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With increasing evidence that microbes colonize tumors, synthetic biology tools are being leveraged to repurpose bacteria as tumor-specific delivery systems. These engineered systems can modulate the tumor microenvironment using a combination of their inherent immunogenicity and local payload production. Here, we review genetic circuits that enhance spatial and temporal control of therapeutic bacteria to improve their safety and efficacy. We describe the engineering of interactions among bacteria, tumor cells, and immune cells, and the progression from bacteria as single agents toward their rational combination with other modalities. Together, these efforts are building toward an emerging concept of engineering interactions between programmable medicines using synthetic biology. [ABSTRACT FROM AUTHOR]

In human medicine, fecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridioides difficile infection. It has also been tested as a treatment for multiple gastrointestinal diseases, including inflammatory bowel disease (IBD). However, only a few studies have focused on the changes in the microbiome following FMT for canine IBD. Here, we performed FMT in nine dogs with IBD using the fecal matter of healthy dogs and investigated the subsequent changes in the fecal microbiome and clinical signs. In three dogs, the fecal microbiome was examined by 16S rRNA sequencing. Fusobacteria were observed at a low proportion in dogs with IBD. However, the post-FMT microbiome became diverse and showed a significant increase in Fusobacteria proportion. Fusobacterium was detected in the nine dogs by quantitative polymerase chain reaction. The proportion of Fusobacterium in the post-FMT fecal microbiome was significantly increased (p<0.05). The changes in clinical signs (e.g., vomiting, diarrhea, and weight loss) were evaluated according to the canine inflammatory bowel disease activity index. The score of this index significantly decreased in all dogs (p<0.05) with improvements in clinical signs. These improvements were related to the changes in the proportion of microbes, particularly the increase in Fusobacterium. The dogs with IBD showed a lower proportion of Fusobacterium than healthy dogs. This suggests that a low proportion of Fusobacterium is a characteristic feature of canine IBD and that Fusobacterium is involved in this disease. The results of this study may help elucidate the pathogenesis of this disease and its association with Fusobacterium. [ABSTRACT FROM AUTHOR]

The human intestine contains thousands of bacterial species essential for optimal health. Aside from their pathogenic effects, these bacteria have been associated with the efficacy of various treatments of diseases. Due to their impact on many human diseases, intestinal bacteria are receiving increasing research attention, and recent studies on intestinal bacteria and their effects on treatments has yielded valuable results. Particularly, intestinal bacteria can affect responses to numerous forms of immunotherapy, especially cancer therapy. With the development of precision medicine, understanding the factors that influence intestinal bacteria and how they can be regulated to enhance immunotherapy effects will improve the application prospects of intestinal bacteria therapy. Further, biomaterials employed for the convenient and efficient delivery of intestinal bacteria to the body have also become a research hotspot. In this review, we discuss the recent findings on the regulatory role of intestinal bacteria in immunotherapy, focusing on immune cells they regulate. We also summarize biomaterials used for their delivery. [ABSTRACT FROM AUTHOR]

Anti–programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti–PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti–PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti–PD-1 in patients with PD-1–refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti–PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8– expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti–PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti–PD-1 in a subset of PD-1 advanced melanoma. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Fecal microbiota transplantation (FMT) has emerged as an effective treatment option for Clostridioides difficile infection (CDI) and is considered an investigational therapy for a number of other diseases. Social media has facilitated widespread exposure of the public to the gut microbiome and FMT, ultimately acting as a catalyst for the Do-It-Yourself (DIY)-FMTmovement. The aims of this study were to identify factors that influenced willingness to pursue DIY-FMT including common indications, screening processes, sample preparation, and self-reported efficacy and safety outcomes. METHODS: A twenty-five-point cross-sectional survey was posted online through the websites and social media pages of the Peggy Lillis Foundation, The Fecal Transplant Foundation, and The Power of Poop. Responses were cataloged through the Research Electronic Data Capture tool, and descriptive analyses were performed. RESULTS: Eighty-four respondents completed the survey between January 2018 and February 2019. The majority were female (71%) and white (92%). Most (80%) reported performing FMT on themselves; 87% used Internet resources to assist in the process, and92%knew their stool donor. Inflammatory bowel disease (35%) and irritable bowel syndrome (29%) were the 2 most common conditions that respondents attempted to treat. Only 12% reported adverse events, whereas 82% reported improvement in their condition. DISCUSSION: DIY-FMT is being used for many indications, including those for which there is little evidence. There was a high self-reported success rate among respondents with few adverse events. There is a need for increased awareness around DIY-FMT and research around this phenomenon, which may impact public health. [ABSTRACT FROM AUTHOR]

