Biology subjects

Marchesi, J. R.

Publications and source records attributed to Marchesi, J. R..

5 recordsLinked to original sources

bioRxiv2024

Vancomycin-resistant Enterococcus colonise the antibiotic-treated intestine by occupying distinct nutrient- and metabolite-defined intestinal niches

Antibiotic treatment significantly disrupts the gut microbiome and promotes vancomycin-resistant enterococci (VRE) intestinal colonisation. These disruptions cause the intestine to act as a reservoir for VRE that seed difficult-to-treat infections. Patients would benefit from new treatments that prevent or treat VRE intestinal colonisation. However, the factors that drive VRE growth in the gut are poorly understood. We demonstrated that multiple antibiotics that promote VRE intestinal colonisation increased the concentration of a wide range of nutrients and decreased the concentration of a wide range of microbial metabolites. We found significant but incomplete suppression of VRE growth by individual short chain fatty acids that were decreased in antibiotic-treated faecal microbiomes. However, we showed that mixtures of short chain fatty acids provided complete or near complete suppression of VRE growth. We also showed that VRE could use most nutrients increased in antibiotic-treated faecal microbiomes as carbon or nitrogen sources to support their growth. Enterococcus faecium and Enterococcus faecalis had some common and some distinct preferences for use of specific nutrients that were enriched in antibiotic-treated faecal microbiomes. Finally, we showed that E. faecium and E. faecalis occupied overlapping but distinct nutrient-defined intestinal niches that promoted high growth when cultured with each other and when cultured with carbapenem-resistant Enterobacteriaceae (another group of multidrug-resistant pathogens). Our results demonstrated that VRE occupy distinct intestinal niches in the antibiotic-treated intestine, defined by their abilities to utilise specific enriched nutrients and their abilities to grow with reduced concentrations of inhibitory microbial metabolites.

microbiology↗

bioRxiv2024

Lactobacillus crispatus S-layer proteins modulate innate immune response and inflammation in the lower female reproductive tract.

Lactobacillus species dominance of the vaginal microbiome is a hallmark of vaginal health. Pathogen displacement of vaginal lactobacilli drives innate immune activation and mucosal barrier disruption which increases the risks of STI acquisition and, in pregnancy, of preterm birth. Using cell reporter systems, we describe differential TLR mediated activation of the proinflammatory transcription factor NF-{kappa}B by vaginal pathogens and commensals. Vaginal Lactobacillus strains associated with optimal health were shown to selectively interact with anti-inflammatory innate immune receptors whereas species associated with suboptimal health including L. iners and Gardnerella vaginalis interacted with both pro- and anti-inflammatory receptors. Anti-inflammatory action of L. crispatus was regulated by surface layer protein (SLPs)-mediated shielding of TLR ligands and selective interaction with anti-inflammatory receptor, DC-SIGN. In pregnant women, cervicovaginal SLPs were predominately associated with Lactobacillus-enriched microbiota. These data offer new mechanistic insights into how vaginal microbiota modulate host immune response and influences risk of preterm birth.

microbiology↗

bioRxiv2023

Impact of Yaq-001, a non-absorbable, engineered carbon bead of controlled porosity in rodent models of cirrhosis and acute on chronic liver failure

