Publications by authors named "Colin Hill"

434 Publications

The microbiome of deep-sea fish reveals new microbial species and a sparsity of antibiotic resistance genes.

Gut Microbes 2021 Jan-Dec;13(1):1-13

Teagasc Food Research Centre, Fermoy, Ireland.

Adaptation to life in the deep-sea can be dramatic, with fish displaying behaviors and appearances unlike those seen in any other aquatic habitat. However, the extent of which adaptations may have developed at a microbial scale is not as clear. Shotgun metagenomic sequencing of the intestinal microbiome of 32 species of deep-sea fish from across the Atlantic Ocean revealed that many of the associated microbes differ extensively from those previously identified in reference databases. 111 individual metagenome-assembled genomes (MAGs) were constructed representing individual microbial species from the microbiomes of these fish, many of which are potentially novel bacterial taxa and provide a window into the microbial diversity in this underexplored environment. These MAGs also demonstrate how these microbes have adapted to deep-sea life by encoding a greater capacity for several cellular processes such as protein folding and DNA replication that can be inhibited by high pressure. Another intriguing feature was the almost complete lack of genes responsible for acquired resistance to known antibiotics in many of the samples. This highlights that deep-sea fish microbiomes may represent one of few animal-associated microbiomes with little influence from human activity. The ability of the microbes in these samples to bioluminesce is lower than expected given predictions that this trait has an important role in their life cycle at these depths. The study highlights the uniqueness, complexity and adaptation of microbial communities living in one of the largest and harshest environments on Earth.
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http://dx.doi.org/10.1080/19490976.2021.1921924DOI Listing
May 2021

The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics.

Nat Rev Gastroenterol Hepatol 2021 May 4. Epub 2021 May 4.

Instituto de Lactología Industrial (CONICET-UNL), Faculty of Chemical Engineering, National University of Litoral, Santa Fe, Argentina.

In 2019, the International Scientific Association for Probiotics and Prebiotics (ISAPP) convened a panel of experts specializing in nutrition, microbial physiology, gastroenterology, paediatrics, food science and microbiology to review the definition and scope of postbiotics. The term 'postbiotics' is increasingly found in the scientific literature and on commercial products, yet is inconsistently used and lacks a clear definition. The purpose of this panel was to consider the scientific, commercial and regulatory parameters encompassing this emerging term, propose a useful definition and thereby establish a foundation for future developments. The panel defined a postbiotic as a "preparation of inanimate microorganisms and/or their components that confers a health benefit on the host". Effective postbiotics must contain inactivated microbial cells or cell components, with or without metabolites, that contribute to observed health benefits. The panel also discussed existing evidence of health-promoting effects of postbiotics, potential mechanisms of action, levels of evidence required to meet the stated definition, safety and implications for stakeholders. The panel determined that a definition of postbiotics is useful so that scientists, clinical triallists, industry, regulators and consumers have common ground for future activity in this area. A generally accepted definition will hopefully lead to regulatory clarity and promote innovation and the development of new postbiotic products.
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http://dx.doi.org/10.1038/s41575-021-00440-6DOI Listing
May 2021

The Advantages and Challenges of Using Endolysins in a Clinical Setting.

Viruses 2021 04 15;13(4). Epub 2021 Apr 15.

School of Microbiology, University College Cork, T12 YT20 Cork, Ireland.

Antibiotic-resistant pathogens are increasingly more prevalent and problematic. Traditional antibiotics are no longer a viable option for dealing with these multidrug-resistant microbes and so new approaches are needed. Bacteriophage-derived proteins such as endolysins could offer one effective solution. Endolysins are bacteriophage-encoded peptidoglycan hydrolases that act to lyse bacterial cells by targeting their cell's wall, particularly in Gram-positive bacteria due to their naturally exposed peptidoglycan layer. These lytic enzymes have received much interest from the scientific community in recent years for their specificity, mode of action, potential for engineering, and lack of resistance mechanisms. Over the past decade, a renewed interest in endolysin therapy has led to a number of successful applications. Recombinant endolysins have been shown to be effective against prominent pathogens such as MRSA, strains in biofilm formation, and . Endolysins have also been studied in combination with other antimicrobials, giving a synergistic effect. Although endolysin therapy comes with some regulatory and logistical hurdles, the future looks promising, with the emergence of engineered "next-generation" lysins. This review will focus on the likelihood that endolysins will become a viable new antimicrobial therapy and the challenges that may have to be overcome along the way.
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http://dx.doi.org/10.3390/v13040680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071259PMC
April 2021

Nisin variants from Streptococcus and Staphylococcus successfully express in Lactococcus lactis NZ9800.

J Appl Microbiol 2021 Apr 19. Epub 2021 Apr 19.

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

Aims: Increases in antimicrobial resistance has meant that the antimicrobial potential of lantibiotics is now being investigated irrespective of the nature of the producing organism. The aim of this study was to investigate if natural nisin variants produced by non- GRAS strains, such as nisin H, nisin J and nisin P, could be expressed in a well characterized GRAS host.

Methods And Results: This study involved cloning the nisin A promoter and leader sequence fused to either nisin H, nisin J or nisin P structural gene sequences originally produced by Streptococcus hyointestinalis DPC 6484, Staphylococcus capitis APC 2923, and Streptococcus agalactiae DPC 7040, respectively. This resulted in their expression in Lactococcus lactis NZ9800, a genetically modified strain that does not produce nisin A.

Conclusions: Induction of the nisin controlled gene expression system demonstrates that these 3 nisin variants could be acted on by nisin A machinery provided by the host strain.

Significance And Impact Of The Study: Describes the first successful heterologous production of three natural nisin variants by a GRAS strain, and demonstrates how such systems could be harnessed not only for lantibiotic production, but also in the expansion of their structural diversity and development for use as future biotherapeutics.
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http://dx.doi.org/10.1111/jam.15107DOI Listing
April 2021

Pharmaceutical design of a delivery system for the bacteriocin lacticin 3147.

