Oral Phage Research Articles

The salivary virome during childhood dental caries.

While many studies have examined the bacterial taxa associated with dental caries, the most common chronic infectious disease globally, little is known about the caries-associated virome. In this study, the salivary viromes of 21 children with severe caries (>2 dentin lesions) and 23 children with healthy dentition were examined. 2,485 viral metagenome-assembled genomes (vMAGs) were identified, binned, and quantified from the metagenomic assemblies. These vMAGs were mostly phage, and represented 1,547 unique species-level vOTUs, 247 of which appear to be novel. The metagenomes were also queried for all 3,835 unique species-level vOTUs of DNA viruses with a human host on NCBI Virus, however all but Human betaherpesvirus 7 were at very low abundance in the saliva. The oral viromes of the children with caries exhibited significantly different beta diversity compared to the oral virome of the children with healthy dentition; several vOTUs predicted to infect Pauljensenia and Neisseria were strongly correlated with health, and two vOTUs predicted to infect Saccharibacteria and Prevotella histicola, respectively, were correlated with caries. Co-occurrence analysis indicated that phage typically co-occurred with both their predicted hosts and with bacteria that were themselves associated with the same disease status. Overall, this study provided the sequences of 53 complete or nearly complete novel oral phages and illustrated the significance of the oral virome in the context of dental caries, which has been largely overlooked. This work represents an important step towards the identification and study of phage therapy candidates which treat or prevent caries pathogenesis.

Dynamics of changes in the microflora of the oral fluid after the removal of lower wisdom teeth against the background of antibiotic therapy and phage therapy

The purpose of our study was to study the effectiveness of the drug «Sextafag» as a therapeutic and prophylactic agent after the removal of impacted lower third molars.Recently, there has been a large number of patients with antibiotic resistance, so it is to find an alternative to traditional antibiotic therapy. This article examines the qualitative and quantitative composition of the oral microbiota after removal of impacted lower wisdom teeth. We studied the dynamics of changes in microflora during antibacterial treatment and phage therapy. The data obtained confirm the clinical and bacteriological effectiveness of oral phage therapy for inflammatory diseases in dental practice and can serve as the basis for the development of a new algorithm for the use of bacteriophages in the treatment of purulent-inflammatory diseases of the oral cavity.

The Microbiome and Acne: Perspectives for Treatment.

The skin microbiome consists of the microorganisms populating the human skin. Cutibacterium acnes (C.acnes, formerly named Propionibacterium acnes) is recognized as a key factor in acne development, regulating inflammatory and immune pathways. Dysbiosis has been described as the imbalance in skin microbiome homeostasis and may play a role in acne pathogenesis. Microbial interference has been shown to be a contributor to healthy skin homeostasis and staphylococcal strains may exclude acne-associated C.acnes phylotypes. In this review we present an update on the skin microbiome in acne and discuss how current acne treatments such as benzoyl peroxide, orally administered isotretinoin, and antibiotics may affect the skin microbiome homeostasis. We highlight the collateral damage of acne antibiotics on the skin microbiome, including the risk of antimicrobial resistance and the dysregulation of the microbiome equilibrium that may occur even with short-term antibiotic courses. Consequently, the interest is shifting towards new non-antibiotic pharmacological acne treatments. Orally administered spironolactone is an emerging off-label treatment for adult female patients and topical peroxisome proliferator-activated receptor gamma (PPARγ) modulation is being studied for patients with acne. The potential application of topical or oral probiotics, bacteriotherapy, and phage therapy for acne are further promising areas of future research.

