Publications by authors named "Cormac G M Gahan"

104 Publications

Functional and Phylogenetic Diversity of BSH and PVA Enzymes.

Microorganisms 2021 Mar 31;9(4). Epub 2021 Mar 31.

Alimentary Pharmabiotic Centre Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland.

Bile salt hydrolase (BSH) and penicillin V acylase (PVA) are related enzymes that are classified as choloylglycine hydrolases (CGH). BSH enzymes have attracted significant interest for their ability to modulate the composition of the bile acid pool, alter bile acid signaling events mediated by the host bile acid receptors FXR and TGR5 and influence cholesterol homeostasis in the host, while PVA enzymes have been widely utilised in an industrial capacity in the production of semi-synthetic antibiotics. The similarities between BSH and PVA enzymes suggest common evolution of these enzymes and shared mechanisms for substrate binding and catalysis. Here, we compare BSH and PVA through analysis of the distribution, phylogeny and biochemistry of these microbial enzymes. The development of new annotation approaches based upon functional enzyme analyses and the potential implications of BSH enzymes for host health are discussed.
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http://dx.doi.org/10.3390/microorganisms9040732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066178PMC
March 2021

Immunomodulation of J774A.1 Murine Macrophages by Strains Isolated From the Human Gastrointestinal Tract and Fermented Foods.

Front Microbiol 2020 12;11:557143. Epub 2021 Jan 12.

Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.

species (recently re-named subsp. ) can be isolated from both either the mammalian gut or specific fermented foods where they may be present at high concentrations. Whilst strains have been proposed as potential probiotic candidates, the ability of resident strains consumed in fermented foods to interact with the host is unclear. The main objective of this study was to investigate the cellular location and ability of three different food-borne strains isolated from different sources (table olives and cheese) to modulate the immune response of a murine macrophage-like cell line (J774A.1). For that purpose, macrophages were exposed to the three different strains for 24 h and the expression of a panel of genes involved in the immune response, including genes encoding pattern-recognition receptors (TLRs and NLRs) and cytokines was evaluated by qRT-PCR. We also utilized chemical inhibitors of intracellular pathways to gain some insight into potential signaling mechanisms. Results showed that the native food strains of were able to modulate the response of J774A.1 murine macrophages through a predominately NOD signaling pathway that reflects the transient intracellular location of these strains within the macrophage. The data indicate the capacity of food-dwelling strains to influence macrophage-mediated host responses if consumed in sufficient quantities.
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http://dx.doi.org/10.3389/fmicb.2020.557143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835322PMC
January 2021

Chitin Attenuates Expression of Virulence Genes .

Front Microbiol 2020 3;11:588906. Epub 2020 Dec 3.

Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, Food Safety and Zoonoses-University of Copenhagen, Frederiksberg, Denmark.

External signals are crucial for bacteria to sense their immediate environment and fine-tune gene expression accordingly. The foodborne pathogen senses a range of environmental cues in order to activate or deactivate the virulence-inducing transcriptional factor PrfA during transition between infectious and saprophytic lifecycles. Chitin is an abundant biopolymer formed from linked β-(1-4)-N-acetyl-D-glucosamine residues associated with fungi, the exoskeleton of insects and often incorporated into foods as a thickener or stabilizer. evolved to hydrolyse chitin, presumably, to facilitate nutrient acquisition from competitive environments such as soil where the polymer is abundant. Since mammals do not produce chitin, we reasoned that the polymer could serve as an environmental signal contributing to repression of PrfA-dependent expression. This study shows a significant downregulation of the core PrfA-regulon during virulence-inducing conditions in the presence of chitin. Our data suggest this phenomenon occurs through a mechanism that differs from PTS-transport of oligosaccharides generated from either degradation or chitinase-mediated hydrolysis of the polymer. Importantly, an indication that chitin can repress virulence expression of a constitutively active PrfA mutant is shown, possibly mediated via a post-translational modification inhibiting PrfA activity. To our knowledge, this is the first time that chitin is reported as a molecule with anti-virulence properties against a pathogenic bacterium. Thus, our findings identify chitin as a signal which may downregulate the virulence potential of the pathogen and may provide an alternative approach toward reducing disease risk.
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http://dx.doi.org/10.3389/fmicb.2020.588906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744463PMC
December 2020

Characterizing Phage-Host Interactions in a Simplified Human Intestinal Barrier Model.

Microorganisms 2020 Sep 7;8(9). Epub 2020 Sep 7.

APC Microbiome Ireland, Bioscience institute, University College Cork, Cork T12 YT20 , Ireland.

An intestinal epithelium model able to produce mucus was developed to provide an environment suitable for testing the therapeutic activity of gut bacteriophages. We show that adheres more effectively in the presence of mucus, can invade the intestinal epithelia and is able to translocate after damaging tight junctions. Furthermore, phage vB_EfaM_A2 (a member of that possesses virion associated immunoglobin domains) was found to translocate through the epithelium in the presence and absence of its host bacteria. Phage A2 protected eukaryotic cells by reducing mortality and maintaining the structure of the cell layer structure. We suggest the mammalian cell model utilized within this study as an adaptable in vitro model that can be employed to enable a better understanding of phage-bacteria interactions and the protective impact of phage therapy relating to the intestinal epithelium.
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http://dx.doi.org/10.3390/microorganisms8091374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563437PMC
September 2020

Effectiveness of current hygiene practices on minimization of in different mushroom production-related environments.

Food Sci Nutr 2020 Jul 20;8(7):3456-3468. Epub 2020 May 20.

Teagasc research centre Moorepark Ireland.

Background: The commercial production of is a three stage process: 1) production of compost, also called "substrate"; 2) production of casing soil; and 3) production of the mushrooms. Hygiene practices are undertaken at each stage: pasteurization of the substrate, hygiene practices applied during the production of casing soil, postharvest steam cookout, and disinfection at the mushroom production facilities. However, despite these measures, foodborne pathogens, including are reported in the mushroom production environment. In this work, the presence of was evaluated before and after the application of hygiene practices at each stage of mushroom production with swabs, samples of substrate, casing, and spent mushroom growing substrates.