Drug Deliv Transl Res 2021 Apr 19. Epub 2021 Apr 19.

Department of Chemical Sciences, Bernal Institute, University of Limerick, Limerick, Ireland.

Lacticin 3147 is a dual-acting two-peptide bacteriocin which is generally active against Gram-positive bacteria, including Listeria monocytogenes and antimicrobial-resistant bacteria such as Closteroides difficile in the colon. L. monocytogenes infections can cause life-long effects in the elderly and vulnerable and can cause severe complications in pregnant women. C. difficile causes one of the most common healthcare-associated infections and can be fatal in vulnerable groups such as the elderly. Although lacticin 3147 is degraded by intestinal proteases and has poor aqueous solubility, encapsulation of the bacteriocin could enable its use as an antimicrobial for treating these bacterial infections locally in the gastrointestinal tract. Lacticin 3147 displayed activity in aqueous solutions at a range of pH values and in gastric and intestinal fluids. Exposure to trypsin and α-chymotrypsin resulted in complete inactivation, implying that lacticin 3147 should be protected from these enzymes to achieve successful local delivery to the gastrointestinal tract. The amount of lacticin 3147 dissolved, i.e. its solution concentration, in water or buffered solutions at pH 1.6 and 7.4 was low and varied with time but increased and was stabilized in gastrointestinal fluids by the phospholipid and bile salt components present. Thus, the feasibility of a solid lipid nanoparticle (SLN) delivery system for local administration of lacticin 3147 was investigated. Bacteriocin activity was observed after encapsulation and release from a lipid matrix. Moreover, activity was seen after exposure to degrading enzymes. Further optimization of SLN delivery systems could enable the successful pharmaceutical development of active lacticin 3147 as an alternative to traditional antibiotics.
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http://dx.doi.org/10.1007/s13346-021-00984-9DOI Listing
April 2021

Isolation and characterisation of ΦcrAss002, a crAss-like phage from the human gut that infects Bacteroides xylanisolvens.

Microbiome 2021 04 12;9(1):89. Epub 2021 Apr 12.

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

Background: The gut phageome comprises a complex phage community of thousands of individual strains, with a few highly abundant bacteriophages. CrAss-like phages, which infect bacteria of the order Bacteroidales, are the most abundant bacteriophage family in the human gut and make an important contribution to an individual's core virome. Based on metagenomic data, crAss-like phages form a family, with four sub-families and ten candidate genera. To date, only three representatives isolated in pure culture have been reported: ΦcrAss001 and two closely related phages DAC15 and DAC17; all are members of the less abundant candidate genus VI. The persistence at high levels of both crAss-like phage and their Bacteroidales hosts in the human gut has not been explained mechanistically, and this phage-host relationship can only be properly studied with isolated phage-host pairs from as many genera as possible.

Results: Faeces from a healthy donor with high levels of crAss-like phage was used to initiate a faecal fermentation in a chemostat, with selected antibiotics chosen to inhibit rapidly growing bacteria and selectively enrich for Gram-negative Bacteroidales. This had the objective of promoting the simultaneous expansion of crAss-like phages on their native hosts. The levels of seven different crAss-like phages expanded during the fermentation, indicating that their hosts were also present in the fermenter. The enriched supernatant was then tested against individual Bacteroidales strains isolated from the same faecal sample. This resulted in the isolation of a previously uncharacterised crAss-like phage of candidate genus IV of the proposed Alphacrassvirinae sub-family, ΦcrAss002, that infects the gut commensal Bacteroides xylanisolvens. ΦcrAss002 does not form plaques or spots on lawns of sensitive cells, nor does it lyse liquid cultures, even at high titres. In keeping with the co-abundance of phage and host in the human gut, ΦcrAss002 and Bacteroides xylanisolvens can also co-exist at high levels when co-cultured in laboratory media.

Conclusions: We report the isolation and characterisation of ΦcrAss002, the first representative of the proposed Alphacrassvirinae sub-family of crAss-like phages. ΦcrAss002 cannot form plaques or spots on bacterial lawns but can co-exist with its host, Bacteroides xylanisolvens, at very high levels in liquid culture without impacting on bacterial numbers. Video abstract.
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http://dx.doi.org/10.1186/s40168-021-01036-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042965PMC
April 2021

Biases in Viral Metagenomics-Based Detection, Cataloguing and Quantification of Bacteriophage Genomes in Human Faeces, a Review.

Microorganisms 2021 Mar 4;9(3). Epub 2021 Mar 4.

APC Microbiome Ireland and School of Microbiology, University College Cork, T12 YT20 Cork, Ireland.

The human gut is colonised by a vast array of microbes that include bacteria, viruses, fungi, and archaea. While interest in these microbial entities has largely focused on the bacterial constituents, recently the viral component has attracted more attention. Metagenomic advances, compared to classical isolation procedures, have greatly enhanced our understanding of the composition, diversity, and function of viruses in the human microbiome (virome). We highlight that viral extraction methodologies are crucial in terms of identifying and characterising communities of viruses infecting eukaryotes and bacteria. Different viral extraction protocols, including those used in some of the most significant human virome publications to date, have introduced biases affecting their a overall conclusions. It is important that protocol variations should be clearly highlighted across studies, with the ultimate goal of identifying and acknowledging biases associated with different protocols and, perhaps, the generation of an unbiased and standardised method for examining this portion of the human microbiome.
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http://dx.doi.org/10.3390/microorganisms9030524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000950PMC
March 2021

Bio-Engineered Nisin with Increased Anti- and Selectively Reduced Anti- Activity for Treatment of Bovine Mastitis.

Int J Mol Sci 2021 Mar 27;22(7). Epub 2021 Mar 27.

APC Microbiome Ireland, T12 YT20 Cork, Ireland.