Oral phages prophylaxis against mixed Escherichia coli O157:H7 and Salmonella Typhimurium infections in weaned piglets

Escherichia coli and Salmonella Typhimurium are the main pathogens of diarrhea in weaned piglets. The prevention of bacterial diarrhea in weaned piglets by phage is rarely reported. We conducted this study to evaluate the preventive effect of phages on mixed Escherichia coli and Salmonella Typhimurium infections in weaned piglets. A novel phage named NJ12 was isolated by using Salmonella Typhimurium SM022 as host bacteria and characterized by electron microscopy, genomic analysis and in vitro bacteriostatic activity. Phage NJ12 and a previously reported phage EP01 were microencapsulated with sodium alginate to make phage cocktail. Microencapsulated phage cocktail and PBS (Phosphate buffer solution) were used to piglets the phage and phage-free group through oral administration before bacterial infection 2 h, respectively. Piglets of the phage and phage-free group were consumed with feed contaminated with 6 mL (108CFU/mL) Escherichia coli O157:H7 GN07 (GXEC-N07) and 6 mL (108CFU/mL) SM022 every day for seven consecutive days. The results showed that piglets in the phage-free group had more severe diarrhea, larger decreased average weight gain and higher levels of neutrophils compared with piglets in phage group. Meanwhile, piglets in the phage-free group had higher load of SM022 and GN07 in jejunal tissue and more severe intestinal damage compared with piglets in group phage in vivo. In addition, oral administration phage can significant decreased the relative abundance of Enterobacteriaceae but hardly repaired the changes of diversity and composition of gut microbiota caused by the mixed infection of SM022 and GN07. This implies that phage used as a feed additive have a marvelous preventive effect on bacterial diarrhea during weaning of piglets.

Impact of mutagenesis and lateral gene transfer processes in bacterial susceptibility to phage in food biocontrol and phage therapy.

The emergence of resistance and interference mechanisms to phage infection can hinder the success of bacteriophage-based applications, but the significance of these mechanisms in phage therapy has not been determined. This work studies the emergence of Salmonella isolates with reduced susceptibility to a cocktail of three phages under three scenarios: i) Salmonella cultures (LAB), ii) biocontrol of cooked ham slices as a model of food safety (FOOD), and iii) oral phage therapy in broilers (PT). S. Typhimurium ATCC 14028 RifR variants with reduced phage susceptibility were isolated from the three scenarios and conventional and molecular microbiology techniques were applied to study them. In LAB, 92% of Salmonella isolates lost susceptibility to all three phages 24 h after phage infection. This percentage was lower in FOOD, with 4.3% of isolates not susceptible to at least two of the three phages after seven days at 4°C following phage treatment. In PT, 9.7% and 3.3 % of isolates from untreated and treated broilers, respectively, displayed some mechanism of interference with the life cycle of some of the phages. In LAB and FOOD scenarios, resistant variants carrying mutations in rfc and rfaJ genes involved in lipopolysaccharide synthesis (phage receptor) were identified. However, in PT, the significant decrease of EOP, ECOI, and burst size observed in isolates was prompted by lateral gene transfer of large IncI1 plasmids, which may encode phage defense mechanisms. These data indicate that the acquisition of specific conjugative plasmids has a stronger impact than mutagenesis on the emergence of reduced phage-susceptibility bacteria in certain environments. In spite of this, neither mechanism seems to significantly impair the success of Salmonella biocontrol and oral phage therapy.

Oral phage therapy with microencapsulated phage A221 against Escherichia coli infections in weaned piglets