Results: was not detected in any casing or substrate sample by enumeration according to BS EN ISO 11290-2:1998. Analysis of the substrate showed that was absent in 10 Phase II samples following pasteurization, but was then present in 40% of 10 Phase III samples. At the casing production facility, 31% of 59 samples were positive. Hygiene improvements were applied, and after four sampling occasions, 22% of 37 samples were positive, but no statistically significant difference was observed ( > .05). At mushroom production facilities, the steam cookout process inactivated in the spent growth substrate, but 13% of 15 floor swabs at Company 1 and 19% of 16 floor swabs at Company 2, taken after disinfection, were positive.

Conclusion: These results showed the possibility of recontamination of Phase III substrate, cross-contamination at the casing production stage and possible survival after postharvest hygiene practices at the mushroom growing facilities. This information will support the development of targeted measures to minimize in the mushroom industry.
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http://dx.doi.org/10.1002/fsn3.1629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382171PMC
July 2020

Impact of phospholipid digests and bile acid pool variations on the crystallization of atazanavir from supersaturated solutions.

Eur J Pharm Biopharm 2020 Aug 27;153:68-83. Epub 2020 May 27.

Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN 47907, United States. Electronic address:

Oral delivery of poorly water-soluble drugs (PWSDs), which predominate the development pipeline, poses significant challenges. Weakly basic compounds, such as atazanavir, represent a critical class of PWSDs as even the administration of the crystalline solid may invoke supersaturation during gastric-intestinal transfer. The absorption advantage afforded by this supersaturated state can be offset by inherent metastability and a tendency to revert to the lower energy crystalline state. Therefore, it is important to understand the physiological factors that can affect crystallization to improve in vitro-in vivo predictiveness and to regulate inter-individual responses. The first aim of this study was to elucidate the influence of lyso-phosphatidylcholine (lyso-PC) and sodium oleate on crystallization, as the products of phosphatidylcholine (PC) hydrolysis and the major lipid components of human intestinal fluid (HIF) and updated fasted state simulated intestinal fluid version 3 (FaSSIF-V3). Secondly, as an individual's bile acid pool is unique, dynamic and related to gut microbiome community structure, it was of interest to investigate the impact of bile acid pool variations on crystallization from supersaturated solutions. To study the effect of PC hydrolysis, media with 2.8 mM sodium glycocholate (GCA) and sodium taurocholate (TCA) (1:1) but varying concentrations of PC, lyso-PC or sodium oleate were prepared. To investigate the influence of inter-individual variations in intestinal bile acid pool size and composition, media simulating the profiles of six healthy Western volunteers were prepared based on previously published data. The crystalline and amorphous solubility of atazanavir, a weakly basic antiretroviral drug, was firstly determined in these media. Nucleation-induction time experiments were then performed at an equivalent extent of supersaturation in each medium (corresponding to the amorphous solubility). At a constant level of GCA/TCA, increasing concentrations of both PC and lyso-PC accelerated crystallization onset; however, this was at least 2-fold more pronounced with lyso-PC at a given molar concentration. The addition of sodium oleate was also observed to induce crystallization. Interestingly, substituting GCA/TCA with the bile salt fraction of other biorelevant media partially circumvented the crystallization-inducing effect of phospholipids and their digests. The presence of dihydroxy bile salts was found to be particularly significant in decelerating the crystallization process. Nucleation-induction times in simulated volunteer pools were found to be dependent upon bile salt concentration, with higher bile salt levels generally prolonging supersaturation. Differences of up to 6-fold were observed. This study demonstrates that the choice of biorelevant medium used to evaluate supersaturating formulations can influence the observed crystallization kinetics. While the presence of lyso-PC and sodium oleate in FaSSIF-V3 medium is more physiologically relevant, further attention should be paid to the bile salt fraction when designing a biorelevant medium for supersaturating formulations. In vivo, inter-individual differences in the amount and types of bile acids and phospholipids present may influence the behaviour of supersaturating formulations.
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http://dx.doi.org/10.1016/j.ejpb.2020.05.022DOI Listing
August 2020

When Rhythms Meet the Blues: Circadian Interactions with the Microbiota-Gut-Brain Axis.

Cell Metab 2020 03;31(3):448-471

APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland. Electronic address:

The microbiota-gut-brain axis encompasses a bidirectional mode of communication between the microorganisms residing in our gut, and our brain function and behavior. The composition of the gut microbiota is subject to diurnal variation and is entrained by host circadian rhythms. In turn, a diverse microbiota is essential for optimal regulation of host circadian pathways. Disruption of the cyclical nature of this microbe-host interaction profoundly influences disease pathology and severity. This review aims to summarize current knowledge on this bidirectional relationship. Indeed, the past few years have revealed promising data regarding the relationship between the microbiota-gut-brain axis and circadian rhythms and how they act in concert to influence disease, but further research needs to be done to examine how they coalesce to modulate severity of, and risk for, certain diseases. Moreover, there is a need for a greater understanding of the molecular mechanisms underlying the close relationship between circadian-microbiome-brain interactions.
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http://dx.doi.org/10.1016/j.cmet.2020.02.008DOI Listing
March 2020

Different carbon sources result in differential activation of sigma B and stress resistance in Listeria monocytogenes.

Int J Food Microbiol 2020 May 30;320:108504. Epub 2019 Dec 30.

Food Microbiology, Wageningen University & Research, the Netherlands. Electronic address:

Listeria monocytogenes is an important food-borne pathogen that is ubiquitous in the environment. It is able to utilize a variety of carbon sources, to produce biofilms on food-processing surfaces and to survive food preservation-associated stresses. In this study, we investigated the effect of three common carbon sources, namely glucose, glycerol and lactose, on growth and activation of the general stress response Sigma factor, SigB, and corresponding phenotypes including stress resistance. A fluorescent reporter coupled to the promoter of lmo2230, a highly SigB-dependent gene, was used to determine SigB activation via quantitative fluorescence spectroscopy. This approach, combined with Western blotting and fluorescence microscopy, showed the highest SigB activation in lactose grown cells and lowest in glucose grown cells. In line with this observation, lactose grown cells showed the highest resistance to lethal heat and acid stress, the highest biofilm formation, and had the highest adhesion/invasion capacity in Caco-2-derived C2Bbe1 cell lines. Our data suggest that lactose utilisation triggers a strong SigB dependent stress response and this may have implications for the resistance of L. monocytogenes along the food chain.
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http://dx.doi.org/10.1016/j.ijfoodmicro.2019.108504DOI Listing
May 2020

The Cholesterol-Lowering Effect of Oats and Oat Beta Glucan: Modes of Action and Potential Role of Bile Acids and the Microbiome.