Bovine mastitis is a significant economic burden for dairy enterprises, responsible for premature culling, prophylactic and therapeutic antibiotic use, reduced milk production and the withholding (and thus wastage) of milk. There is a desire to identify novel antimicrobials that are expressly directed to veterinary applications, do not require a lengthy milk withholding period and that will not have a negative impact on the growth of lactic acid bacteria involved in downstream dairy fermentations. Nisin is the prototypical lantibiotic, a family of highly modified antimicrobial peptides that exhibit potent antimicrobial activity against many Gram-positive microbes, including human and animal pathogens including species of and . Although not yet utilized in the area of human medicine, nisin is currently applied as the active agent in products designed to prevent bovine mastitis. Over the last decade, we have harnessed bioengineering strategies to boost the specific activity and target spectrum of nisin against several problematic microorganisms. Here, we screen a large bank of engineered nisin derivatives to identify novel derivatives that exhibit improved specific activity against a selection of staphylococci, including mastitis-associated strains, but have unchanged or reduced activity against dairy lactococci. Three such peptides were identified; nisin A M17Q, nisin A T2L and nisin A HTK.
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http://dx.doi.org/10.3390/ijms22073480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036683PMC
March 2021

Probing the "Dark Matter" of the Human Gut Phageome: Culture Assisted Metagenomics Enables Rapid Discovery and Host-Linking for Novel Bacteriophages.

Front Cell Infect Microbiol 2021 15;11:616918. Epub 2021 Mar 15.

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

Recent years have been marked by the growing interest towards virulent and temperate bacteriophage populations inhabiting the human lower gastrointestinal tract - the gut phageome. A number of studies demonstrated high levels of specificity and temporal stability of individual gut phageomes, as well as their specific alterations in disease cohorts, in parallel with changes in the bacteriome. It has been speculated that phages might have an active role in shaping the taxonomic composition and functional properties of the human gut bacteriome. An overwhelming majority of gut bacteriophages, however, remain uncultured, unclassified, and their specific hosts and infection strategies are still unknown. They are often referred to as "the viral dark matter". A possible breakthrough in understanding of the phageome can only become possible when a significant proportion of the "the viral dark matter" is identified and linked to bacterial hosts. Here, we describe a method that enables rapid discovery and host-linking of novel bacteriophages in the gut a combination of serial enrichment cultures and shotgun metagenomics of viral DNA. Using this approach dozens of novel and previously known bacteriophages were detected, including the ones infecting difficult-to-culture anaerobic bacteria. The majority of phages failed to produce lysis and propagate on host cultures in traditional assays. The newly identified phages include representatives of , , , and crAss-like viruses, infecting diverse bacterial taxa of Bacteroidetes, Firmicutes, Actinobacteria, Verrucomicrobia and Proteobacteria phyla. The proposed new method has a potential for high-throughput screening applications for mass discovery of new phages in different environments.
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http://dx.doi.org/10.3389/fcimb.2021.616918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005731PMC
March 2021

Fiducial-based image-guided SBRT for pancreatic adenocarcinoma: Does inter-and intra-fraction treatment variation warrant adaptive therapy?

Radiat Oncol 2021 Mar 19;16(1):53. Epub 2021 Mar 19.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, 401 N. Broadway, Suite 1440, Baltimore, MD, 21231, USA.

Purpose: Variation in target positioning represents a challenge to set-up reproducibility and reliability of dose delivery with stereotactic body radiation therapy (SBRT) for pancreatic adenocarcinoma (PDAC). While on-board imaging for fiducial matching allows for daily shifts to optimize target positioning, the magnitude of the shift as a result of inter- and intra-fraction variation may directly impact target coverage and dose to organs-at-risk. Herein, we characterize the variation patterns for PDAC patients treated at a high-volume institution with SBRT.

Methods: We reviewed 30 consecutive patients who received SBRT using active breathing coordination (ABC). Patients were aligned to bone and then subsequently shifted to fiducials. Inter-fraction and intra-fraction scans were reviewed to quantify the mean and maximum shift along each axis, and the shift magnitude. A linear regression model was conducted to investigate the relationship between the inter- and intra-fraction shifts.

Results: The mean inter-fraction shift in the LR, AP, and SI axes was 3.1 ± 1.8 mm, 2.9 ± 1.7 mm, and 3.5 ± 2.2 mm, respectively, and the mean vector shift was 6.4 ± 2.3 mm. The mean intra-fraction shift in the LR, AP, and SI directions were 2.0 ± 0.9 mm, 2.0 ± 1.3 mm, and 2.3 ± 1.4 mm, respectively, and the mean vector shift was 4.3 ± 1.8 mm. A linear regression model showed a significant relationship between the inter- and intra-fraction shift in the AP and SI axis and the shift magnitude.

Conclusions: Clinically significant inter- and intra-fraction variation occurs during treatment of PDAC with SBRT even with a comprehensive motion management strategy that utilizes ABC. Future studies to investigate how these variations could lead to variation in the dose to the target and OAR should be investigated. Strategies to mitigate the dosimetric impact, including real time imaging and adaptive therapy, in select cases should be considered.
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http://dx.doi.org/10.1186/s13014-021-01782-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980583PMC
March 2021

Geometric Reproducibility of Fiducial Markers and Efficacy of a Patient-Specific Margin Design Using Deep Inspiration Breath Hold for Stereotactic Body Radiation Therapy for Pancreatic Cancer.

Adv Radiat Oncol 2021 Mar-Apr;6(2):100655. Epub 2021 Jan 22.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University of School of Medicine, Baltimore, Maryland.

Purpose: In patients undergoing stereotactic body radiation therapy (SBRT) for pancreatic adenocarcinoma, the reproducibility of tumor positioning between deep-inspiration breath holds is unclear. We characterized this variation with fiducials at simulation and treatment and investigated whether a patient-specific breath-hold (PSBH) margin would help account for intrafraction variation at treatment.

