Molecular microbiological analysis of airway samples in asthma has demonstrated an altered microbiome in comparison to healthy controls. Such changes may have relevance to treatment-resistant severe ...asthma, particularly those with neutrophilic airway inflammation, as bacteria might be anticipated to activate the innate immune response, a process that is poorly steroid responsive. An understanding of the relationship between airway bacterial presence and dominance in severe asthma may help direct alternative treatment approaches.
We aimed to use a culture independent analysis strategy to describe the presence, dominance and abundance of bacterial taxa in induced sputum from treatment resistant severe asthmatics and correlate findings with clinical characteristics and airway inflammatory markers.
Induced sputum was obtained from 28 stable treatment-resistant severe asthmatics. The samples were divided for supernatant IL-8 measurement, cytospin preparation for differential cell count and Terminal Restriction Fragment Length Polymorphism (T-RFLP) profiling for bacterial community analysis.
In 17/28 patients, the dominant species within the airway bacterial community was Moraxella catarrhalis or a member of the Haemophilus or Streptococcus genera. Colonisation with these species was associated with longer asthma disease duration (mean (SD) 31.8 years (16.7) vs 15.6 years (8.0), p = 0.008), worse post-bronchodilator percent predicted FEV1 (68.0% (24.0) vs 85.5% (19.7), p = 0.025) and higher sputum neutrophil differential cell counts (median (IQR) 80% (67-83) vs 43% (29-67), p = 0.001). Total abundance of these organisms significantly and positively correlated with sputum IL-8 concentration and neutrophil count.
Airway colonisation with potentially pathogenic micro-organisms in asthma is associated with more severe airways obstruction and neutrophilic airway inflammation. This altered colonisation may have a role in the development of an asthma phenotype that responds less well to current asthma therapies.
The microbial community of the gut conveys significant benefits to host physiology. A clear relationship has now been established between gut bacteria and host metabolism in which microbial-mediated ...gut hormone release plays an important role. Within the gut lumen, bacteria produce a number of metabolites and contain structural components that act as signaling molecules to a number of cell types within the mucosa. Enteroendocrine cells within the mucosal lining of the gut synthesize and secrete a number of hormones including CCK, PYY, GLP-1, GIP, and 5-HT, which have regulatory roles in key metabolic processes such as insulin sensitivity, glucose tolerance, fat storage, and appetite. Release of these hormones can be influenced by the presence of bacteria and their metabolites within the gut and as such, microbial-mediated gut hormone release is an important component of microbial regulation of host metabolism. Dietary or pharmacological interventions which alter the gut microbiome therefore pose as potential therapeutics for the treatment of human metabolic disorders. This review aims to describe the complex interaction between intestinal microbiota and their metabolites and gut enteroendocrine cells, and highlight how the gut microbiome can influence host metabolism through the regulation of gut hormone release.
Background and Aims
Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the adult population. A significant subset of patients are lean, but their underlying pathophysiology is not well ...understood.
Approach and Results
We investigated the role of bile acids (BAs) and the gut microbiome in the pathogenesis of lean NAFLD. BA and fibroblast growth factor (FGF) 19 levels (a surrogate for intestinal farnesoid X receptor FXR activity), patatin‐like phospholipase domain containing 3 (PNPLA3), and transmembrane 6 superfamily member 2 (TM6SF2) variants, and gut microbiota profiles in lean and nonlean NAFLD were investigated in a cohort of Caucasian patients with biopsy‐proven NAFLD (n = 538), lean healthy controls (n = 30), and experimental murine models. Patients with lean NAFLD had a more favorable metabolic and histological profile compared with those with nonlean NAFLD (P < 0.05 for all). BA levels were significantly higher in NAFLD with advanced compared with earlier stages of liver fibrosis. Patients with lean NAFLD had higher serum secondary BA and FGF19 levels and reduced 7‐alpha‐hydroxy‐4‐cholesten‐3‐one (C4) levels (P < 0.05 for all). These differences were more profound in early compared with advanced stages of fibrosis (P < 0.05 for both). Lean patients demonstrated an altered gut microbiota profile. Similar findings were demonstrated in lean and nonlean murine models of NAFLD. Treating mice with an apical sodium‐dependent BA transporter inhibitor (SC‐435) resulted in marked increases in fgf15, a shift in the BA and microbiota profiles, and improved steatohepatitis in the lean model.
Conclusions
Differences in metabolic adaptation between patients with lean and nonlean NAFLD, at least in part, explain the pathophysiology and provide options for therapy.
Abstract
Serotonin (5-hydroxytryptamine or 5-HT) is a multifunctional bioamine with important signaling roles in a range of physiological pathways. Almost all of the 5-HT in our bodies is synthesized ...in specialized enteroendocrine cells within the gastrointestinal (GI) mucosa called enterochromaffin (EC) cells. These cells provide all of our circulating 5-HT. We have long appreciated the important contributions of 5-HT within the gut, including its role in modulating GI motility. However, evidence of the physiological and clinical significance of gut-derived 5-HT outside of the gut has recently emerged, implicating 5-HT in regulation of glucose homeostasis, lipid metabolism, bone density, and diseases associated with metabolic syndrome, such as obesity and type 2 diabetes. Although a new picture has developed in the last decade regarding the various metabolic roles of peripheral serotonin, so too has our understanding of the physiology of EC cells. Given that they are scattered throughout the lining of the GI tract within the epithelial cell layer, these cells are typically difficult to study. Advances in isolation procedures now allow the study of pure EC-cell cultures and single cells, enabling studies of EC-cell physiology to occur. EC cells are sensory cells that are capable of integrating cues from ingested nutrients, the enteric nervous system, and the gut microbiome. Thus, levels of peripheral 5-HT can be modulated by a multitude of factors, resulting in both local and systemic effects for the regulation of a raft of physiological pathways related to metabolism and obesity.