BackgroundEscherichia coli (E. coli) is a common pathogen that often causes diarrhea in piglets. Since bacteria are becoming more and more resistant to antibiotics, phages have become a promising alternative therapy. However, the therapy of oral phage often fails to achieve the desired effect. A novel phage named A221 was isolated by using E. coli GXXW-1103 as host strain, characterized by electron microscopy, genomic sequencing and analyzed by measuring lysis ability in vitro.ResultsPhage A221 was identified as a member of Ackermannviridae, Aglimvirinae, Agtrevirus with 153297 bp genome and effectively inhibited bacterial growth in vitro for 16 h. This study was conducted to evaluate the therapeutic effect of oral microencapsulated phage A221 on E. coli GXXW-1103 infections in weaned piglets. The protective effect of phage was evaluated by body weight analysis, bacterial load and histopathological changes. The results showed that with the treatment of phage A221, the body weight of piglets increased, the percentage of Enterobacteriaceae in duodenum decreased to 0.64%, the lesions in cecum and duodenum were alleviated, and the bacterial load in the jejunal lymph nodes, cecum and spleen were also significantly different with infected group (P < 0.001).ConclusionsThe results showed that phage A221 significantly increased the daily weight gain of piglets, reduced the bacterial load of tissues and the intestinal lesions, achieved the same therapeutic effect as antibiotic Florfenicol. Taken together, oral microencapsulated phage A221 has a good therapeutic effect on bacterial diarrhea of weaned piglets, which provides guidance for the clinical application of phage therapy in the future.

SVep1, a temperate phage of human oral commensal Streptococcus vestibularis.

Bacteriophages play a vital role in the human oral microbiome, yet their precise impact on bacterial physiology and microbial communities remains relatively understudied due to the limited isolation and characterization of oral phages. To address this gap, the current study aimed to isolate and characterize novel oral phages. To achieve this, oral bacteria were isolated using a culture-omics method from 30 samples collected from healthy individuals. These bacteria were then cultured in three different types of media under both aerobic and anaerobic conditions. The samples were subsequently subjected to full-length 16S rRNA gene sequencing for analysis. Subsequently, we performed the isolation of lytic and lysogenic phages targeting all these bacteria. In the initial step, a total of 75 bacterial strains were successfully isolated, representing 30 species and 9 genera. Among these strains, Streptococcus was found to have the highest number of species. Using a full-length 16S rRNA gene similarity threshold of 98.65%, 14 potential novel bacterial species were identified. In the subsequent phase, a temperate phage, which specifically targets the human oral commensal bacterium S. vestibularis strain SVE8, was isolated. The genome of S. vestibularis SVE8 consists of a 1.96-megabase chromosome, along with a 43,492-base pair prophage designated as SVep1. Annotation of SVep1 revealed the presence of 62 open reading frames (ORFs), with the majority of them associated with phage functions. However, it is worth noting that no plaque formation was observed in S. vestibularis SVE8 following lytic induction using mitomycin C. Phage particles were successfully isolated from the supernatant of mitomycin C-treated cultures of S. vestibularis SVE8, and examination using transmission electron microscopy confirmed that SVep1 is a siphovirus. Notably, phylogenetic analysis suggested a common ancestral origin between phage SVep1 and the cos-type phages found in S. thermophilus. The presence of SVep1 may confer immunity to S. vestibularis against infection by related phages and holds potential for being engineered as a genetic tool to regulate oral microbiome homeostasis and oral diseases.

Vibrio Phage VMJ710 Can Prevent and Treat Disease Caused by Pathogenic MDR V. cholerae O1 in an Infant Mouse Model.

Cholera, a disease of antiquity, is still festering in developing countries that lack safe drinking water and sewage disposal. Vibrio cholerae, the causative agent of cholera, has developed multi-drug resistance to many antimicrobial agents. In aquatic habitats, phages are known to influence the occurrence and dispersion of pathogenic V. cholerae. We isolated Vibrio phage VMJ710 from a community sewage water sample of Manimajra, Chandigarh, in 2015 during an outbreak of cholera. It lysed 46% of multidrug-resistant V. cholerae O1 strains. It had significantly reduced the bacterial density within the first 4-6 h of treatment at the three multiplicity of infection (MOI 0.01, 0.1, and 1.0) values used. No bacterial resistance was observed against phage VMJ710 for 20 h in the time-kill assay. It is nearest to an ICP1 phage, i.e., Vibrio phage ICP1_2012 (MH310936.1), belonging to the class Caudoviricetes. ICP1 phages have been the dominant bacteriophages found in cholera patients' stools since 2001. Comparative genome analysis of phage VMJ710 and related phages indicated a high level of genetic conservation. The phage was stable over a wide range of temperatures and pH, which will be an advantage for applications in different environmental settings. The phage VMJ710 showed a reduction in biofilm mass growth, bacterial dispersal, and a clear disruption of bacterial biofilm structure. We further tested the phage VMJ710 for its potential therapeutic and prophylactic properties using infant BALB/c mice. Bacterial counts were reduced significantly when phages were administered before and after the challenge of orogastric inoculation with V. cholerae serotype O1. A comprehensive whole genome study revealed no indication of lysogenic genes, genes associated with possible virulence factors, or antibiotic resistance. Based on all these properties, phage VMJ710 can be a suitable candidate for oral phage administration and could be a viable method of combatting cholera infection caused by MDR V. cholerae pathogenic strains.