Methods And Materials: We analyzed 20 consecutive patients with pancreatic cancer who underwent SBRT with deep-inspiration breath holds. At simulation, 3 additional breath-hold scans were acquired immediately after the contrast-enhanced planning computed tomography (CT) scan and used to quantify the mean and maximum variations in the simulation fiducial position ( and ), as well as to design the internal target volume (ITV) incorporating a PSBH margin.

Results: At treatment, a mean of 5 breath-hold cone beam CT (CBCT) scans were acquired per fraction for each patient to quantify the mean and maximum variations in the treatment fiducial position ( and ). Various planning target volume (PTV) margins on the gross tumor volume (GTV) versus ITV were evaluated using CBCT scans, with the goal of >95% of fiducials being covered at treatment. The and were 0.9 ± 0.5 mm and 1.5 ± 0.8 mm in the left-right (LR) direction, 0.9 ± 0.4 mm and 1.4 ± 0.4 mm in the anteroposterior (AP) direction, and 1.5 ± 0.9 mm and 2.1 ± 1.0 mm in the superoinferior (SI) direction, respectively. The and were 1.2 ± 0.4 mm and 2.0 ± 0.7 mm in the LR direction, 1.1 ± 0.4 mm and 1.8 ± 0.6 mm in the AP direction, and 1.9 ± 1.0 mm and 3.1 ± 1.4 mm in the SI direction, respectively. The ITV was increased by 21.0% ± 8.6% compared with the GTV alone. The PTV margin necessary to encompass >95% of the fiducial locations was 2 mm versus 4 mm in both LR and AP and 4 mm versus 6 mm in SI for the ITV and the GTV, respectively.

Conclusions: The interbreath-hold variation is not insignificant, especially in the SI direction. Acquiring multiple breath-hold CT scans at simulation can help quantify the reproducibility of the interbreath hold and design a PSBH margin for treatment.
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http://dx.doi.org/10.1016/j.adro.2021.100655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940819PMC
January 2021

Microbiome-based environmental monitoring of a dairy processing facility highlights the challenges associated with low microbial-load samples.

NPJ Sci Food 2021 Feb 15;5(1). Epub 2021 Feb 15.

Food Bioscience Department, Teagasc Food Research Centre, Cork, Ireland.

Efficient and accurate identification of microorganisms throughout the food chain can potentially allow the identification of sources of contamination and the timely implementation of control measures. High throughput DNA sequencing represents a potential means through which microbial monitoring can be enhanced. While Illumina sequencing platforms are most typically used, newer portable platforms, such as the Oxford Nanopore Technologies (ONT) MinION, offer the potential for rapid analysis of food chain microbiomes. Initial assessment of the ability of rapid MinION-based sequencing to identify microbes within a simple mock metagenomic mixture is performed. Subsequently, we compare the performance of both ONT and Illumina sequencing for environmental monitoring of an active food processing facility. Overall, ONT MinION sequencing provides accurate classification to species level, comparable to Illumina-derived outputs. However, while the MinION-based approach provides a means of easy library preparations and portability, the high concentrations of DNA needed is a limiting factor.
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http://dx.doi.org/10.1038/s41538-021-00087-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884712PMC
February 2021

Influence of Game Design, Physical Demands, and Skill Involvement on the Subjective Task Load Associated With Various Small-Sided Games Among Elite Junior Rugby League Players.

Int J Sports Physiol Perform 2021 Feb 14:1-9. Epub 2021 Feb 14.

Purpose: To determine if small-sided games (SSGs) could be designed to target specific task loads using the National Aeronautics and Space Administration task load index as well as reporting the influence of the physical and technical demands.

Methods: Using a within-session, repeated-measures design, 26 junior rugby league players completed 5 SSGs focused on physical, technical, temporal, cognitive, and frustration task loads. National Aeronautics and Space Administration task load index responses were evaluated after each game; the physical demands were recorded using microtechnology; and skill involvement recorded using video analysis.

Results: In each SSG, the task load emphasized (eg, physical load/physical game) emerged with a higher score than the other loads and SSGs. The physical demands were lowest during the physical game (effect size = -3.11 to 3.50) and elicited greater defensive involvements (effect size = 0.12 to 3.19). The highest physical demands and attacking involvements were observed during the temporal game. Lower intensity activities were generally negatively associated with physical, performance, temporal, and total load (η2 = -.07 to -.43) but positively associated with technical, effort, cognitive, and frustration (η2 = .01 to .33). Distance covered in total and at higher speeds was positively associated with physical, effort, performance, total load (η2 = .18 to .65), and negatively associated with technical, frustration, and cognitive load (η2 = -.10 to -.36). Attacking and defensive involvements generally increased the respective task loads (η2 = .03 to .41).

Conclusion: Coaches and sport scientists can design SSGs specifically targeted at subjective task loads in a sport-specific manner and through manipulation of the physical and technical demands.
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http://dx.doi.org/10.1123/ijspp.2020-0257DOI Listing
February 2021

A postbiotic consisting of heat-treated lactobacilli has a bifidogenic effect in pure culture and in human fermented faecal communities.

Appl Environ Microbiol 2021 Feb 12. Epub 2021 Feb 12.