Front Nutr 2019 27;6:171. Epub 2019 Nov 27.

APC Microbiome Ireland, University College Cork, Cork, Ireland.

Consumption of sufficient quantities of oat products has been shown to reduce host cholesterol and thereby modulate cardiovascular disease risk. The effects are proposed to be mediated by the gel-forming properties of oat β-glucan which modulates host bile acid and cholesterol metabolism and potentially removes intestinal cholesterol for excretion. However, the gut microbiota has emerged as a major factor regulating cholesterol metabolism in the host. Oat β-glucan has been shown to modulate the gut microbiota, particularly those bacterial species that influence host bile acid metabolism and production of short chain fatty acids, factors which are regulators of host cholesterol homeostasis. Given a significant role for the gut microbiota in cholesterol metabolism it is likely that the effects of oat β-glucan on the host are multifaceted and involve regulation of microbe-host interactions at the gut interface. Here we consider the potential for oat β-glucan to influence microbial populations in the gut with potential consequences for bile acid metabolism, reverse cholesterol transport (RCT), short-chain fatty acid (SCFA) production, bacterial metabolism of cholesterol and microbe-host signaling.
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http://dx.doi.org/10.3389/fnut.2019.00171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892284PMC
November 2019

The ability of Listeria monocytogenes to form biofilm on surfaces relevant to the mushroom production environment.

Int J Food Microbiol 2020 Mar 22;317:108385. Epub 2019 Oct 22.

Food Safety Department, Teagasc Food Research Centre, Ashtown Dublin 15, Ireland. Electronic address:

Due to its ubiquitous nature, Listeria monocytogenes is a threat to all fresh fruits and vegetables, including mushrooms, which are Ireland's largest horticultural crop. Although fresh cultivated mushrooms (Agaricus bisporus) have not been previously linked with listeriosis outbreaks, the pathogen still poses a threat to the industry, particularly due to its ability to form biofilms. This threat is highlighted by the multiple recalls of mushroom products caused by L. monocytogenes contamination and by previous studies demonstrating that L. monocytogenes is present in the mushroom production environment. In this study, the biofilm formation potential of L. monocytogenes strains isolated from the mushroom production environment was investigated on materials and at temperatures relevant to mushroom production. A preliminary assessment of biofilm formation of 73 mushroom industry isolates was undertaken using a crystal violet assay on polystyrene microtitre plates. The biofilm formation of a subset (n = 7) of these strains was then assessed on twelve different materials, including materials that are representative of the materials commonly found in the mushroom production environments, using the CDC biofilm reactor. Vertical scanning interferometry was used to determine the surface roughness of the chosen materials. All the strains tested using the CDC biofilm reactor were able to form biofilms on the different surfaces tested but material type was found to be a key determining factor on the levels of biofilm formed. Stainless steel, aluminium, rubber, polypropylene and polycarbonate were all able to support biofilm levels in the range of 4-4.9 log CFU/cm, for seven different L. monocytogenes strains. Mushroom industry-specific materials, including growing nets and tarpaulins, were found to support biofilms levels between 4.7 and 6.7 log CFU/cm. Concrete was found to be of concern as it supported 7.7 log CFU/cm of biofilm for the same strains; however, sealing the concrete resulted in an approximately 2-log reduction in biofilm levels. The surface roughness of the materials varied greatly between the materials (0.7-3.5 log Ra) and was found to have a positive correlation with biofilm formation (r = 0.573) although marginally significant (P = 0.051). The results of this study indicate that L. monocytogenes can readily form biofilms on mushroom industry relevant surfaces, and additionally identifies surfaces of specific concern, where rigorous cleaning and disinfection is required.
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http://dx.doi.org/10.1016/j.ijfoodmicro.2019.108385DOI Listing
March 2020

Genomic and Ecogenomic Characterization of Bacteriophages.

Front Microbiol 2019 6;10:1783. Epub 2019 Aug 6.

School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, United Kingdom.

often complicates the care of catheterized patients through the formation of crystalline biofilms which block urine flow. Bacteriophage therapy has been highlighted as a promising approach to control this problem, but relatively few phages infecting have been characterized. Here we characterize five phages capable of infecting , including those shown to reduce biofilm formation, and provide insights regarding the wider ecological and evolutionary relationships of these phages. Transmission electron microscopy (TEM) imaging of phages vB_PmiP_RS1pmA, vB_PmiP_RS1pmB, vB_PmiP_RS3pmA, and vB_PmiP_RS8pmA showed that all share morphologies characteristic of the family. The genome sequences of vB_PmiP_RS1pmA, vB_PmiP_RS1pmB, and vB_PmiP_RS3pmA showed these are species of the same phage differing only by point mutations, and are closely related to vB_PmiP_RS8pmA. Podophages characterized in this study were also found to share similarity in genome architecture and composition to other previously described podophages (PM16 and PM75). In contrast, vB_PimP_RS51pmB showed morphology characteristic of the family, with no notable similarity to other phage genomes examined. Ecogenomic profiling of all phages revealed no association with human urinary tract viromes, but sequences similar to vB_PimP_RS51pmB were found within human gut, and human oral microbiomes. Investigation of wider host-phage evolutionary relationships through tetranucleotide profiling of phage genomes and bacterial chromosomes, indicated vB_PimP_RS51pmB has a relatively recent association with and other non- members of the family. Subsequent host range assays confirmed vB_PimP_RS51pmB can infect .
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http://dx.doi.org/10.3389/fmicb.2019.01783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691071PMC
August 2019

Lactococcus lactis subsp. lactis as a natural anti-listerial agent in the mushroom industry.