Imbalance in skin microflora, particularly related to certain Cutibacterium acnes strains, may trigger acne. Application of non-acne-causing strains to the skin may modulate the skin microbiome and thereby lead to a reduction in acne. This pilot study evaluates the safety and efficacy of microbiome modulation on acneprone skin. The study had 2 phases: active induction (5% benzoyl peroxide gel, 7 days) and interventional C. acnes strains treatment (5 weeks). Patients were randomized to either topical skin formulations PT1 (2 strains of C. acnes Single Locus Sequence Typing [SLST] type C3 and K8, 50% each) or PT2 (4 strains of C. acnes SLST type C3 [55%], K8 [5%], A5 [30%] and F4 [10%]). Safety and efficacy was evaluated in 14 patients (PT1=8/14, PT2=6/14). Skin microbiome composition shifted towards study formulations. No untoward adverse events, visible irritation, or significant flare-up were observed. Non-inflamed lesions and skin pH were reduced. Comedone counts improved clinically with no deterioration in inflammatory lesions. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The impact of the 2019 US Food and Drug Administration safety alert involving transmission of multidrug resistant organisms through fecal microbiota transplantation (FMT), and the COVID-19 pandemic on the use of FMT in children, is unknown. METHODS: A survey of pediatric gastroenterologists performing FMT for Clostridioides difficile infection was conducted. RESULTS: Of 36 respondents, 17(47%) and 30(83%) changed their FMT practices related to theUSFood and Drug Administration safety alert and COVID-19 pandemic, respectively, with 22 (61%) of programs halted. DISCUSSION: The US Food and Drug Administration safety alert and COVID-19 pandemic have substantially influenced the availability and access of FMT for children. [ABSTRACT FROM AUTHOR]

Introduction and Objective: The therapeutic role of fecal microbiota transplantation in ulcerative colitis varies across different reports. This study aims to evaluate the long-term safety and efficacy of a strategy called step-up fecal microbiota transplantation for ulcerative colitis.Methods: Two clinical trials (NCT01790061, NCT02560727) for moderate-to-severe ulcerative colitis (Mayo score range 6-12) were performed from November 2012 to July 2017. Both studies were pooled for analysis on the safety and efficacy of fecal microbiota transplantation in patients with ulcerative colitis over a 1-year follow-up. The step-up fecal microbiota transplantation strategy included step 1: single fecal microbiota transplantation; step 2: two or more fecal microbiota transplantations; and step 3: fecal microbiota transplantations followed by immunosuppressants. Long-term clinical efficacy and adverse events were assessed, and multiple factors related to fecal microbiota transplantation were evaluated.Results: Of 134 eligible patients in this real-word study, 81.3% (109/134) were included for analysis. The follow-up ranged from 1 to 5 years. Fecal microbiota transplantation-related adverse events were observed in 17.4% (43/247) of fecal microbiota transplantation procedures including one serious adverse event (myasthenia gravis) and 56 non-serious adverse events. Multivariable logistic regression analysis showed that both the method of preparation of microbiota from stool using the automatic system and the delivery method of colonic transendoscopic enteral tubing were associated with a lower rate of fecal microbiota transplantation-related adverse events (p = 0.023, p = 0.017, respectively). In total, 74.3% (81/109) and 51.4% (56/109) of patients achieved clinical response at 1 month and 3 months after step-up fecal microbiota transplantation, respectively.Conclusions: Fecal microbiota transplantation should be a safe and promising therapy for ulcerative colitis. The improved fecal microbiota preparation and colonic transendoscopic enteral tubing might reduce the rate of adverse events in ulcerative colitis.Trial Registration: ClinicalTrials.gov NCT01790061, NCT02560727. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the clinical association between Lactobacillus and the efficacy of adjuvant treatment of severe periodontitis, periodontal parameters, and halitosis. Methods: 60 healthy volunteers with severe periodontitis were randomized into two groups to receive periodontal therapy in a single session and lactobacillus or a placebo for 90 days. The test group received Lactobacillus reuteri, salivarius and acidophilus, and the control group received placebo with xylitol. Results: There was a reduction in the depth levels of the probing pocket and the level of relative attachment after 90 days (P< 0.01). Regarding bleeding after pocket probing, the full-mouth with lactobacillus groups also showed more reduction than the placebo group (P< 0.01). The same results were observed with the halitosis parameters (P< 0.01). Oral administration of lactobacillus reduced periodontal parameters and halitosis and could contribute to the beneficial effects on periodontal conditions and halitosis. [ABSTRACT FROM AUTHOR]