Bacteriophage therapy against pathological Klebsiella pneumoniae ameliorates the course of primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is characterized by progressive biliary inflammation and fibrosis. Although gut commensals are associated with PSC, their causative roles and therapeutic strategies remain elusive. Here we detect abundant Klebsiella pneumoniae (Kp) and Enterococcus gallinarum in fecal samples from 45 PSC patients, regardless of intestinal complications. Carriers of both pathogens exhibit high disease activity and poor clinical outcomes. Colonization of PSC-derived Kp in specific pathogen-free (SPF) hepatobiliary injury-prone mice enhances hepatic Th17 cell responses and exacerbates liver injury through bacterial translocation to mesenteric lymph nodes. We developed a lytic phage cocktail that targets PSC-derived Kp with a sustained suppressive effect in vitro. Oral administration of the phage cocktail lowers Kp levels in Kp-colonized germ-free mice and SPF mice, without off-target dysbiosis. Furthermore, we demonstrate that oral and intravenous phage administration successfully suppresses Kp levels and attenuates liver inflammation and disease severity in hepatobiliary injury-prone SPF mice. These results collectively suggest that using a lytic phage cocktail shows promise for targeting Kp in PSC.

Oral microbiota, co-evolution, and implications for health and disease: The case of indigenous peoples.

Evidence indicates that oral microbiota plays a crucial role in human health and disease. For instance, diseases with multifactorial etiology, such as periodontitis and caries, which cause a detrimental impact on human well-being and health, can be caused by alterations in the host-microbiota interactions, where non-pathogenic bacteria give way to pathogenic orange/red-complex bacterial species (a change from a eubiotic to dysbiotic state). In this scenario, where thousands of oral microorganisms, including fungi, archaea, and phage species, and their host are co-evolving, a set of phenomena, such as the arms race and Red or Black Queen dynamics, are expected to operate. We review concepts on the subject and revisit the nature of bacterial complexes linked to oral health and diseases, as well as the problem of the bacterial resistome in the face of the use of antibiotics and what is the impact of this on the evolutionary trajectory of the members of this symbiotic ecosystem. We constructed a 16SrRNA tree to show that adaptive consortia of oral bacterial complexes do not necessarily rescue phylogenetic relationships. Finally, we remember that oral health is not exempt from health disparity trends in some populations, such as Native Americans, when compared with non-Indigenous people.

Evaluation on the effects of phage cocktail in preventing Aeromonas veronii infection in Gibel carps (Carassius auratus gibelio)