Food Microbiol 2019 Sep 28;82:30-35. Epub 2019 Jan 28.

Food Safety Department, Teagasc Food Research Centre, Ashtown, Dublin 15, Ireland. Electronic address:

Mushroom growth substrates from different commercial producers of mushrooms (Agaricus bisporus) were screened for the presence of bacteria with potential for use as biocontrol agents for controlling Listeria monocytogenes in the mushroom production environment. Eight anti-listerial strains were isolated from different sources and all were identified using 16s rRNA gene sequencing as Lactococcus lactis subsp. lactis. Whole-genome sequencing of the Lc. lactis isolates indicated that strains from different sites and substrate types were highly similar. Colony MALDI-TOF mass spectrometry found that these strains were Nisin Z producers but inhibitory activity was highly influenced by the incubation conditions and was strain dependant. The biofilm forming ability of these strains was tested using a crystal violet assay and all were found to be strong biofilm formers. Growth of Lc. lactis subsp. lactis using mixed-biofilm conditions with L. monocytogenes on stainless steel resulted in a 4-log reduction of L. monocytogenes cell numbers. Additional sampling of mushroom producers showed that these anti-listerial Lc. lactis strains are commonly present in the mushroom production environment. Lc. lactis has a generally regarded as safe (GRAS) status and therefore has potential for use as an environmentally benign solution to control L. monocytogenes in order to prevent product contamination and to enhance consumer confidence in the mushroom industry.
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http://dx.doi.org/10.1016/j.fm.2019.01.015DOI Listing
September 2019

Microbial bile salt hydrolases mediate the efficacy of faecal microbiota transplant in the treatment of recurrent infection.

Gut 2019 10 11;68(10):1791-1800. Epub 2019 Feb 11.

Division of Integrative Systems Medicine and Digestive Disease, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK.

Objective: Faecal microbiota transplant (FMT) effectively treats recurrent infection (rCDI), but its mechanisms of action remain poorly defined. Certain bile acids affect germination or vegetative growth. We hypothesised that loss of gut microbiota-derived bile salt hydrolases (BSHs) predisposes to CDI by perturbing gut bile metabolism, and that BSH restitution is a key mediator of FMT's efficacy in treating the condition.

Design: Using stool collected from patients and donors pre-FMT/post-FMT for rCDI, we performed 16S rRNA gene sequencing, ultra performance liquid chromatography mass spectrometry (UPLC-MS) bile acid profiling, BSH activity measurement, and qPCR of /CD genes involved in bile metabolism. Human data were validated in batch cultures and a C57BL/6 mouse model of rCDI.

Results: From metataxonomics, pre-FMT stool demonstrated a reduced proportion of BSH-producing bacterial species compared with donors/post-FMT. Pre-FMT stool was enriched in taurocholic acid (TCA, a potent germinant); TCA levels negatively correlated with key bacterial genera containing BSH-producing organisms. Post-FMT samples demonstrated recovered BSH activity and /CD gene copy number compared with pretreatment (p<0.05). In batch cultures, supernatant from engineered -expressing and naturally BSH-producing organisms ( and ) reduced TCA-mediated germination relative to culture supernatant of wild-type (BSH-negative) total viable counts were ~70% reduced in an rCDI mouse model after administration of expressing highly active BSH relative to mice administered BSH-negative (p<0.05).

Conclusion: Restoration of gut BSH functionality contributes to the efficacy of FMT in treating rCDI.
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http://dx.doi.org/10.1136/gutjnl-2018-317842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839797PMC
October 2019

Lactobacillus mucosae DPC 6426 as a bile-modifying and immunomodulatory microbe.

BMC Microbiol 2019 02 8;19(1):33. Epub 2019 Feb 8.

Teagasc Food Research Centre, Food Biosciences Department, Moorepark, Fermoy, Co, Cork, Ireland.

Background: Lactobacillus mucosae DPC 6426 has previously demonstrated potentially cardio-protective properties, in the form of dyslipidaemia and hypercholesterolemia correction in an apolipoprotein-E deficient mouse model. This study aims to characterise the manner in which this microbe may modulate host bile pool composition and immune response, in the context of cardiovascular disease. Lactobacillus mucosae DPC 6426 was assessed for bile salt hydrolase activity and specificity. The microbe was compared against several other enteric strains of the same species, as well as a confirmed bile salt hydrolase-active strain, Lactobacillus reuteri APC 2587.

Results: Quantitative bile salt hydrolase assays revealed that enzymatic extracts from Lactobacillus reuteri APC 2587 and Lactobacillus mucosae DPC 6426 demonstrate the greatest activity in vitro. Bile acid profiling of porcine and murine bile following incubation with Lactobacillus mucosae DPC 6426 confirmed a preference for hydrolysis of glyco-conjugated bile acids. In addition, the purified exopolysaccharide and secretome of Lactobacillus mucosae DPC 6426 were investigated for immunomodulatory capabilities using RAW264.7 macrophages. Gene expression data revealed that both fractions stimulated increases in interleukin-6 and interleukin-10 gene transcription in the murine macrophages, while the entire secretome was necessary to increase CD206 transcription. Moreover, the exopolysaccharide elicited a dose-dependent increase in nitric oxide and interleukin-10 production from RAW264.7 macrophages, concurrent with increased tumour necrosis factor-α secretion at all doses.

Conclusions: This study indicates that Lactobacillus mucosae DPC 6426 modulates both bile pool composition and immune system tone in a manner which may contribute significantly to the previously identified cardio-protective phenotype.
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http://dx.doi.org/10.1186/s12866-019-1403-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368806PMC
February 2019

Short-term consumption of a high-fat diet increases host susceptibility to Listeria monocytogenes infection.

Microbiome 2019 01 18;7(1). Epub 2019 Jan 18.

APC Microbiome Ireland, University College Cork, Cork, Ireland.

Background: A westernized diet comprising a high caloric intake from animal fats is known to influence the development of pathological inflammatory conditions. However, there has been relatively little focus upon the implications of such diets for the progression of infectious disease. Here, we investigated the influence of a high-fat (HF) diet upon parameters that influence Listeria monocytogenes infection in mice.