Key Clinical Message: We have presented the first case report of FMT therapy for a patient with chronic intractable constipation. This therapy resulted in good, medium‐term outcomes. Follow‐up analysis of the intestinal flora suggested that transplanted microbes from the donor, particularly Bifidobacterium and Clostridium cluster IX, may have been incorporated into the recipient. We have presented the first case report of FMT therapy for a patient with chronic intractable constipation. This therapy resulted in good, medium‐term outcomes. Follow‐up analysis of the intestinal flora suggested that transplanted microbes from the donor, particularly Bifidobacterium and Clostridium cluster IX, may have been incorporated into the recipient. [ABSTRACT FROM AUTHOR]

Abstract: VNP20009 is a genetically modified strain of Salmonella typhimurium and has a good anticancer effect wildly used in tumour therapy on animal models. For its clinical application, an accurate bio‐safety assessment on sensitive models is necessary. In this study, we use TNFR1 KO mice as a susceptive model to assess the virulence of bacterial VNP20009 and its derivative ΔhtrA. By intraperitoneal administration of Salmonella, the increased lethality was observed in TNFR1 KO mice infected with VNP20009, but not with ΔhtrA. We performed a systemically comparative analysis of their toxicity, and ΔhtrA shows a better bio‐safety for TNFR1 KO mice. Since the macrophages with TNFR1 deficiency exhibit a reduced ability of bacteria clearance, ΔhtrA with lower survival ability in normal macrophages restores its viability in TNFR1 KO macrophages. Thus, ΔhtrA was further tested for its antitumour effect in TNFR1 KO mice bearing a B16F10 melanoma model. It displays a moderate antitumour effect, suggesting ΔhtrA instead of VNP20009 might be a promising candidate for bacteria‐mediated tumour therapy specific to those with low immunity. Significant and Impact of the Study: VNP20009 is attenuated Salmonella with a good safety widely used for tumour‐targeting bacterial therapies. Little is known about its toxicity in hosts with low immunity. This study is the first systemically comparative analysis of their toxicity of VNP20009 and its mutant ΔhtrA in TNFR1‐KO mice. Research on toxicity of tumour‐targeting Salmonella in mice with immunodeficiency can facilitate the optimization of bacterial therapies with reduced adverse effects in future clinical trials. [ABSTRACT FROM AUTHOR]