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

The gut microbiota has a significant impact on host health. Dietary interventions using probiotics, prebiotics and postbiotics have the potential to alter microbiota composition and function. Other therapeutic interventions such as antibiotics and faecal microbiota transplantation have also been shown to significantly alter the microbiota and its metabolites. Supplementation of a faecal fermentation model of the human gut with a postbiotic product Lactobacillus LB led to changes in microbiome composition (i.e. increase in beneficial bifidobacteria) and associated metabolic changes (i.e. increased acid production). Lactobacillus LB is a heat-treated preparation of cellular biomass and a fermentate generated by CNCM MA65/4E-1b (formerly known as CNCM MA65/4E-1b) and ssp. CNCM MA65/4E-2z, medically relevant strains used to produce antidiarrheal preparations. In pure culture, Lactobacillus LB also stimulates the growth of a range of bifidobacterial species and strains. Lactobacillus LB-like preparations generated using other including commercially available probiotic bacteria, did not have the same impact on a model strain ( subsp. ATCC 15697). This bifidogenic activity is heat- and enzyme-stable and cannot be attributed to lactose, which is a major constituent of Lactobacillus LB. CNCM MA65/4E-1b is largely responsible for the observed activity and there is a clear role for compounds smaller than 1 kDa. In general, disruptions to the gut microbiota are associated with multiple disorders in humans. The presence of high levels of spp. in the human gut is commonly considered to be beneficial. Bifidobacteria can be supplemented in the diet (as probiotics) or those bifidobacteria already present in the gut can be stimulated by the consumption of prebiotics such as inulin. We demonstrate that Lactobacillus LB (a product consisting of two heat-killed lactic acid bacteria and their metabolites) can stimulate the growth of bifidobacteria in human fermented faecal communities and in pure culture. Given the heat-treatment applied during the production process, there is no risk of the lactic acid bacteria colonising (or causing bacteraemia) in vulnerable consumers (infants, immunocompromised, etc). Lactobacillus LB has the potential to affect human health by selectively promoting the growth of beneficial bacteria.
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http://dx.doi.org/10.1128/AEM.02459-20DOI Listing
February 2021

A Place for Viruses on the Tree of Life.

Front Microbiol 2020 14;11:604048. Epub 2021 Jan 14.

APC Microbiome Ireland, College of Medicine and Health, University College Cork, Cork, Ireland.

Viruses are ubiquitous. They infect almost every species and are probably the most abundant biological entities on the planet, yet they are excluded from the Tree of Life (ToL). However, there can be no doubt that viruses play a significant role in evolution, the force that facilitates all life on Earth. Conceptually, viruses are regarded by many as non-living entities that hijack living cells in order to propagate. A strict separation between living and non-living entities places viruses far from the ToL, but this may be theoretically unsound. Advances in sequencing technology and comparative genomics have expanded our understanding of the evolutionary relationships between viruses and cellular organisms. Genomic and metagenomic data have revealed that co-evolution between viral and cellular genomes involves frequent horizontal gene transfer and the occasional co-option of novel functions over evolutionary time. From the giant, ameba-infecting marine viruses to the tiny Porcine circovirus harboring only two genes, viruses and their cellular hosts are ecologically and evolutionarily intertwined. When deciding how, if, and where viruses should be placed on the ToL, we should remember that the Tree functions best as a model of biological evolution on Earth, and it is important that models themselves evolve with our increasing understanding of biological systems.
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http://dx.doi.org/10.3389/fmicb.2020.604048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840587PMC
January 2021

The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on fermented foods.

Nat Rev Gastroenterol Hepatol 2021 03 4;18(3):196-208. Epub 2021 Jan 4.

Department of Food Science and Technology, University of Nebraska - Lincoln, Lincoln, NE, USA.

An expert panel was convened in September 2019 by The International Scientific Association for Probiotics and Prebiotics (ISAPP) to develop a definition for fermented foods and to describe their role in the human diet. Although these foods have been consumed for thousands of years, they are receiving increased attention among biologists, nutritionists, technologists, clinicians and consumers. Despite this interest, inconsistencies related to the use of the term 'fermented' led the panel to define fermented foods and beverages as "foods made through desired microbial growth and enzymatic conversions of food components". This definition, encompassing the many varieties of fermented foods, is intended to clarify what is (and is not) a fermented food. The distinction between fermented foods and probiotics is further clarified. The panel also addressed the current state of knowledge on the safety, risks and health benefits, including an assessment of the nutritional attributes and a mechanistic rationale for how fermented foods could improve gastrointestinal and general health. The latest advancements in our understanding of the microbial ecology and systems biology of these foods were discussed. Finally, the panel reviewed how fermented foods are regulated and discussed efforts to include them as a separate category in national dietary guidelines.
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http://dx.doi.org/10.1038/s41575-020-00390-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925329PMC
March 2021

Assessing the ability of nisin A and derivatives thereof to inhibit gram-negative bacteria from the genus Thermus.

J Dairy Sci 2021 Mar 25;104(3):2632-2640. Epub 2020 Dec 25.

Teagasc Food Research Centre, Moorepark, Fermoy, Co. Cork, Ireland P61 C996; APC Microbiome Ireland, Cork, Ireland T12 YT20. Electronic address:

Nisin is a bacteriocin that is globally employed as a biopreservative in food systems to control gram-positive, and some gram-negative, bacteria. Here we tested the bioactivity of nisin A-producing Lactococcus lactis NZ9700 and producers of bioengineered variants thereof against representatives of the gram-negative genus Thermus, which has been associated with the pink discoloration defect in cheese. Starting with a total of 73 nisin variant-producing Lactococcus lactis, bioactivity against Thermus was assessed via agar diffusion assays, and 22 variants were found to have bioactivity greater than or equal to that of the nisin A-producing control. To determine to what extent this enhanced bioactivity was attributable to an increase in specific activity, minimum inhibitory concentrations were determined using the corresponding purified form of these 22 nisin A derivatives. From these experiments, nisin M17Q and M21F were identified as peptides with enhanced antimicrobial activity against the majority of Thermus target strains tested. In addition, several other peptide variants were found to exhibit enhanced specific activity against a subset of strains.
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http://dx.doi.org/10.3168/jds.2020-19350DOI Listing
March 2021

A New Phage Lysin Isolated from the Oral Microbiome Targeting .

Pharmaceuticals (Basel) 2020 Dec 19;13(12). Epub 2020 Dec 19.