Results: We determined that short-term administration of a HF diet increases the number of goblet cells, a known binding site for the pathogen, in the gut and also induces profound changes to the microbiota and promotes a pro-inflammatory gene expression profile in the host. Host physiological changes were concordant with significantly increased susceptibility to oral L. monocytogenes infection in mice fed a HF diet relative to low fat (LF)- or chow-fed animals. Prior to Listeria infection, short-term consumption of HF diet elevated levels of Firmicutes including Coprococcus, Butyricicoccus, Turicibacter and Clostridium XIVa species. During active infection with L. monocytogenes, microbiota changes were further exaggerated but host inflammatory responses were significantly downregulated relative to Listeria-infected LF- or chow-fed groups, suggestive of a profound tempering of the host response influenced by infection in the context of a HF diet. The effects of diet were seen beyond the gut, as a HF diet also increased the sensitivity of mice to systemic infection and altered gene expression profiles in the liver.

Conclusions: We adopted a systems approach to identify the effects of HF diet upon L. monocytogenes infection through analysis of host responses and microbiota changes (both pre- and post-infection). Overall, the results indicate that short-term consumption of a westernized diet has the capacity to significantly alter host susceptibility to L. monocytogenes infection concomitant with changes to the host physiological landscape. The findings suggest that diet should be a consideration when developing models that reflect human infectious disease.
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http://dx.doi.org/10.1186/s40168-019-0621-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339339PMC
January 2019

Gut Microbiota-Mediated Bile Acid Transformations Alter the Cellular Response to Multidrug Resistant Transporter Substrates in Vitro: Focus on P-glycoprotein.

Mol Pharm 2018 12 16;15(12):5711-5727. Epub 2018 Nov 16.

School of Pharmacy , ‡APC Microbiome Ireland , §School of Biochemistry and Cell Biology , ∥School of Microbiology , ⊥School of Medicine , University College Cork , Cork , Ireland.

Pharmacokinetic research at the host-microbe interface has been primarily directed toward effects on drug metabolism, with fewer investigations considering the absorption process. We previously demonstrated that the transcriptional expression of genes encoding intestinal transporters involved in lipid translocation are altered in germ-free and conventionalized mice possessing distinct bile acid signatures. It was consequently hypothesized that microbial bile acid metabolism, which is the deconjugation and dehydroxylation of the bile acid steroid nucleus by gut bacteria, may impact upon drug transporter expression and/or activity and potentially alter drug disposition. Using a panel of three human intestinal cell lines (Caco-2, T84, and HT-29) that differ in basal transporter expression level, bile acid conjugation-, and hydroxylation-status was shown to influence the transcription of genes encoding several major influx and efflux transporter proteins. We further investigated if these effects on transporter mRNA would translate to altered drug disposition and activity. The results demonstrated that the conjugation and hydroxylation status of the bile acid steroid nucleus can influence the cellular response to multidrug resistance (MDR) substrates, a finding that did not directly correlate with directionality of gene or protein expression. In particular, we noted that the cytotoxicity of cyclosporine A was significantly augmented in the presence of the unconjugated bile acids deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) in P-gp positive cell lines, as compared to their taurine/glycine-conjugated counterparts, implicating P-gp in the molecular response. Overall this work identifies a novel mechanism by which gut microbial metabolites may influence drug accumulation and suggests a potential role for the microbial bile acid-deconjugating enzyme bile salt hydrolase (BSH) in ameliorating multidrug resistance through the generation of bile acid species with the capacity to access and inhibit P-gp ATPase. The physicochemical property of nonionization is suggested to underpin the preferential ability of unconjugated bile acids to attenuate the efflux of P-gp substrates and to sensitize tumorigenic cells to cytotoxic therapeutics in vitro. This work provides new impetus to investigate whether perturbation of the gut microbiota, and thereby the bile acid component of the intestinal metabolome, could alter drug pharmacokinetics in vivo. These findings may additionally contribute to the development of less toxic P-gp modulators, which could overcome MDR.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b00875DOI Listing
December 2018

Microbiome-mediated bile acid modification: Role in intestinal drug absorption and metabolism.

Pharmacol Res 2018 07 13;133:170-186. Epub 2018 Apr 13.

APC Microbiome Ireland, University College Cork, Cork, Ireland; School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland. Electronic address:

Once regarded obscure and underappreciated, the gut microbiota (the microbial communities colonizing the gastrointestinal tract) is gaining recognition as an influencer of many aspects of human health. Also increasingly apparent is the breadth of interindividual variation in these co-evolved microbial-gut associations, presenting novel quests to explore implications for disease and therapeutic response. In this respect, the unearthing of the drug-metabolizing capacity of the microbiota has provided impetus for the integration of microbiological and pharmacological research. This review considers a potential mechanism, 'microbial bile acid metabolism', by which the intricate interplay between the host and gut bacteria may influence drug pharmacokinetics. Bile salts traditionally regarded as biological surfactants, synthesized by the host and biotransformed by gut bacteria, are now also recognized as signalling molecules that affect diverse physiological processes. Accumulating data indicate that bile salts are not equivalent with respect to their physicochemical properties, micellar solubilization capacities for poorly water-soluble drugs, crystallization inhibition tendencies nor potencies for bile acid receptor activation. Herein, the origin, physicochemical properties, physiological functions, plasticity and pharmaceutical significance of the human bile acid pool are discussed. Microbial dependant differences in the composition of the human bile acid pool, simulated intestinal media and commonly used preclinical species is highlighted to better understand in vivo performance predictiveness. While the precise impact of an altered gut microbiome, and consequently bile acid pool, in the biopharmaceutical setting remains largely elusive, the objective of this article is to aid knowledge acquisition through a detailed review of the literature.
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http://dx.doi.org/10.1016/j.phrs.2018.04.009DOI Listing
July 2018

Genomic Characterization of Listeria monocytogenes Isolates Associated with Clinical Listeriosis and the Food Production Environment in Ireland.

Genes (Basel) 2018 Mar 20;9(3). Epub 2018 Mar 20.