Members in Aeromonas genus especially for Aeromonas veronii isolates are ubiquitous in aquaculture environments and have increasingly implicated in diseases of fish, and many of them have multidrug resistance. In this work, we used a phage cocktail as an alternative strategy to combat the infection of A. veronii 1810 in gibel carps. Three bacteriophages were isolated and designated as pAEv1810, pAEv1812 and pAEv1818. Electron microscopy observation revealed that all three phages belonged to the order of Caudovirales. Host spectrum assay showed that all three phages were lytic to A. veronii 1810 and pAEv1812 had a relatively broad host range. The cocktail combined with the three phages performed a significant inhibition (P < 0.05) of growth of A. veronii 1810 compared with the untreated cultures. During the 60 days of cultivation time in the in vivo trial, our results revealed that feeding the diet containing the phage cocktail cannot affect the growth performance and digestive enzyme activities of gibel carps. At the end of the 12-day observation in the challenge phase, the survival rate of gibel carps was calculated as 80% for the phage cocktail treatment, which was almost caught up with the rate of antibiotic treatment. For the digestive enzyme activities, our results indicated that the oral administrated phages helped the main enzymes including amylase, lipase and proteinase return to normal. Additionally, certain numbers of phages steadily existed in the cultured water, gills and intestines of gibel carps during the 60 days of phage feeding time. Subsequently, the intestinal microbiota of gibel carps in the group of CAbc (blank control), CABT (Bacterial challenge treatment) and CApt (phage cocktail treatment) were analyzed at the genus level. The Aeromonas abundance in the CApt group was significantly decreased compared to that of CABT (P < 0.05) and the intestinal microbiota in the CApt group presented high similarity compared to that of the CAbc group, suggesting the applied phages could effectively protect the structure and bacterial communities in the intestinal tracts of gibel carps. Together, the overall results of this experiment indicated that using a phage cocktail could be effective in combating A. veronii infections in gibel carps.

Exploitation of a Bacterium-Encoded Lytic Transglycosylase by a Human Oral Lytic Phage To Facilitate Infection.

Bacteriophages (phages) are an integral part of the human oral microbiome. Their roles in modulating bacterial physiology and shaping microbial communities have been discussed but remain understudied due to limited isolation and characterization of oral phage. Here, we report the isolation of LC001, a lytic phage targeting human oral Schaalia odontolytica (formerly known as Actinomyces odontolyticus) strain XH001. We showed that LC001 attached to and infected surface-grown, but not planktonic, XH001 cells, and it displayed remarkable host specificity at the strain level. Whole-genome sequencing of spontaneous LC001-resistant, surface-grown XH001 mutants revealed that the majority of the mutants carry nonsense or frameshift mutations in XH001 gene APY09_05145 (renamed ltg-1), which encodes a putative lytic transglycosylase (LT). The mutants are defective in LC001 binding, as revealed by direct visualization of the significantly reduced attachment of phage particles to the XH001 spontaneous mutants compared that to the wild type. Meanwhile, targeted deletion of ltg-1 produced a mutant that is defective in LC001 binding and resistant to LC001 infection even as surface-grown cells, while complementation of ltg-1 in the mutant background restored the LC001-sensitive phenotype. Intriguingly, similar expression levels of ltg-1 were observed in surface-grown and planktonic XH001, which displayed LC001-binding and nonbinding phenotypes, respectively. Furthermore, the overexpression of ltg-1 failed to confer an LC001-binding and -sensitive phenotype to planktonic XH001. Thus, our data suggested that rather than directly serving as a phage receptor, ltg-1-encoded LT may increase the accessibility of phage receptor, possibly via its enzymatic activity, by cleaving the peptidoglycan structure for better receptor exposure during peptidoglycan remodeling, a function that can be exploited by LC001 to facilitate infection. IMPORTANCE The evidence for the presence of a diverse and abundant phage population in the host-associated oral microbiome came largely from metagenomic analysis or the observation of virus-like particles within saliva/plaque samples, while the isolation of oral phage and investigation of their interaction with bacterial hosts are limited. Here, we report the isolation of LC001, the first lytic phage targeting oral Schaalia odontolytica. Our study suggested that LC001 may exploit the host bacterium-encoded lytic transglycosylase function to gain access to the receptor, thus facilitating its infection.

