Major historical advances in cystic fibrosis (CF) respiratory clinical care, including mechanical airway clearance and inhaled medications, have aimed to address the consequences of cystic fibrosis ...transmembrane conductance regulator (CFTR) dysfunction. In contrast, CFTR modulator therapies instead target the underlying protein defect that leads to CF lung disease. The extent to which these therapies might reduce susceptibility to chronic lung infections remains to be seen. However, by improving airway clearance, reducing the requirement for antibiotics, and in some cases, through direct antimicrobial effects, CFTR modulators are likely to result in substantial changes in CF airway microbiology. These changes could contribute substantially to the clinical benefit associated with modulator therapies, as well as providing an important indicator of treatment efficacy and residual pathophysiology. Indeed, the widespread introduction of modulator therapies might require us to re-consider our models of CF airway microbiology.
•Emerging CFTR modulators might result in substantial changes in CF airway microbiology.•This maybe by improving airway clearance, reducing antibiotic requirements and in some cases via direct antimicrobial effects.•Changes may contribute to clinical benefit as well as providing an indicator of drug efficacy and residual pathophysiology.•The widespread introduction of modulator therapies might require us to re-consider our models of CF airway microbiology.
Faecal microbiota transplantation (FMT) has been shown to be effective in the treatment of a growing number of conditions, and its clinical use continues to rise. However, recent cases of ...antibiotic-resistant pathogen transmission through FMT, resulting in at least one case of fatal sepsis, highlight the need to reevaluate current donor screening practices. Commensal gut microbes profoundly influence infection risk but are not routinely assessed in donor stool. Extending the assessment of donor material beyond pathogen populations to include the composition and structure of the wider faecal microbiota has the potential to reduce infectious complications in FMT recipients.
FMT has demonstrated clinical efficacy for a growing number of conditions.High rates of systemic infection in transplant recipients, and recent cases of sepsis caused by antibiotic-resistant pathogens transmitted through FMT, highlight the need to improve FMT safety.Commensal gut microbes can substantially reduce sepsis risk through interactions with both pathogens and the host.In addition to screening for pathogens, assessment of donor material should consider the composition and structure of the wider faecal microbiota.Measures to protect commensal microbes during transplant preparation, and to deplete pathogen populations, could substantially improve the safety of FMT.
Compulsive- and anxiety-like behaviour can be efficiently modelled in SAPAP3 knockout (KO) mice, a preclinical model of relevance to obsessive-compulsive disorder (OCD). Although there is emerging ...evidence in the clinical literature of gastrointestinal dysfunction in OCD, no previous studies have investigated gut function in preclinical models of relevance to OCD. Similarly, the effects of voluntary exercise (EX) or environmental enrichment (EE) have not yet been explored in this context.
We comprehensively phenotyped the SAPAP3 KO mouse model, including the assessment of grooming microstructure, anxiety- and depressive-like behaviour, and gastrointestinal function. Mice were exposed to either standard housing (SH), exercise (EX, provided by giving mice access to running wheels), or environmental enrichment (EE) for 4 weeks to investigate the effects of enriched housing conditions in this animal model relevant to OCD.
Our study is the first to assess grooming microstructure, perseverative locomotor activity, and gastrointestinal function in SAPAP3 KO mice. We are also the first to report a sexually dimorphic effect of grooming in young-adult SAPAP3 KO mice; along with changes to grooming patterning and indicators of gut dysfunction, which occurred in the absence of gut dysbiosis in this model. Overall, we found no beneficial effects of voluntary exercise or environmental enrichment interventions in this mouse model; and unexpectedly, we revealed a deleterious effect of wheel-running exercise on grooming behaviour. We suspect that the detrimental effects of experimental housing in our study may be indicative of off-target effects of stress—a conclusion that warrants further investigation into the effects of chronic stress in this preclinical model of compulsive behaviour.