APC Microbiome Ireland, University College Cork, Cork T12 K8AF, Ireland.

is a major human foodborne pathogen that is prevalent in the natural environment and has a high case fatality rate. Whole genome sequencing (WGS) analysis has emerged as a valuable methodology for the classification of isolates and the identification of virulence islands that may influence infectivity. In this study, WGS was used to provide an insight into 25 isolates from cases of clinical infection in Ireland between 2013 and 2015. Clinical strains were either lineage I (14 isolates) or lineage II (11 isolates), with 12 clonal complexes (CC) represented, of which CC1 (6) and CC101 (4) were the most common. Single nucleotide polymorphism (SNP) analysis demonstrated that clinical isolates from mother-infant pairs (one isolate from the mother and one from the infant) were highly related (3 SNP differences in each) and also identified close similarities between isolates from otherwise distinct cases (1 SNP difference). Clinical strains were positive for common virulence-associated loci and 13 isolates harbour the LIPI-3 locus. Pulsed-field gel electrophoresis (PFGE) was used to compare strains to a database of 1300 Irish food and food processing environment isolates and determined that 64% of clinical pulsotypes were previously encountered in the food or food processing environment. Five of the matching food and food processing environment isolates were sequenced and results demonstrated a correlation between pulsotype and genotype. Overall, the work provides insights into the nature of strains currently causing clinical disease in Ireland and indicates that similar isolates can be found in the food or food processing environment.
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http://dx.doi.org/10.3390/genes9030171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867892PMC
March 2018

Determinants of Reduced Genetic Capacity for Butyrate Synthesis by the Gut Microbiome in Crohn's Disease and Ulcerative Colitis.

J Crohns Colitis 2018 Jan;12(2):204-216

APC Microbiome Institute, University College Cork, Cork, Ireland.

Background And Aims: Alterations in short chain fatty acid metabolism, particularly butyrate, have been reported in inflammatory bowel disease, but results have been conflicting because of small study numbers and failure to distinguish disease type, activity or other variables such as diet. We performed a comparative assessment of the capacity of the microbiota for butyrate synthesis, by quantifying butyryl-CoA:acetate CoA-transferase [BCoAT] gene content in stool from patients with Crohn's disease [CD; n = 71], ulcerative colitis [UC; n = 58] and controls [n = 75], and determined whether it was related to active vs inactive inflammation, microbial diversity, and composition and/or dietary habits.

Methods: BCoAT gene content was quantified by quantitative polymerase chain reaction [qPCR]. Disease activity was assessed clinically and faecal calprotectin concentration measured. Microbial composition was determined by sequencing 16S rRNA gene. Dietary data were collected using an established food frequency questionnaire.

Results: Reduced butyrate-synthetic capacity was found in patients with active and inactive CD [p < 0.001 and p < 0.01, respectively], but only in active UC [p < 0.05]. In CD, low BCoAT gene content was associated with ileal location, stenotic behaviour, increased inflammation, lower microbial diversity, greater microbiota compositional change, and decreased butyrogenic taxa. Reduced BCoAT gene content in patients with CD was linked with a different regimen characterised by lower dietary fibre.

Conclusions: Reduced butyrate-synthetic capacity of the microbiota is more evident in CD than UC and may relate to reduced fibre intake. The results suggest that simple replacement of butyrate per se may be therapeutically inadequate, whereas manipulation of microbial synthesis, perhaps by dietary means, may be more appropriate.
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http://dx.doi.org/10.1093/ecco-jcc/jjx137DOI Listing
January 2018

Development of a Click Beetle Luciferase Reporter System for Enhanced Bioluminescence Imaging of : Analysis in Cell Culture and Murine Infection Models.

Front Microbiol 2017 26;8:1797. Epub 2017 Sep 26.

APC Microbiome Institute, University College Cork, Cork, Ireland.

is a Gram-positive facultative intracellular pathogen that is widely used as a model organism for the analysis of infection biology. In this context, there is a current need to develop improved reporters for enhanced bioluminescence imaging (BLI) of the pathogen in infection models. We have developed a click beetle red luciferase (CBR-) based vector (pPL2CBR) expressing codon optimized CBR- under the control of a highly expressed Listerial promoter (P) for and have compared this to a -based system expressing bacterial luciferase for BLI of the pathogen using growth experiments and models. The CBR- plasmid stably integrates into the chromosome and can be used to label field isolates and laboratory strains of the pathogen. Growth experiments revealed that CBR- labeled emits a bright signal in exponential phase that is maintained during stationary phase. In contrast, -labeled bacteria produced a light signal that peaked during exponential phase and was significantly reduced during stationary phase. Light from CBR- labeled bacteria was more efficient than the signal from -labeled bacteria in penetrating an artificial tissue depth assay system. A cell invasion assay using C2Bbe1 cells and a systemic murine infection model revealed that CBR- is suited to BLI approaches and demonstrated enhanced sensitivity relative to in the context of infection models. Overall, we demonstrate that this novel CBR reporter system provides efficient, red-shifted light production relative to and may have significant applications in the analysis of pathogenesis.
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http://dx.doi.org/10.3389/fmicb.2017.01797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622934PMC
September 2017

Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism.

EBioMedicine 2017 Oct 21;24:166-178. Epub 2017 Sep 21.

APC Microbiome Institute, University College Cork, Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland. Electronic address:

Autism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental conditions worldwide. There is growing awareness that ASD is highly comorbid with gastrointestinal distress and altered intestinal microbiome, and that host-microbiome interactions may contribute to the disease symptoms. However, the paucity of knowledge on gut-brain axis signaling in autism constitutes an obstacle to the development of precision microbiota-based therapeutics in ASD. To this end, we explored the interactions between intestinal microbiota, gut physiology and social behavior in a BTBR TItpr3/J mouse model of ASD. Here we show that a reduction in the relative abundance of very particular bacterial taxa in the BTBR gut - namely, bile-metabolizing Bifidobacterium and Blautia species, - is associated with deficient bile acid and tryptophan metabolism in the intestine, marked gastrointestinal dysfunction, as well as impaired social interactions in BTBR mice. Together these data support the concept of targeted manipulation of the gut microbiota for reversing gastrointestinal and behavioral symptomatology in ASD, and offer specific plausible targets in this endeavor.
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http://dx.doi.org/10.1016/j.ebiom.2017.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652137PMC
October 2017

Interactions between gut bacteria and bile in health and disease.