Salmonella VNP20009 inhibits tumor growth in preclinical models but its efficacy in humans is limited, potentially because cells mount an autophagy response that destroys the therapeutic bacteria. To neutralize this protective response, we combined VNP20009 with long-circulating liposomes containing the autophagy arrest agent hydroxychloroquine. This combination was associated with significantly larger numbers of intracellular Salmonella, accumulated autophagic vacuoles and much greater cell death in vitro . The combination was also associated with greater tumor-targeting ability, slower tumor growth and longer survival than free hydroxychloroquine in a murine model of melanoma. Our results suggest that combining tumor-targeting Salmonella with autophagy arrest may be effective for treating highly aggressive melanoma. [ABSTRACT FROM AUTHOR]

Extraintestinal infection with Clostridium difficile has been reported but remains uncommon. Treatment of this unusual complication is complex given the limitations of current therapeutic options. Here we report a novel case of recurrent extraintestinal C. difficile infection that occurred following fecal microbiota transplantation. Using whole genome sequencing, we confirmed recrudescence rather than reinfection was responsible. The patient ultimately responded to prolonged, targeted antimicrobial therapy informed by susceptibility testing. [ABSTRACT FROM AUTHOR]

With the aim of studying the biodiversity and the antimicrobial potential of three rare actinobacterial genera: Planomonospora, Saccharothrix and Actinophytocola in Algerian Saharan soils, 65 isolates representing the morphological characteristics of Planomonospora (17) and Saccharothrix/Actinophytocola (48) were isolated from 13 soil samples at 4 different sites in southern Algeria. The isolation was carried out on humic acid-vitamin agar medium using dilution techniques with several soil pretreatment and antibiotics as selective agents. Based on preliminary examination, 21 out of 65 isolates were kept for further investigations: Planomonospora (10) and Saccharothrix/Actinophytocola (11). 16S rRNA gene sequence analysis and DNA/DNA hybridization (DDH) showed that four strains, isolated from two different sites: Béchar (PM3) and Ghardaïa (MB20 and MB27), were found to represent four novel species. Moreover, they formed a distinct phyletic line within the clade of the most related genus: PM3 (DSM 46752T) with Planomonospora, MB27 (DSM 46885T) and MB46 (DSM 46886T) with Saccharothrix and MB20 (DSM 46746T) with Actinophytocola. While many novel species belonging to the genera Saccharothrix have been isolated from Algerian Saharan soils, this is the first report to describe the isolation of new species of Planomonospora and Actinophytocola from this extreme habitat. An assessment of the antimicrobial properties of the actinobacterial strains showed that 38 out of 65 have moderate to strong antimicrobial activities against Gram positive bacteria, fungi or yeasts. These results indicated the importance of further exploration of rare Saharan Actinobacteria for potentially original antimicrobial agents. [ABSTRACT FROM AUTHOR]

Antisense therapeutics are a biotechnological form of antibiotic therapy using chemical analogues of short single-stranded nucleic acid sequences modified to form stable oligomers. These molecules are termed antisense oligonucleotides (ASOs) because their sequence is complementary, via Watson-Crick specific base pairing, to their target messenger RNA (mRNA). ASOs modify gene expression in this sequence-dependent manner by binding to its complementary mRNA and inhibiting its translation into protein through steric blockage and/or through RNase degradation of the ASO/RNA duplex. The widespread use of conventional antibiotics has led to the increasing emergence of multiple drug-resistant pathogenic bacteria. There is an urgent need to develop alternative therapeutic strategies to reduce the morbidity and mortality associated with bacterial infections, and until recently, the use of ASOs as therapeutic agents has been essentially limited to eukaryotic cells, with ASOs as antibacterials having been largely unexplored primarily due to the poor uptake efficiency of antisense molecules by bacteria. There are conceptual advantages to bacterial antisense antibiotic therapies, including a sequence-dependent approach that allows for a rational design to multiple specific molecular targets. This review summarizes the current knowledge of antisense bacterial biotechnology and highlights the recent progress and the current obstacles in their development for therapeutic applications. [ABSTRACT FROM AUTHOR]