Review of the emerging endocrine roles of peripheral serotonin.
We propose the “microbiota‐inflammasome” hypothesis of major depressive disorder (MDD, a mental illness affecting the way a person feels and thinks, characterized by long‐lasting feelings of ...sadness). We hypothesize that pathological shifts in gut microbiota composition (dysbiosis) caused by stress and gut conditions result in the upregulation of pro‐inflammatory pathways mediated by the Nod‐like receptors family pyrin domain containing 3 (NLRP3) inflammasome (an intracellular platform involved in the activation of inflammatory processes). This upregulation exacerbates depressive symptomatology and further compounds gut dysbiosis. In this review we describe MDD/chronic stress‐induced changes in: 1) NLRP3 inflammasome; 2) gut microbiota; and 3) metabolic pathways; and how inflammasome signaling may affect depressive‐like behavior and gut microbiota composition. The implication is that novel therapeutic strategies could emerge for MDD and co‐morbid conditions. A number of testable predictions surface from this microbiota‐gut‐inflammasome‐brain hypothesis of MDD, using approaches that modulate gut microbiota composition via inflammasome modulation, fecal microbiota transplantation, psychobiotics supplementation, or dietary change.
Psychological stress and gut dysbiosis increase pro‐inflammatory signaling, which in turn alters gut microbiota composition to favor the expansion of pro‐inflammatory bacterial clades. The authors hypothesize that those changes drive the development of major depressive disorder and co‐morbid systemic conditions. Therefore, strategies aiming to rebalance gut microbiota equilibria may hold therapeutic value.
Background Asthma pathophysiology and treatment responsiveness are predicted by inflammatory phenotype. However, the relationship between airway microbiology and asthma phenotype is poorly ...understood. Objective We aimed to characterize the airway microbiota in patients with symptomatic stable asthma and relate composition to airway inflammatory phenotype and other phenotypic characteristics. Methods The microbial composition of induced sputum specimens collected from adult patients screened for a multicenter randomized controlled trial was determined by using 16S rRNA gene sequencing. Inflammatory phenotypes were defined by sputum neutrophil and eosinophil cell proportions. Microbiota were defined by using α- and β-diversity measures, and interphenotype differences were identified by using similarity of percentages, network analysis, and taxon fold change. Phenotypic predictors of airway microbiology were identified by using multivariate linear regression. Results Microbiota composition was determined in 167 participants and classified as eosinophilic (n = 84), neutrophilic (n = 14), paucigranulocytic (n = 60), or mixed neutrophilic-eosinophilic (n = 9) asthma phenotypes. Airway microbiology was significantly less diverse ( P = .022) and more dissimilar ( P = .005) in neutrophilic compared with eosinophilic participants. Sputum neutrophil proportions, but not eosinophil proportions, correlated significantly with these diversity measures (α-diversity: Spearman r = −0.374, P < .001; β-diversity: r = 0.238, P = .002). Interphenotype differences were characterized by a greater frequency of pathogenic taxa at high relative abundance and reduced Streptococcus , Gemella , and Porphyromonas taxa relative abundance in patients with neutrophilic asthma. Multivariate regression confirmed that sputum neutrophil proportion was the strongest predictor of microbiota composition. Conclusions Neutrophilic asthma is associated with airway microbiology that is significantly different from that seen in patients with other inflammatory phenotypes, particularly eosinophilic asthma. Differences in microbiota composition might influence the response to antimicrobial and steroid therapies and the risk of lung infection.
Rheumatoid arthritis (RA) is a debilitating autoimmune disorder, the etiology of which is poorly understood. A new study reveals dysbiosis in gut and oral microbiomes of affected individuals, ...potentially providing a basis for patient stratification and clues to pathophysiological mechanisms of RA onset and progression.
Sequencing-based studies of the human faecal microbiota are increasingly common. Appropriate storage of sample material is essential to avoid the introduction of post-collection bias in microbial ...community composition. Rapid freezing to -80 °C is commonly considered to be best-practice. However, this is not feasible in many studies, particularly those involving sample collection in participants' homes. We determined the extent to which a range of stabilisation and storage strategies maintained the composition of faecal microbial community structure relative to freezing to -80 °C. Refrigeration at 4 °C, storage at ambient temperature, and the use of several common preservative buffers (RNAlater, OMNIgene.GUT, Tris-EDTA) were assessed relative to freezing. Following 72 hours of storage, faecal microbial composition was assessed by 16 S rRNA amplicon sequencing. Refrigeration was associated with no significant alteration in faecal microbiota diversity or composition. However, samples stored using other conditions showed substantial divergence compared to -80 °C control samples. Aside from refrigeration, the use of OMNIgene.GUT resulted in the least alteration, while the greatest change was seen in samples stored in Tris-EDTA buffer. The commercially available OMNIgene.GUT kit may provide an important alternative where refrigeration and cold chain transportation is not available.
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