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

is highly pathogenic and causes several mucosal and invasive infections. Due to the rising number of multidrug-resistant (MDR) strains of , new antimicrobials with alternative mechanisms of action are urgently needed. In this study, we identified two new Streptococcal phages from the oral microbiome, 23TH and SA01. Their lysins, 23TH_48 and SA01_53, were recombinantly expressed, characterized and tested for their lethality. SA01_53 was found to only lyse its host strain of , while 23TH_48 was found to possess a broader lytic activity beyond its host strain of , with several isolates sensitive to its lytic activity. 23TH_48 at a concentration of five activity units per mL (U/mL) was found to reduce cell counts of DSM 24048 by 4 log colony forming units per mL (CFU/mL) within 1 h and effectively prevented and destroyed biofilms of R6 at concentrations of 228.8 ng/µL and 14.3 ng/µL, respectively. Given its high lytic activity, 23TH_48 could prove to be a promising candidate to help combat pneumococcal infections.
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http://dx.doi.org/10.3390/ph13120478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767030PMC
December 2020

Building a Resilient, Sustainable, and Healthier Food Supply Through Innovation and Technology.

Annu Rev Food Sci Technol 2021 03 21;12:1-28. Epub 2020 Dec 21.

Department of Nutrition and Food Science, University of Maryland, College Park, Maryland 20742, USA.

The modern food supply faces many challenges. The global population continues to grow and people are becoming wealthier, so the food production system must respond by creating enough high-quality food to feed everyone with minimal damage to our environment. The number of people suffering or dying from diet-related chronic diseases, such as obesity, diabetes, heart disease, stroke, and cancer, continues to rise, which is partly linked to overconsumption of highly processed foods, especially high-calorie or rapidly digestible foods. After falling for many years, the number of people suffering from starvation or malnutrition is rising, and thishas been exacerbated by the global COVID-19 pandemic. The highly integrated food supply chains that spread around the world are susceptible to disruptions due to policy changes, economic stresses, and natural disasters, as highlighted by the recent pandemic. In this perspective article, written by members of the Editorial Committee of the , we highlight some of the major challenges confronting the modern food supply chain as well as how innovations in policy and technology can be used to address them. Pertinent technological innovations include robotics, machine learning, artificial intelligence, advanced diagnostics, nanotechnology, biotechnology, gene editing, vertical farming, and soft matter physics. Many of these technologies are already being employed across the food chain by farmers, distributors, manufacturers, and consumers to improve the quality, nutrition, safety, and sustainability of the food supply. These innovations are required to stimulate the development and implementation of new technologies to ensure a more equitable, resilient, and efficient food production system. Where appropriate, these technologies should be carefully tested before widespread implementation so that proper risk-benefit analyses can be carried out. They can then be employed without causing unforeseen adverse consequences. Finally, it is important to actively engage all stakeholders involved in the food supply chain throughout the development and testing of these new technologies to support their adoption if proven safe and effective.
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http://dx.doi.org/10.1146/annurev-food-092220-030824DOI Listing
March 2021

Poles Apart: Where and How Cells Construct Nisin.

Authors:
Colin Hill

mBio 2020 12 15;11(6). Epub 2020 Dec 15.

APC Microbiome Ireland and School of Microbiology, University College Cork, Cork, Ireland

Nisin is a 34-amino-acid lantibiotic that has been used commercially for almost a century as a food preservative. In order to produce active nisin, requires an 11-gene operon that encodes proteins involved in modification, processing, transport, immunity, and regulation. While the role of each of the 11 proteins is well understood, the location and spatial organization of the biosynthetic machinery that involves NisA, NisB, NisC, NisT, and NisP remain to be determined. In this elegant paper (J. Chen, A. J. van Heel, and O. P. Kuipers, mBio 11:e02825-20, 2020, https://doi.org/10.1128/mBio.02825-20), we learn that a NisB dimer is recruited to the "old" pole of a dividing cell, where it assembles with NisC to form a modification complex that can engage with NisA. Unexpectedly, the NisT transporter does not stably assemble into this complex but is distributed around the membrane until it engages with the NisABC complex to transport NisA across the membrane, whereupon it dissociates from NisBC.
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http://dx.doi.org/10.1128/mBio.02991-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773994PMC
December 2020

Gut Colonization Mechanisms of and : An Argument for Personalized Designs.

Annu Rev Food Sci Technol 2021 03 14;12:213-233. Epub 2020 Dec 14.

School of Microbiology and APC Microbiome Institute, University College Cork, Cork T12 YN60, Ireland; email:

and spp. are best understood for their applications as probiotics, which are often transient, but as commensals it is probable that stable colonization in the gut is important for their beneficial roles. Recent research suggests that the establishment and persistence of strains of and in the gut are species- and strain-specific and affected by natural history, genomic adaptability, and metabolic interactions of the bacteria and the microbiome and immune aspects of the host but also regulated by diet. This provides new perspectives on the underlying molecular mechanisms. With an emphasis on host-microbe interaction, this review outlines how the characteristics of individual and bacteria, the host genotype and microbiome structure,diet, and host-microbe coadaptation during bacterial gut transition determine and influence the colonization process. The diet-tuned and personally tailored colonization can be achieved via a machine learning prediction model proposed here.
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http://dx.doi.org/10.1146/annurev-food-061120-014739DOI Listing
March 2021

Inhibition of Listeria monocytogenes by the Staphylococcus capitis - derived bacteriocin capidermicin.

Food Microbiol 2021 Apr 10;94:103661. Epub 2020 Oct 10.