Side effects associated with conventional anticancer therapies have prompted the new idea of solid tumor treatment strategy. One of them is using bacteria explored as potential antitumor agents over more than one century. Notably, the ideal therapy is a specifical target to tumors with limited toxicity. Here, we take "Clostridium novyi" for the search keyword in the PubMed from 2000 to 2015 and describe that C. novyi-NT spores act as "Trojan horse" for bacteriolytic therapy. This therapy is based on the fact that the live and attenuated obligate anaerobic bacteria are capable of binary fission selectively in anoxic areas of solid tumors and direct tumoricidal effects. Our succinct review mainly concentrates on the potential mechanisms of combination bacteriolytic therapy, an effective and safe tumor therapy with the help of C. novyi-NT. Importantly, C. novyi-NT spores were shown to induce solid tumor regression and exhibit the property to initiate an immune response. Therefore, C. novyi-NT spores should be an effective and safe tumor therapy. [ABSTRACT FROM AUTHOR]

Current methods for treatment of cellular and organ pathologies are extremely diverse and constantly evolving, going beyond the use of drugs, based on chemical interaction with biological targets to normalize the functions of the system. Because pharmacological approaches are often untenable, recent strategies in the therapy of different pathological conditions are of particular interest through introducing into the organism of some living system or its components, in particular, bacteria or isolated subcellular structures such as mitochondria. This review describes the most interesting and original examples of therapy using bacteria and mitochondria, which in perspective can dramatically change our views on the principles for the treatment of many diseases. Thus, we analyze such therapeutic effects from the perspective of the similarities between mitochondria and bacteria as the evolutionary ancestors of mitochondria. [ABSTRACT FROM AUTHOR]

Elasmobranchs represent a distinct group of cartilaginous fishes that harbor a remarkable ability to heal wounds rapidly and without infection. To date very little work has addressed this phenomenon although it is suggested that antibiotic capabilities associated with epidermal surfaces may be a factor. The study of benefits derived from mutualistic interactions between unicellular and multicellular organisms is a rapidly growing area of research. Here we survey and identify bacterial associates of three ray and one skate species in order to assess the potential for antibiotic production from elasmobranch associated bacteria as a novel source for new antibiotics. [ABSTRACT FROM AUTHOR]

Objective: Antibiotic therapy is a major risk factor for the development of diarrhea and colitis with varying severity. Often the origin of antibiotic-associated gastrointestinal deterioration remains elusive and no specific infectious agents could be discerned.Patients: We represent three cases of intractable high-volume diarrhea associated with combined antibiotic and steroid therapy in critically ill patients not fitting into established disease entities. Cases presented with severe apoptotic enterocolitis resembling acute intestinal graft-versus-host-disease. Microbiologic workup precluded known enteropathogens, but microbiota analysis revealed a severely depleted gut microbiota with concomitant opportunistic pathogen overgrowth.Interventions: Fecal microbiota transplantation, performed in one patient, was associated with correction of dysbiosis, rapid clinical improvement, and healing of enterocolitis.Conclusions: Our series represents a severe form of antibiotic-associated colitis in critically ill patients signified by microbiota depletion, and reestablishment of a physiologic gastrointestinal microbiota might be beneficial for this condition. [ABSTRACT FROM AUTHOR]

Recurrence of acute otitis media (RAOM) is a relevant issue in the clinical practice. "Bacteriotherapy" has been proposed as an option in children with RAOM. Streptococcus salivarius 24SMB nasal spray has been previously demonstrated to reduce the risk of acute otitis media (AOM) in otitis-prone children. The current retrospective and observational study aimed to confirm this outcome in a real-life setting, such as the common pediatric practice. Group A (108 children) served as control; group B (159 children) was treated with S. salivarius 24SMB and Streptococcus oralis 89a nasal spray after the first AOM episode. Active treatment consisted of 3 monthly courses: 2 puffs per nostril twice/day for a week. Group B showed a significant reduction of AOM episodes in comparison with group A (p<0.0001). Notably, all actively treated children with the highest AOM recurrence had a reduction of recurrence, whereas only 50% of the control group children had reduced RAOM (p<0.0001). Also, severity grade of AOM significantly diminished after the preventive bacteriotherapy (p<0.0001). In conclusion, the current retrospective and observational study demonstrated that S. salivarius 24SMB and S. oralis 89a nasal spray could be effective in the prevention of RAOM in a real-life setting. [ABSTRACT FROM AUTHOR]