•We investigated grooming microstructure and gastrointestinal function in SAPAP3 KO mice, a model of compulsive-like behaviour•In the first gastrointestinal study of an OCD-relevant preclinical model, we found gut dysfunction in the absence of dysbiosis•We also identified sexually dimorphic grooming effects in young-adult SAPAP3 KO mice, along with changes to grooming patterning•There was no beneficial impact of exercise or environmental enrichment•In fact, wheel-running exercise worsened grooming behaviour, which may be indicative of off-target effects of stress
Background The gut microbiota influences many aspects of host physiology, including immune regulation, and is predictive of outcomes in cancer patients. However, whether conventional myelosuppressive ...chemotherapy affects the gut microbiota in humans with non-haematological malignancy, independent of antibiotic exposure, is unknown. Methods Faecal samples from 19 participants with non-haematological malignancy, who were receiving conventional chemotherapy regimens but not antibiotics, were examined prior to chemotherapy, 7-12 days after chemotherapy, and at the end of the first cycle of treatment. Gut microbiota diversity and composition was determined by 16S rRNA gene amplicon sequencing. Results Compared to pre-chemotherapy samples, samples collected 7-12 days following chemotherapy exhibited increased richness (mean 120 observed species + or - SD 38 vs 134 + or - 40; p = 0.007) and diversity (Shannon diversity: mean 6.4 + or - 0.43 vs 6.6 + or - 0.41; p = 0.02). Composition was significantly altered, with a significant decrease in the relative abundance of gram-positive bacteria in the phylum Firmicutes (pre-chemotherapy median relative abundance IQR 0.78 0.11 vs 0.75 0.11; p = 0.003), and an increase in the relative abundance of gram-negative bacteria (Bacteroidetes: median IQR 0.16 0.13 vs 0.21 0.13; p = 0.01 and Proteobacteria: 0.015 0.018 vs 0.03 0.03; p = 0.02). Differences in microbiota characteristics from baseline were no longer significant at the end of the chemotherapy cycle. Conclusions Conventional chemotherapy results in significant changes in gut microbiota characteristics during the period of predicted myelosuppression post-chemotherapy. Further study is indicated to link microbiome changes during chemotherapy to clinical outcomes. Keywords: Chemotherapy, Cancer, Microbiome
Iron deficiency is the most common nutritional deficiency worldwide, particularly for young children and females of reproductive age. Although oral iron supplements are routinely recommended and ...generally considered safe, iron supplementation has been shown to alter the fecal microbiota in low-income countries. Little is known about the effect of iron supplementation on the fecal microbiota in high-income settings.
To assess the effect of oral iron supplementation compared with placebo on the gut microbiome in nonpregnant females of reproductive age in a high-income country.
A 21-d prospective parallel design double-blind, randomized control trial conducted in South Australia, Australia. Females (18-45 y) were randomly assigned to either iron (65.7 mg ferrous fumarate) or placebo. Fecal samples were collected prior to commencing supplements and after 21 d of supplementation. The primary outcome was microbiota β-diversity (paired-sample weighted unique fraction metric dissimilarity) between treatment and placebo groups after 21 d of supplementation. Exploratory outcomes included changes in the relative abundance of bacterial taxa.
Of 82 females randomly assigned, 80 completed the trial. There was no significant difference between the groups for weighted unique fraction metric dissimilarity (mean difference: 0.003; 95% confidence interval: -0.007, 0.014; P = 0.52) or relative abundance of common bacterial taxa or Escherichia-Shigella (q > 0.05).
Iron supplementation did not affect the microbiome of nonpregnant females of reproductive age in Australia. This trial was registered at clinicaltrials.gov as NCT05033483.
Therapeutic Targeting of the Respiratory Microbiome Chotirmall, Sanjay H; Bogaert, Debby; Chalmers, James D ...
American journal of respiratory and critical care medicine,
09/2022, Letnik:
206, Številka:
5
Journal Article
•Targeted multidrug-resistant organism screening of migrant groups can be stigmatizing and divisive.•Screening instead by risk of disseminated infection protects those most vulnerable.•Metagenomics ...is an emerging technology for comprehensive screening of multidrug-resistant organism carriage.