Salmonella Phages Affect the Intestinal Barrier in Chicks by Altering the Composition of Early Intestinal Flora: Association With Time of Phage Use

Phages show promise in replacing antibiotics to treat or prevent bacterial diseases in the chicken breeding industry. Chicks are easily affected by their environment during early growth. Thus, this study investigated whether oral phages could affect the intestinal barrier function of chicks with a focus on the cecal microbiome. In a two-week trial, forty one-day-old hens were randomly divided into four groups: (1) NC, negative control; (2) Phage 1, 109 PFU phage/day (days 3–5); (3) Phage 2, 109 PFU phage/day (days 8–10); and (4) AMX, 1 mg/mL amoxicillin/day (days 8–10). High-throughput sequencing results of cecal contents showed that oral administration of phages significantly affected microbial community structure and community composition, and increased the relative abundance of Enterococcus. The number of different species in the Phage 1 group was much higher than that in the Phage 2 group, and differences in alpha and beta diversity also indicated that the magnitude of changes in the composition of the cecal microbiota correlated with the time of phage use. Particularly in the first stage of cecal microbiota development, oral administration of bacteriophages targeting Salmonella may cause substantial changes in chicks, as evidenced by the results of the PICRUSt2 software function prediction, reminding us to be cautious about the time of phage use in chicks and to avoid high oral doses of phages during the first stage. Additionally, the Phage 2 samples not only showed a significant increase in the relative abundance of Bifidobacterium and Subdoligranulum, but also improved the intestinal morphology (jejunum) and increased the mRNA expression level of occludin and ZO-1. We concluded that phages do not directly interact with eukaryotic cells. The enhancement of intestinal barrier function by phages in chicks may be related to changes in the intestinal flora induced by phages. This implies that phages may affect intestinal health by regulating the intestinal flora. This study provides new ideas for phage prevention of intestinal bacterial infections and promotes large-scale application of phages in the poultry industry.

A Cocktail of Three Virulent Phages Controls Multidrug-Resistant Salmonella Enteritidis Infection in Poultry.

Salmonella enterica is not only the most common pathogen of poultry and poultry-derived products but is also a significant foodborne pathogen. In recent years, many S. enterica isolates have exhibited multi-drug resistance, which places huge pressure on global economy and health. Since phages are an attractive alternative to biocontrol pathogens, we isolated a total of 15 Salmonella phages from sewage effluent, sediment, and chicken manure. The GRNsp1, GRNsp3, GRNsp6, GRNsp21, GRNsp27, GRNsp30, GRNsp50, and GRNsp51 phages exhibited a wide host range against S. enterica serovars Enteritidis and Typhimurium in vitro. In particular, GRNsp51 exerted highly efficient lytic effects against a large proportion of S. Enteritidis and S. Typhimurium strains isolated from different regions of China. Meanwhile, GRNsp8 expanded the host range of GRNsp6 and GRNsp51. Based on their host ranges and lytic capacities, GRNsp6, GRNssp8, and GRNsp51 were selected for further investigation. Morphology, one-step growth curves, and stability assays revealed that GRNsp6, GRNsp8, and GRNsp51 all belong to the Caudovirales order and display relatively short latency periods with broad pH and thermal stability. Genomic analysis indicated that the genomes of these three phages contained no genes related to virulence, antibiotic resistance, or lysogeny. In addition, we tested the effectiveness of a cocktail composed of these three phages against S. Enteritidis in a chicken model. Treatment with the oral phage cocktail 24 h before or alongside Salmonella challenge significantly reduced colonization of the intestinal tract and decreased the mRNA expression of IL-6, IFN-γ, and IL-1β in the duodenum. Together, these findings indicate that a cocktail of the GRNsp6, GRNsp8, and GRNsp51 phages could serve as an effective antimicrobial therapeutic agent against multidrug-resistant Salmonella in animal production to mitigate infections by multiple zoonotic Salmonella species.

Современные подходы к лечению хронического бактериального простатита.

