE) or resistance training exercise (RTE). Twenty-eight subjects (21 F; aged 18-26) were recruited for our CRE study and 28 subjects (17 F; aged 18-33) were recruited for our RTE study. Fecal samples for gut microbiome profiling were collected twice weekly during the pre-intervention phase (three weeks), intervention phase (eight weeks), and post-intervention phase (three weeks). Pre/post VO2max, three repetition maximum (3RM), and body composition measurements were conducted. Heart rate ranges for CRE were determined by subjects' initial VO2max test. RTE weight ranges were established by subjects' initial 3RM testing for squat, bench press, and bent-over row. Gut microbiota were profiled using 16S rRNA gene sequencing. Microbiome sequence data were analyzed with QIIME 2. CRE resulted in initial changes to the gut microbiome which were not sustained through or after the intervention period, while RTE resulted in no detectable changes to the gut microbiota. For both CRE and RTE, we observe some evidence that the baseline microbiome composition may be predictive of exercise gains. This work suggests that the human gut microbiome can change in response to a new exercise program, but the type of exercise likely impacts whether a change occurs. The changes observed in our CRE intervention resemble a disturbance to the microbiome, where an initial shift is observed followed by a return to the baseline state. More work is needed to understand how sustained changes to the microbiome occur, resulting in differences that have been reported in cross sectional studies of athletes and non-athletes.

Do the Bugs in Your Gut Eat Your Memories? Relationship between Gut Microbiota and Alzheimer's Disease.

The human microbiota is composed of trillions of microbial cells inhabiting the oral cavity, skin, gastrointestinal (GI) tract, airways, and reproductive organs. The gut microbiota is composed of dynamic communities of microorganisms that communicate bidirectionally with the brain via cytokines, neurotransmitters, hormones, and secondary metabolites, known as the gut microbiota-brain axis. The gut microbiota-brain axis is suspected to be involved in the development of neurological diseases, including Alzheimer's disease (AD), Parkinson's disease, and Autism Spectrum Disorder. AD is an irreversible, neurodegenerative disease of the central nervous system (CNS), characterized by amyloid-ß plaques, neurofibrillary tangles, and neuroinflammation. Microglia and astrocytes, the resident immune cells of the CNS, play an integral role in AD development, as neuroinflammation is a driving factor of disease severity. The gut microbiota-brain axis is a novel target for Alzheimer's disease therapeutics to modulate critical neuroimmune and metabolic pathways. Potential therapeutics include probiotics, prebiotics, fecal microbiota transplantation, and dietary intervention. This review summarizes our current understanding of the role of the gut microbiota-brain axis and neuroinflammation in the onset and development of Alzheimer's disease, limitations of current research, and potential for gut microbiota-brain axis targeted therapies.

Co-infection of Malassezia sympodialis With Bacterial Pathobionts Pseudomonas aeruginosa or Staphylococcus aureus Leads to Distinct Sinonasal Inflammatory Responses in a Murine Acute Sinusitis Model.

Host-associated bacteria and fungi, comprising the microbiota, are critical to host health. In the airways, the composition and diversity of the mucosal microbiota of patients are associated with airway health status. However, the relationship between airway microbiota and respiratory inflammation is not well-understood. Chronic rhinosinusitis (CRS) is a complex disease that affects up to 14% of the US population. Previous studies have shown decreased microbial diversity in CRS patients and enrichment of either Staphylococcus aureus or Pseudomonas aeruginosa. Although bacterial community composition is variable across CRS patients, Malassezia is a dominant fungal genus in the upper airways of the majority of healthy and CRS subjects. We hypothesize that distinct bacterial-fungal interactions differentially influence host mucosal immune response. Thus, we investigated in vitro and in vivo interactions between Malassezia sympodialis, P. aeruginosa, and S. aureus. The in vitro interactions were evaluated using the modified Kirby-Bauer Assay, Crystal Violet assay for biofilm, and FISH. A pilot murine model of acute sinusitis was used to investigate relationships with the host immune response. S. aureus and P. aeruginosa were intranasally instilled in the presence or absence of M. sympodialis (n = 66 total mice; 3-5/group). Changes in the microbiota were determined using 16S rRNA gene sequencing and host immune response was measured using quantitative real-time PCR (qRT-PCR). In vitro, only late stage planktonic P. aeruginosa and its biofilms inhibited M. sympodialis. Co-infection of mice with M. sympodialis and P. aeruginosa or S. aureus differently influenced the immune response. In co-infected mice, we demonstrate different expression of fungal sensing (Dectin-1), allergic responses (IL-5, and IL-13) and inflammation (IL-10, and IL-17) in murine sinus depending on the bacterial species that co-infected with M. sympodialis (p < 0.05). The pilot results suggest that species-specific interactions in airway-associated microbiota may be implicated driving immune responses. The understanding of the role of bacterial-fungal interactions in CRS will contribute to development of novel therapies toward manipulation of the airway microbiota.