Department of Biological Sciences, Cork Institute of Technology, Cork, Ireland; APC Microbiome Ireland, University College Cork, Ireland. Electronic address:

Natural methods to control food pathogens are required and bacteriocins have received much interest in this regard. The aim of this study was to investigate the ability of the novel bacteriocin capidermicin to inhibit Listeria monocytogenes. Agar-based deferred antagonism assays were carried out with the capidermicin producer against 17 L. monocytogenes strains and large zones of inhibition were observed for 12 strains. Minimal inhibitory concentration assays performed with purified capidermicin peptide revealed MIC values between 680 nM and 11 μM. Biofilm assays were performed with five L. monocytogenes strains. Addition of capidermicin prevented biofilm formation by one strain and could remove pre-established biofilms of all five strains. Broth based growth experiments demonstrated that addition of capidermicin resulted in an extended lag phase of both L. monocytogenes strains tested. Kill-curve experiments showed that capidermicin was able to potentiate the anti-Listeria effects of the lantibiotic nisin. This enhanced killing by the combination of both peptides was also observed in model food systems (cottage cheese and chocolate milk). In summary, we show that capidermicin can inhibit L. monocytogenes and warrants further investigation as a potential natural agent for the control of this pathogen.
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http://dx.doi.org/10.1016/j.fm.2020.103661DOI Listing
April 2021

Should There Be a Recommended Daily Intake of Microbes?

J Nutr 2020 12;150(12):3061-3067

International Scientific Association for Probiotics and Prebiotics, Centennial, CO, USA.

The collective findings from human microbiome research, randomized controlled trials on specific microbes (i.e., probiotics), and associative studies of fermented dairy consumption provide evidence for the beneficial effects of the regular consumption of safe live microbes. To test the hypothesis that the inclusion of safe, live microbes in the diet supports and improves health, we propose assessment of the types and evidentiary quality of the data available on microbe intake, including the assembly and evaluation of evidence available from dietary databases. Such an analysis would help to identify gaps in the evidence needed to test this hypothesis, which can then be used to formulate and direct initiatives focused on prospective and randomized controlled trials on live microbe consumption. Outcomes will establish whether or not the evidence exists, or can be generated, to support the establishment of dietary recommendations for live microbes.
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http://dx.doi.org/10.1093/jn/nxaa323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726123PMC
December 2020

Autochthonous faecal viral transfer (FVT) impacts the murine microbiome after antibiotic perturbation.

BMC Biol 2020 11 20;18(1):173. Epub 2020 Nov 20.

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

Background: It has become increasingly accepted that establishing and maintaining a complex and diverse gut microbiota is fundamental to human health. There are growing efforts to identify means of modulating and influencing the microbiota, especially in individuals who have experienced a disruption in their native microbiota. Faecal microbiota transplantation (FMT) is one method that restores diversity to the microbiota of an individual by introducing microbes from a healthy donor. FMT introduces the total microbial load into the recipient, including the bacteria, archaea, yeasts, protists and viruses. In this study, we investigated whether an autochthonous faecal viral transfer (FVT), in the form of a sterile faecal filtrate, could impact the recovery of a bacteriome disrupted by antibiotic treatment.

Results: Following antibiotic disruption of the bacteriome, test mice received an FVT harvested prior to antibiotic treatment, while control mice received a heat- and nuclease-treated FVT. In both groups of mice, the perturbed microbiome reverted over time to one more similar to the pre-treatment one. However, the bacteriomes of mice that received an FVT, in which bacteriophages predominate, separated from those of the control mice as determined by principal co-ordinate analysis (PCoA). Moreover, analysis of the differentially abundant taxa indicated a closer resemblance to the pre-treatment bacteriome in the test mice that had received an FVT. Similarly, metagenomic sequencing of the virome confirmed that faecal bacteriophages of FVT and control mice differed over time in both abundance and diversity, with the phages constituting the FVT persisting in mice that received them.

Conclusions: An autochthonous virome transfer reshaped the bacteriomes of mice post-antibiotic treatment such that they more closely resembled the pre-antibiotic microbiota profile compared to mice that received non-viable phages. Thus, FVT may have a role in addressing antibiotic-associated microbiota alterations and potentially prevent the establishment of post-antibiotic infection. Given that bacteriophages are biologically inert in the absence of their host bacteria, they could form a safe and effective alternative to whole microbiota transplants that could be delivered during/following perturbation of the gut flora.
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http://dx.doi.org/10.1186/s12915-020-00906-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679995PMC
November 2020

Patient-Reported Outcome Measures and Dosimetric Correlates for Early Detection of Acute Radiation Therapy-Related Esophagitis.

Pract Radiat Oncol 2021 May-Jun;11(3):185-192. Epub 2020 Oct 31.

Department of Medicine, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.

Background: We investigate the time to and clinical factors associated with patient-reported difficulty swallowing in lung cancer patients treated with radiation therapy (RT).

Methods: Between October 2016 and October 2019, lung cancer patients treated with conventionally fractionated RT at a tertiary cancer center were identified. Weekly, patients reported difficulty swallowing (patient-reported outcome version of the Common Terminology Criteria for Adverse Events [PRO-CTCAE] v.1: 0-none, 1-mild, 2-moderate, 3-severe, 4-very severe). Physicians graded dysphagia (CTCAE v.4: 0-none, 1-symptoms without altered intake, 2-symptomatic; altered eating/swallowing, 3-severely altered eating/swallowing, 4-life-threatening consequences, 5-death). Tumor-related difficulty swallowing was not recorded at baseline; thus, patients reporting ≥moderate symptoms ≤7 days of RT start were excluded. We evaluated the time to new patient reports of ≥moderate difficulty swallowing and CTCAE grade 2+ dysphagia and development over time using the cumulative incidence method. Multivariable logistic regression evaluated associations between clinical factors, esophageal V60, and development of esophageal symptoms.