Multidrug-resistant organisms (MDROs) are a major international health threat. In many low and middle-income countries poorly regulated antibiotic use, limited surveillance, and inadequate sanitation give rise to high rates of antibiotic resistance. A resulting reliance on last-line antibiotic options further contributes to the emergence of MDROs. The potential for these pathogens to spread across international borders is a matter of considerable concern. However, this problem is commonly framed as primarily a threat to the health security of countries where resistance is not yet endemic. In fact, it is little acknowledged that those at greatest risk from antibiotic treatment failure are individuals who move from regions of high MDRO prevalence to settings where standard empirical treatment options remain largely effective. In this perspective, we highlight the poor treatment outcomes for disseminated bacterial infections in individuals who have moved from settings in which MDROs are common to those where MDROs are currently less common. We discuss MDRO screening strategies that could avoid stigmatizing vulnerable populations by focusing on future risk of disseminated infection, rather than past risk of acquisition. In practical terms, this means screening individuals before childbirth, immunosuppressive treatments, major surgery, or other events associated with disseminated infection risk, rather than prioritizing screening for individuals from regions with high carriage rates. We argue that such measures would reduce antibiotic treatment failure and improve outcomes while protecting migrant populations from the divisive consequences of targeted screening programs.
Determining whether associations between gut microbiota characteristics and host physiology represent causal relationships is a fundamental challenge for microbiome research. We report a detailed ...investigation of microbiome assembly in C57BL/6 germ-free mice across a period of 70 days and compare the effects of single and multiple rounds of gavage, using both native and antibiotic-disrupted murine donor material. Recipients of the native microbiota did not achieve compositional stability until day 28 and persistent differences to donor microbiota remained until day 70. Performing multiple rounds of gavage significantly increased the cumulative number of detected taxa (mean increase: 10.4%) and compositional similarity to donor, and significantly reduced within-group variance (p < 0.05). Multiple rounds of gavage with antibiotic-disrupted microbiota provided no substantial benefit in relation to compositional similarity to donor or within-group variance. The process of donor microbiota establishment in recipient animals is necessary before experimentation commences and is considerably influenced by donor microbiota characteristics.
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•Gut microbiota in germ-free mice stabilize 28 days after native microbiota gavage•Repeated gavage of native microbiota increases similarity to donor microbiota•Establishment of antibiotic-disrupted microbiota does not improve with repeated gavage•Donor microbiota characteristics influence fidelity of microbiota re-establishment
Biological Sciences; Microbiology; Microbiome
To determine the existence of mucosal dysbiosis in siblings of patients with Crohn's disease (CD) using 454 pyrosequencing and to comprehensively characterise and determine the influence of ...genotypical and phenotypical factors, on that dysbiosis. Siblings of patients with CD have elevated risk of developing CD and display aspects of disease phenotype, including faecal dysbiosis. Whether the mucosal microbiota is disrupted in these at-risk individuals is unknown.
Rectal biopsy DNA was extracted from 21 patients with quiescent CD, 17 of their healthy siblings and 19 unrelated healthy controls. Mucosal microbiota was analysed by 16S rRNA gene pyrosequencing and were classified into core and rare species. Genotypical risk was determined using Illumina Immuno BeadChip, faecal calprotectin by ELISA and blood T-cell phenotype by flow cytometry.
Core microbiota of both patients with CD and healthy siblings was significantly less diverse than controls. Metacommunity profiling (Bray-Curtis (SBC) index) showed the sibling core microbial composition to be more similar to CD (SBC=0.70) than to healthy controls, whereas the sibling rare microbiota was more similar to healthy controls (SBC=0.42). Faecalibacterium prausnitzii contributed most to core metacommunity dissimilarity both between siblings and controls, and between patients and controls. Phenotype/genotype markers of CD risk significantly influenced microbiota variation between and within groups, of which genotype had the largest effect.
Individuals with elevated CD-risk display mucosal dysbiosis characterised by reduced diversity of core microbiota and lower abundance of F. prausnitzii. This dysbiosis in healthy people at risk of CD implicates microbiological processes in CD pathogenesis.
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