Mol Aspects Med 2017 08 21;56:54-65. Epub 2017 Jun 21.

APC Microbiome Institute, University College Cork, Cork, Ireland; School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.

Bile acids are synthesized from cholesterol in the liver and released into the intestine to aid the digestion of dietary lipids. The host enzymes that contribute to bile acid synthesis in the liver and the regulatory pathways that influence the composition of the total bile acid pool in the host have been well established. In addition, the gut microbiota provides unique contributions to the diversity of bile acids in the bile acid pool. Gut microbial enzymes contribute significantly to bile acid metabolism through deconjugation and dehydroxylation reactions to generate unconjugated bile acids and secondary bile acids. These microbial enzymes (which include bile salt hydrolase (BSH) and bile acid-inducible (BAI) enzymes) are essential for bile acid homeostasis in the host and represent a vital contribution of the gut microbiome to host health. Perturbation of the gut microbiota in disease states may therefore significantly influence bile acid signatures in the host, especially in the context of gastrointestinal or systemic disease. Given that bile acids are ligands for host cell receptors (including the FXR, TGR5 and Vitamin D Receptor) alterations to microbial enzymes and associated changes to bile acid signatures have significant consequences for the host. In this review we examine the contribution of microbial enzymes to the process of bile acid metabolism in the host and discuss the implications for microbe-host signalling in the context of C. difficile infection, inflammatory bowel disease and other disease states.
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http://dx.doi.org/10.1016/j.mam.2017.06.002DOI Listing
August 2017

Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism but Exacerbates Liver Damage in a Piglet Model of Short-Bowel Syndrome.

Cell Mol Gastroenterol Hepatol 2017 Jul 6;4(1):65-74. Epub 2017 Mar 6.

Intestinal Failure and Clinical Nutrition Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.

Background & Aims: Options for the prevention of short-bowel syndrome-associated liver disease (SBS-ALDs) are limited and often ineffective. The farnesoid X receptor (FXR) is a newly emerging pharmaceutical target and FXR agonists have been shown to ameliorate cholestasis and metabolic disorders. The aim of this study was to assess the efficacy of obeticholic acid (OCA) treatment in preventing SBS-ALDs.

Methods: Piglets underwent 75% small-bowel resection (SBS) or sham surgery (sham) and were assigned to either a daily dose of OCA (2.4 mg/kg/day) or were untreated. Clinical measures included weight gain and stool studies. Histologic features were assessed. Ultraperformance liquid chromatography tandem mass spectrometry was used to determine bile acid composition in end point bile and portal serum samples. Gene expression of key FXR targets was assessed in intestinal and hepatic tissues via quantitative polymerase chain reaction.

Results: OCA-treated SBS piglets showed decreased stool fat and altered liver histology when compared with nontreated SBS piglets. OCA prevented SBS-associated taurine depletion, however, further analysis of bile and portal serum samples indicated that OCA did not prevent SBS-associated alterations in bile acid composition. The expression of FXR target genes involved in bile acid transport and synthesis increased within the liver of SBS piglets after OCA administration whereas, paradoxically, intestinal expression of FXR target genes were decreased by OCA administration.

Conclusions: Administration of OCA in SBS reduced fat malabsorption and altered bile acid composition, but did not prevent the development of SBS-ALDs. We postulate that extensive small resection impacts the ability of the remnant intestine to respond to FXR activation.
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http://dx.doi.org/10.1016/j.jcmgh.2017.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439235PMC
July 2017

Draft Genome Sequences of 25 Isolates Associated with Human Clinical Listeriosis in Ireland.

Genome Announc 2017 May 11;5(19). Epub 2017 May 11.

APC Microbiome Institute, University College Cork, Cork, Ireland

is a Gram-positive opportunistic pathogen that is the causative agent of listeriosis. Here, we report the draft genome sequences of 25 strains isolated from patients with clinical listeriosis in the Republic of Ireland between 2013 and 2015.
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http://dx.doi.org/10.1128/genomeA.00184-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427197PMC
May 2017

Disease-Associated Changes in Bile Acid Profiles and Links to Altered Gut Microbiota.

Dig Dis 2017 1;35(3):169-177. Epub 2017 Mar 1.

APC Microbiome Institute, University College Cork, Cork, Ireland.

The gastrointestinal microbiota plays a central role in the host metabolism of bile acids through deconjugation and dehydroxylation reactions, which generate unconjugated free bile acids and secondary bile acids respectively. These microbially generated bile acids are particularly potent signalling molecules that interact with host bile acid receptors (including the farnesoid X receptor, vitamin D receptor and TGR5 receptor) to trigger cellular responses that play essential roles in host lipid metabolism, electrolyte transport and immune regulation. Perturbations of microbial populations in the gut can therefore profoundly alter bile acid profiles in the host to impact upon the digestive and signalling properties of bile acids in the human superorganism. A number of recent studies have clearly demonstrated the occurrence of microbial disturbances allied to alterations in host bile acid profiles that occur across a range of disease states. Intestinal diseases including irritable bowel syndrome, inflammatory bowel disease (IBD), short bowel syndrome and Clostridium difficile infection all exhibit concurrent alterations in the composition of the gut microbiota and changes to host bile acid profiles. Similarly, extraintestinal diseases and syndromes such as asthma and obesity may be linked to aberrant bile acid profiles in the host. Here, we focus upon recent studies that highlight the links between alterations to gut microbial communities and altered bile acid profiles across a range of diseases from asthma to IBD.
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http://dx.doi.org/10.1159/000450907DOI Listing
May 2017

Impact of Gut Microbiota-Mediated Bile Acid Metabolism on the Solubilization Capacity of Bile Salt Micelles and Drug Solubility.

Mol Pharm 2017 04 24;14(4):1251-1263. Epub 2017 Feb 24.