Results: Of the 200 patients identified: median age was 69 years, 52% were male, and 89% had stage III+ disease. Patients received a median of 63 Gy with chemotherapy (91.5%). At least moderate difficulty swallowing during RT was reported by 76 of 200 patients (38%); clinicians rated dysphagia as altering oral intake or worse for 26 of 200 (13%). Median time to first report of symptoms was 21 days (interquartile ratio [IQR], 18-34.5) for the 76 patients who reported ≥moderate symptoms and 33 days (IQR, 24-42) in the 26 patients whose provider reported grade 2+ dysphagia. The 30-day incidence of patient-reported ≥moderate swallowing difficulty and provider grade 2+ dysphagia was 26% (95% CI: 20%-32%) and 6% (95% CI: 3%-9%), respectively. Esophageal V60 >7 % was the clinical factor most associated with patient-reported ≥moderate esophageal symptoms (odds ratio 6.1, 95% CI: 3.0-12.3).

Conclusions: Patients report at least moderate difficulty swallowing more often and earlier than providers report grade 2+ dysphagia. Esophageal V60 ≥7% was most associated with development of moderate severity or worse patient-reported swallowing difficulty.
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http://dx.doi.org/10.1016/j.prro.2020.10.009DOI Listing
October 2020

Shining Light on Human Gut Bacteriophages.

Front Cell Infect Microbiol 2020 10;10:481. Epub 2020 Sep 10.

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

The human gut is a complex environment that contains a multitude of microorganisms that are collectively termed the microbiome. Multiple factors have a role to play in driving the composition of human gut bacterial communities either toward homeostasis or the instability that is associated with many disease states. One of the most important forces are likely to be bacteriophages, bacteria-infecting viruses that constitute by far the largest portion of the human gut virome. Despite this, bacteriophages (phages) are the one of the least studied residents of the gut. This is largely due to the challenges associated with studying these difficult to culture entities. Modern high throughput sequencing technologies have played an important role in improving our understanding of the human gut phageome but much of the generated sequencing data remains uncharacterised. Overcoming this requires database-independent bioinformatic pipelines and even those phages that are successfully characterized only provide limited insight into their associated biological properties, and thus most viral sequences have been characterized as "viral dark matter." Fundamental to understanding the role of phages in shaping the human gut microbiome, and in turn perhaps influencing human health, is how they interact with their bacterial hosts. An essential aspect is the isolation of novel phage-bacteria host pairs by direct isolation through various screening methods, which can transform phages into a biological reality. However, this is also beset with multiple challenges including culturing difficulties and the use of traditional methods, such as plaquing, which may bias which phage-host pairs that can be successfully isolated. Phage-bacteria interactions may be influenced by many aspects of complex human gut biology which can be difficult to reproduce under laboratory conditions. Here we discuss some of the main findings associated with the human gut phageome to date including composition, our understanding of phage-host interactions, particularly the observed persistence of virulent phages and their hosts, as well as factors that may influence these highly intricate relationships. We also discuss current methodologies and bottlenecks hindering progression in this field and identify potential steps that may be useful in overcoming these hurdles.
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http://dx.doi.org/10.3389/fcimb.2020.00481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511551PMC
September 2020

Bacteriophage endolysins as a potential weapon to combat infection.

Gut Microbes 2020 11;12(1):1813533

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

is the leading cause of health-care-associated infection throughout the developed world and contributes significantly to patient morbidity and mortality. Typically, antibiotics are used for the primary treatment of infections (CDIs), but they are not universally effective for all ribotypes and can result in antibiotic resistance and recurrent infection, while also disrupting the microbiota. Novel targeted therapeutics are urgently needed to combat CDI. Bacteriophage-derived endolysins are required to disrupt the bacterial cell wall of their target bacteria and are possible alternatives to antibiotics. These lytic proteins could potentially replace or augment antibiotics in CDI treatment. We discuss candidate therapeutic lysins derived from phages/prophages of and their potential as antimicrobials against CDI. Additionally, we review the antibacterial potential of some recently identified homologues of endolysins. Finally, the challenges of endolysins are considered with respect to the development of novel lysin-based therapies.
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http://dx.doi.org/10.1080/19490976.2020.1813533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524323PMC
November 2020

Generation of Nonpolar Deletion Mutants in Listeria monocytogenes Using the "SOEing" Method.

Methods Mol Biol 2021 ;2220:165-175

Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.

The ability to manipulate chromosomally encoded genes is a fundamental biological tool for the analysis of gene function. Here, we provide in greater depth a protocol for the creation of nonpolar unlabelled gene deletions in Listeria monocytogenes that are facilitated by the splicing overlap extension PCR technique. For mutagenesis in L. monocytogenes, we describe the pKSV7 plasmid-based approach, which facilitates the introduction of a spliced amplicon in place of the corresponding segment of chromosomal DNA.
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http://dx.doi.org/10.1007/978-1-0716-0982-8_13DOI Listing
April 2021

New developments in RiPP discovery, enzymology and engineering.

Nat Prod Rep 2021 01 16;38(1):130-239. Epub 2020 Sep 16.

Department of Microbiology, University of Granada, Spain.

Covering: up to June 2020Ribosomally-synthesized and post-translationally modified peptides (RiPPs) are a large group of natural products. A community-driven review in 2013 described the emerging commonalities in the biosynthesis of RiPPs and the opportunities they offered for bioengineering and genome mining. Since then, the field has seen tremendous advances in understanding of the mechanisms by which nature assembles these compounds, in engineering their biosynthetic machinery for a wide range of applications, and in the discovery of entirely new RiPP families using bioinformatic tools developed specifically for this compound class. The First International Conference on RiPPs was held in 2019, and the meeting participants assembled the current review describing new developments since 2013. The review discusses the new classes of RiPPs that have been discovered, the advances in our understanding of the installation of both primary and secondary post-translational modifications, and the mechanisms by which the enzymes recognize the leader peptides in their substrates. In addition, genome mining tools used for RiPP discovery are discussed as well as various strategies for RiPP engineering. An outlook section presents directions for future research.
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http://dx.doi.org/10.1039/d0np00027bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864896PMC
January 2021

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