Flux Synthesis of a Metal Carbide Hydride Using Anthracene As a Reactant.

La15(FeC6)4H was synthesized from the reaction of iron and anthracene in La/Ni eutectic flux. Anthracene was the source of both the carbon and hydrogen in the product. The structure of this metal carbide hydride features hydride ions in tetrahedral interstitial sites surrounded by lanthanum ions, which was confirmed by single-crystal neutron diffraction studies. The trigonal planar FeC6 units in which the central iron atom is coordinated by three ethylenide groups are similar to those found in La3.67FeC6, a previously reported compound that is formed in the absence of a hydride source. Magnetic susceptibility data confirm that the iron sites do not have magnetic moments. Density of states calculations indicate that La15(FeC6)4H is metallic and is stabilized by the incorporation of hydride anions.

Microbiotyping the Sinonasal Microbiome.

This study offers a novel description of the sinonasal microbiome, through an unsupervised machine learning approach combining dimensionality reduction and clustering. We apply our method to the International Sinonasal Microbiome Study (ISMS) dataset of 410 sinus swab samples. We propose three main sinonasal "microbiotypes" or "states": the first is Corynebacterium-dominated, the second is Staphylococcus-dominated, and the third dominated by the other core genera of the sinonasal microbiome (Streptococcus, Haemophilus, Moraxella, and Pseudomonas). The prevalence of the three microbiotypes studied did not differ between healthy and diseased sinuses, but differences in their distribution were evident based on geography. We also describe a potential reciprocal relationship between Corynebacterium species and Staphylococcus aureus, suggesting that a certain microbial equilibrium between various players is reached in the sinuses. We validate our approach by applying it to a separate 16S rRNA gene sequence dataset of 97 sinus swabs from a different patient cohort. Sinonasal microbiotyping may prove useful in reducing the complexity of describing sinonasal microbiota. It may drive future studies aimed at modeling microbial interactions in the sinuses and in doing so may facilitate the development of a tailored patient-specific approach to the treatment of sinus disease in the future.

The international sinonasal microbiome study: A multicentre, multinational characterization of sinonasal bacterial ecology.

The sinonasal microbiome remains poorly defined, with our current knowledge based on a few cohort studies whose findings are inconsistent. Furthermore, the variability of the sinus microbiome across geographical divides remains unexplored. We characterize the sinonasal microbiome and its geographical variations in both health and disease using 16S rRNA gene sequencing of 410 individuals from across the world. Although the sinus microbial ecology is highly variable between individuals, we identify a core microbiome comprised of Corynebacterium, Staphylococcus, Streptococcus, Haemophilus and Moraxella species in both healthy and chronic rhinosinusitis (CRS) cohorts. Corynebacterium (mean relative abundance = 44.02%) and Staphylococcus (mean relative abundance = 27.34%) appear particularly dominant in the majority of patients sampled. Amongst patients suffering from CRS with nasal polyps, a statistically significant reduction in relative abundance of Corynebacterium (40.29% vs 50.43%; P = .02) was identified. Despite some measured differences in microbiome composition and diversity between some of the participating centres in our cohort, these differences would not alter the general pattern of core organisms described. Nevertheless, atypical or unusual organisms reported in short-read amplicon sequencing studies and that are not part of the core microbiome should be interpreted with caution. The delineation of the sinonasal microbiome and standardized methodology described within our study will enable further characterization and translational application of the sinus microbiota.