School of Pharmacy, ‡APC Microbiome Institute, §School of Biochemistry & Cell Biology, and ∥School of Microbiology, University College Cork , Cork, Ireland.

In recent years, the gut microbiome has gained increasing appreciation as a determinant of the health status of the human host. Bile salts that are secreted into the intestine may be biotransformed by enzymes produced by the gut bacteria. To date, bile acid research at the host-microbe interface has primarily been directed toward effects on host metabolism. The aim of this work was to investigate the effect of changes in gut microbial bile acid metabolism on the solubilization capacity of bile salt micelles and consequently intraluminal drug solubility. First, the impact of bile acid metabolism, mediated in vivo by the microbial enzymes bile salt hydrolase (BSH) and 7α-dehydroxylase, on drug solubility was assessed by comparing the solubilization capacity of (a) conjugated vs deconjugated and (b) primary vs secondary bile salts. A series of poorly water-soluble drugs (PWSDs) were selected as model solutes on the basis of an increased tendency to associate with bile micelles. Subsequently, PWSD solubility and dissolution was evaluated in conventional biorelevant simulated intestinal fluid containing host-derived bile acids, as well as in media modified to contain microbial bile acid metabolites. The findings suggest that deconjugation of the bile acid steroidal core, as dictated by BSH activity, influences micellar solubilization capacity for some PWSDs; however, these differences appear to be relatively minor. In contrast, the extent of bile acid hydroxylation, regulated by microbial 7α-dehydroxylase, was found to significantly affect the solubilization capacity of bile salt micelles for all nine drugs studied (p < 0.05). Subsequent investigations in biorelevant media containing either the trihydroxy bile salt sodium taurocholate (TCA) or the dihydroxy bile salt sodium taurodeoxycholate (TDCA) revealed altered drug solubility and dissolution. Observed differences in biorelevant media appeared to be both drug- and amphiphile (bile salt/lecithin) concentration-dependent. Our studies herein indicate that bile acid modifications occurring at the host-microbe interface could lead to alterations in the capacity of intestinal bile salt micelles to solubilize drugs, providing impetus to consider the gut microbiota in the drug absorption process. In the clinical setting, disruption of the gut microbial ecosystem, through disease or antibiotic treatment, could transform the bile acid pool with potential implications for drug absorption and bioavailability.
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http://dx.doi.org/10.1021/acs.molpharmaceut.6b01155DOI Listing
April 2017

Unconjugated Bile Acids Influence Expression of Circadian Genes: A Potential Mechanism for Microbe-Host Crosstalk.

PLoS One 2016 1;11(12):e0167319. Epub 2016 Dec 1.

APC Microbiome Institute, University College Cork, Cork, Ireland.

Disruptions to circadian rhythm in mice and humans have been associated with an increased risk of obesity and metabolic syndrome. The gut microbiota is known to be essential for the maintenance of circadian rhythm in the host suggesting a role for microbe-host interactions in the regulation of the peripheral circadian clock. Previous work suggested a role for gut bacterial bile salt hydrolase (BSH) activity in the regulation of host circadian gene expression. Here we demonstrate that unconjugated bile acids, known to be generated through the BSH activity of the gut microbiota, are potentially chronobiological regulators of host circadian gene expression. We utilised a synchronised Caco-2 epithelial colorectal cell model and demonstrated that unconjugated bile acids, but not the equivalent tauro-conjugated bile salts, enhance the expression levels of genes involved in circadian rhythm. In addition oral administration of mice with unconjugated bile acids significantly altered expression levels of circadian clock genes in the ileum and colon as well as the liver with significant changes to expression of hepatic regulators of circadian rhythm (including Dbp) and associated genes (Per2, Per3 and Cry2). The data demonstrate a potential mechanism for microbe-host crosstalk that significantly impacts upon host circadian gene expression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167319PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132238PMC
June 2017

The Impact of the Gut Microbiota on Drug Metabolism and Clinical Outcome.

Yale J Biol Med 2016 09 30;89(3):375-382. Epub 2016 Sep 30.

APC Microbiome Institute, University College Cork, Cork, Ireland; School of Pharmacy, University College Cork, Cork, Ireland.

The significance of the gut microbiota as a determinant of drug pharmacokinetics and accordingly therapeutic response is of increasing importance with the advent of modern medicines characterised by low solubility and/or permeability, or modified-release. These physicochemical properties and release kinetics prolong drug residence times within the gastrointestinal tract, wherein biotransformation by commensal microbes can occur. As the evidence base in support of this supplementary metabolic "organ" expands, novel opportunities to engineer the microbiota for clinical benefit have emerged. This review provides an overview of microbe-mediated alteration of drug pharmacokinetics, with particular emphasis on studies demonstrating proof of concept . Additionally, recent advances in modulating the microbiota to improve clinical response to therapeutics are explored.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045146PMC
September 2016

Draft Genome Sequences of Listeria monocytogenes Serotype 4b Strains 944 and 2993 and Serotype 1/2c Strains 198 and 2932.

Genome Announc 2016 Jun 2;4(3). Epub 2016 Jun 2.

Teagasc Food Research Centre, Moorepark, Fermoy, Co. Cork, Ireland.

Listeria monocytogenes is a foodborne pathogen and the causative agent of listeriosis among humans and animals. The draft genome sequences of L. monocytogenes serotype 4b strains 944 and 2993 and serotype 1/2c strains 198 and 2932 are reported here.
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http://dx.doi.org/10.1128/genomeA.00482-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891646PMC
June 2016

Shedding light on betL*: pPL2-lux mediated real-time analysis of betL* expression in Listeria monocytogenes.

Bioengineered 2016 Apr;7(2):116-9

a Department of Biological Sciences , Cork Institute of Technology , Rossa Avenue, Bishopstown, Cork , Ireland.

We propose a mechanism of action for the betL* mutation which is based on DNA topology. Removing a single thymine residue from the betL σ(A) promoter's -10 and -35 spacer results in a 'twist'-mediated activation of transcription which accounts for the osmotolerance phenotype observed for strains expressing betL*.
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http://dx.doi.org/10.1080/21655979.2016.1171438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879987PMC
April 2016