Introduction. The main treatment option for chronic bacterial prostatitis (CBP) is antimicrobial therapy. However, in connection with the steady increase in resistance to antimicrobial drugs and the high rate of failure in the treatment of such patients, it seems relevant to study new approaches to the treatment of this disease. Materials and methods. The review is based on articles published over the past 10 years (2011-2021) in scientific peer-reviewed journals included in the PubMed databases (https://www.ncbi.nlm.nih.gov/pubmed/) and the Scientific Electronic Library Elibrary.ru (https://elibrary.ru/). The search was carried out for the following keywords: «prostatitis», «chronic prostatitis», «chronic bactrial prostatitis», «chronic infectious prostatitis». At the first stage, 477 sources were found that were relevant to the topic of the review, of which 70 articles were selected for the final version of the review. Results. Oral antibiotic therapy remains the mainstay of treatment for CBP. There is a tendency towards an increase in resistance to traditionally used antimicrobial agents (fluoroquinolones, trimethoprim-sulfamethoxazole, etc.). In this regard, the possibilities of alternative antibacterial drugs (fosfomycin, etc.) and other methods of treatment are actively used and are being studied: direct administration of antimicrobial drugs into the prostate gland, chronic oral antibiotic prophylaxis, phage therapy and surgical interventions. An important role in the treatment of CBP is assigned to other pharmacological groups of drugs and non-drug methods of treatment (primarily physiotherapeutic methods). Conclusion. Many therapies that are used in addition to or instead of oral antibiotic therapy still cannot be recommended for use in general clinical practice, since there is currently a lack of sufficient evidence of their effectiveness and safety. Therefore, considering the existing problems of treating such patients, the need to continue studies to assess the possibilities of new promising approaches to the treatment of CBP remains relevant.

Immune Response of an Oral Enterococcus faecalis Phage Cocktail in a Mouse Model of Ethanol-Induced Liver Disease.

Cytolysin-positive Enterococcus faecalis (E. faecalis) cause more severe alcohol-associated hepatitis, and phages might be used to specifically target these bacteria in a clinical trial. Using a humanized mouse model of ethanol-induced liver disease, the effect of cytolytic E. faecalis phage treatment on the intestinal and liver immune response was evaluated. The observed immune response was predominantly anti-inflammatory and tissue-restoring. Besides, live phages could be readily recovered from the serum, spleen, and liver following oral gavage in ethanol-fed mice. We also isolated 20 new phages from the sewage water; six of them exhibited a relatively broad host range. Taken together, the oral administration of cytolytic E. faecalis phages leads to the translocation of phages to the systemic circulation and appears to be safe, following chronic-binge ethanol administration. A cocktail of three phages covers the majority of tested cytolysin-positive E. faecalis strains and could be tested in a clinical trial.

Impact of Phage Therapy on Multidrug-Resistant Escherichia coli Intestinal Carriage in a Murine Model.

Introduction: The growing resistance of bacteria to antibiotics is a major global public health concern. An important reservoir of this resistance is the gut microbiota. However, limited data are available on the ability of phage therapy to reduce the digestive carriage of multidrug-resistant bacteria. Materials and methods: Four novel lytic phages were isolated in vitro for efficacy against an extended-spectrum beta-lactamase-producing (ESBL) Escherichia coli strain also resistant to carbapenems through a carbapenemase OXA-48. The first step was to develop models of ESBL E. coli digestive carriage in mice. The second step was to test the efficacy of an oral and rectal phage therapy (a cocktail of four phages or microencapsulated phage) to reduce this carriage. Results: The two most intense models of digestive carriage were obtained by administering amoxicillin (0.5 g·L−1) continuously in the drinking water (Model 1) or pantoprazole (0.1 g·L−1) continuously in the drinking water, combined with amoxicillin (0.5 g·L−1), for the first 8 days (Model 2). Oral administration of the phage cocktail to Model 1 resulted in a transient reduction in the concentration of ESBL E. coli in the faeces 9 days after the bacterial challenge (median = 5.33 × 108 versus 2.76 × 109 CFU·g−1, p = 0.02). In contrast, in Model 2, oral or oral + rectal administration of this cocktail did not alter the bacterial titre compared to the control (area under the curve, AUC, 3.49 × 109; 3.41 × 109 and 3.82 × 109 for the control, oral and oral + rectal groups, respectively; p-value > 0.8 for each two-by-two group comparison), as well as the administration of an oral microencapsulated phage in Model 1 (AUC = 8.93 × 109 versus 9.04 × 109, p = 0.81). Conclusions: Oral treatment with amoxicillin promoted digestive carriage in mice, which was also the case for the addition of pantoprazole. However, our study confirms the difficulty of achieving efficacy with phage therapy to reduce multidrug-resistant bacterial digestive carriage in vivo.