ObjectiveTranslocation of gut bacterial lipopolysaccharide (LPS) is associated with complications of cirrhosis. Current strategies to target bacterial translocation are limited to antibiotics with risk of resistance. This study aims to explore therapeutic potential of a non-absorbable, engineered carbon bead, Yaq-001 in cirrhosis and acute-on-chronic liver failure (ACLF) models. DesignThe performance of Yaq-001 was evaluated in in vitro studies. Two-rodent models of cirrhosis (4-week, bile duct ligation (BDL): Sham (n=36); Sham-Yaq-001 (n=30); BDL (n=37); BDL-Yaq-001 (n=44)) and ACLF (BDL-LPS: Sham-LPS (n=9); Sham-LPS-Yaq-001 (n=10); BDL-LPS (n=16); BDL-LPS-Yaq-001(n=12)). The treated-groups received Yaq-001 for 2-weeks. Samples were collected for assessment of organ and immune function, transcriptomics, microbiome composition and metabolomics. ResultsIn vitro, Yaq-001 exhibited rapid adsorption kinetics for endotoxin and bile acids without exerting an antibiotic effect. In vivo, Yaq-001 produced significant improvement in ALT, ammonia, liver cell death, portal pressure, markers of systemic inflammation and renal function in BDL animals. Yaq-001-treated ACLF animals had significantly better survival, ALT, portal pressure, brain water and creatinine. Ex-vivo LPS-induced reactive oxygen species production in portal venous monocytes and Kupffer cell populations was diminished with Yaq-001 treatment. Transcriptome analysis demonstrated a significant modulation of inflammation, cell death and senescence pathways in the liver, kidneys, brain and colon of Yaq-001-treated BDL rats. Yaq-001 impacted positively on the microbiome composition with significant modulation of Family Porphyromonadaceae and Genus Barnesiella. Urinary 1HNMR analysis suggested a shift in metabolomic signature in Yaq-001-treated BDL rats. ConclusionsThis study provides strong pre-clinical rationale for developing Yaq-001 for treatment of patients with cirrhosis. Significance of this studyO_ST_ABSWhat is already known on this topic?C_ST_ABSCurrent strategies to target bacterial translocation in cirrhosis are limited to antibiotics with risk of resistance. Yaq-001 is an insoluble, non-absorbable, non-antibiotic, engineered carbon bead of tailored porosities, which works as an adsorbent in the gut and is completely excreted after oral administration. What this study adds?O_LIYaq-001 rapidly adsorbs endotoxin, ammonia and bile acids without influencing bacterial growth kinetics in vitro. C_LIO_LIYaq-001 reduces mortality of ACLF animals and impacts positively on markers of gut permeability, liver injury, portal pressure, brain and kidneys in rodent models of cirrhosis and ACLF. C_LIO_LIYaq-001 administration was associated with positive impact on the composition of the gut microbiota, reduction in severity of endotoxemia and ammonia, which significantly reduced the severity of inflammation, cell death, signaling pathways and LPS sensitivity. C_LI How this study might affect research, practice or policy?The data provide the pre-clinical rationale to proceed to clinical trials in patients with cirrhosis aiming to prevent the occurrence of complications.

animal behavior and cognition↗

bioRxiv2023

Antibiotics promote intestinal growth of carbapenem-resistant Enterobacteriaceae by enriching nutrients and depleting microbial metabolites

The intestine is the primary colonisation site for carbapenem-resistant Enterobacteriaceae (CRE) and serves as a reservoir of CRE that cause invasive infections (e.g. bloodstream infections). Antibiotics disrupt colonisation resistance mediated by the gut microbiota, promoting the expansion of CRE within the intestine. We used ex vivo faecal cultures to measure the impact of antibiotics (that promote CRE intestinal colonisation) on the faecal microbiota from healthy human donors. We demonstrated that antibiotics decreased the abundance of gut commensals (including Bifidobacteriaceae and Bacteroidales) in human faecal microbiota, resulting in an enrichment of nutrients and a depletion of microbial metabolites. We measured the nutrient utilisation abilities, nutrient preferences, and metabolite inhibition susceptibilities of several carbapenem-resistant Enterobacteriaceae strains, including Escherichia coli, Klebsiella pneumoniae, and Enterobacter hormaechei. Nutrients (which were elevated with antibiotics) acted as carbon and nitrogen sources to support CRE growth, where CRE strains showed an ordered preference for specific nutrients. These nutrients were also increased in faeces from antibiotic-treated mice but decreased following intestinal colonisation with carbapenem-resistant E. coli. Microbial metabolites (which decreased with antibiotics) were inhibitory towards CRE growth in vitro. Carbapenem-resistant E. coli growth was decreased in faecal samples from mice treated with a mixture of inhibitory metabolites compared with PBS-treated mice. These findings demonstrated that killing gut commensals with antibiotics disrupts colonisation resistance by enriching nutrients that support CRE growth and depleting metabolites that inhibit CRE growth. These results support the development of new microbiome therapeutics to prevent CRE intestinal colonisation, which would also prevent the subsequent development of invasive CRE infections.

microbiology↗

bioRxiv2018

Disturbance During Biofilm Community Succession Promotes Cooperation and Diversity

Diversity-disturbance relationships have found widespread application in ecology, conservation and biodiversity management. In spite of their explanatory power, these conceptual frameworks have yet to be systematically applied to understanding succession in diverse microbial biofilms. Here we investigate community assembly in biofilms formed in replicate microbial bioelectrochemical systems using time-course sequencing of community 16S rRNA genes, corresponding to hundreds of operational taxonomic units (OTUs). For the first time we present a statistical model showing that a simple diversity-disturbance relationship can be used to explain dynamic changes in high diversity biofilm communities. This simple model reveals that succession in these systems is guided towards either a low diversity, generalist-dominated biofilm or a high diversity, cooperative-specialist biofilm, depending on the level of endogenous disturbance measured within the community. The pattern observed shows remarkable symmetry with findings from macro-scale communities such as grasslands, forests and coral reefs.

ecology↗