Research progress on the effects of the interactions between phage and periodontal pathogens on periodontal disease

Periodontal disease is among the most prevalent oral diseases. As viruses that may infect bacteria, bacteriophages constitute an important component of the oral microbiome. With the advances in bioinformatics and genomics, the relationships among the bacteriophages, oral microbiome and periodontal disease is gradually being elucidated. As a result, phage therapy has become an emerging approach in the fight against super bacteria and has flourished in recent years. This review article discusses the mechanisms involved in the microbial interactions associated with oral phages and periodontal disease, the role of phages in maintaining a normal periodontal environment, the relationship between the imbalance of phages and the occurrence of periodontal disease, and the use of phage in the treatment of periodontal disease in order to provides references for in-depth research on the mechanisms of phage effects on periodontal disease, as well as the further clinical application of phage therapy.

Bacteriophage Delivery Systems Based on Composite PolyHIPE/Nanocellulose Hydrogel Particles.

The role of bacteriophage therapy in medicine has recently regained an important place. Oral phage delivery for gastrointestinal treatment, transport through the stomach, and fast release in the duodenum is one of such applications. In this work, an efficient polyHIPE/hydrogel system for targeted delivery of bacteriophages with rapid release at the target site is presented. T7 bacteriophages were encapsulated in low crosslinked anionic nanocellulose-based hydrogels, which successfully protected phages at pH < 3.9 (stomach) and completely lost the hydrogel network at a pH above 3.9 (duodenum), allowing their release. Hydrogels with entrapped phages were crosslinked within highly porous spherical polyHIPE particles with an average diameter of 24 μm. PolyHIPE scaffold protects the hydrogels from mechanical stimuli during transport, preventing the collapse of the hydrogel structure and the unwanted phage release. On the other hand, small particle size, due to the large surface-to-volume ratio, enables rapid release at the target site. As a consequence, a fast zero-order release was achieved, providing improved patient compliance and reduced frequency of drug administration. The proposed system therefore exhibits significant potential for a targeted drug delivery in medicine and pharmacy.

The human oral phageome

Oral bacteriophages (or phages), especially periodontal ones, constitute a growing area of interest, but research on oral phages is still in its infancy. Phages are bacterial viruses that may persist as intracellular parasitic deoxyribonucleic acid (DNA) or use bacterial metabolism to replicate and cause bacterial lysis. The microbiomes of saliva, oral mucosa, and dental plaque contain active phage virions, bacterial lysogens (ie, carrying dormant prophages), and bacterial strains containing short fragments of phage DNA. In excess of 2000 oral phages have been confirmed or predicted to infect species of the phyla Actinobacteria (>300 phages), Bacteroidetes (>300 phages), Firmicutes (>1000 phages), Fusobacteria (>200 phages), and Proteobacteria (>700 phages) and three additional phyla (few phages only). This article assesses the current knowledge of the diversity of the oral phage population and the mechanisms by which phages may impact the ecology of oral biofilms. The potential use of phage-based therapy to control major periodontal pathogens is also discussed.