Background: Microbiology of modern war wounds is unique for each military conflict. Climatic and geographical features of the theater of war, contemporary warfare as well as wound management affect the microbial flora of wounds. This study was designed to determine time-specific microbial flora of combat wounds of upper and lower extremities obtained during the war in eastern Ukraine. Methods: The patients enrolled in study had combat wounds of upper or lower extremities which were treated in the Military Medical Clinical Center of Central Region. The wounds were swab-cultured and measured at each surgical debridement. The recovered microorganisms were identified and their antimicrobial resistance profiles were evaluated by disc diffusion method. Results: Forty-nine patients with battle-field wounds were enrolled in the study from July to November 2014; all patients were male with a mean Injury Severity Score and arrival APACHE II scores of 16.2 ± 10.7 and 7.4 ± 4.2 respectively. Among 128 swab cultures, 100 swab cultures were positive. Swab cultures were obtained from 57 wounds of 49 patients. The results of the test showed that 87.7% of all positive swab cultures contained a single-organism while the rest of the swab-culture results showed polymicrobial growth. Among the isolated microorganisms 65% (76 strains) were Gram-negative rods, 22.2% (26 strains) of Gram-positive cocci, followed by Gram-positive rods (12.8%, 15 strains). We found that epidemiology of wound infection changes with the time after injury. The most common bacterial isolates cultured during the first week were Gram-positive microbes with low pathogenicity. The number of Gramnegative rods increased during the wound healing process. The incidence of Gram-positive microorganisms' growth fell after the first week and increased after third week. During wound healing, bacterial microflora of wounds changes with increasing number of Gram-negative rods with predominance of Acinetobacter species. Predominant microorganisms in positive swab-cultures after first week were nonfermentative Gram-negative bacilli (68% of swab-cultures), which in 53% of the swab-cultures belonged to the genus Acinetobacter, and in 15% to the genus Pseudomonas. The incidence of polymicrobial wound cultures increased from first week to second post-injury week. The most frequent microbial mixture were Acinetobacter baumannii with Enterobacteriaceae or other nonfermentative Gram negative rods with Enterococcus spp. We observed bacteria recovery from wounds during proliferation phase. These wounds had no pure inflammation signs and were free of devitalized tissues. Conclusions: Any wound is at some risk of becoming infected. In the event of infection, a wound fails to heal, treatment costs rise, and general wound management practices become more resource demanding. Determining the microorganisms which colonize battle wounds and cause wound infection is paramount. This information can help to treat battle wound infections or even changes infection control strategies. The fact of shifting in wound microbiology in the favor of bacteria responsible for healthcare-associated infections support to the proposition that these changes are nosocomially related [4, 14]. For Ukrainian military medicine this study is the first time-specified assessment of battle wound colonization from the World War II. [ABSTRACT FROM AUTHOR]

The effect of edible films of candelilla wax alone or in combination with a Bacillus subtilis HFC103 strain on shelf life of strawberry, has been assayed. Treatments were: control, film (edible coating), bacteria (inoculated with B. subtilis HFC103) and film + bacteria (edible coating + B. subtilis HFC103). Fruits were treated and stored at 25 °C for six d. Decay percentage and weight loss were assayed daily, while pH and total soluble solids (TSS) were determined at the end of the assay. The film, bacteria and film + bacteria treatments significantly reduced the decay percentage and weight loss with respect to control since day 3. Film + bacteria treatment reduced decay around 100% with respect to control on day 6. Film treatment kept a low weight loss during the assay. There were no changes of pH and TSS as effect of the treatments. Additionally, the effects of the treatments described on the severity of the damage caused by Rhizopus stolonifer were assayed. All the treatments were inoculated with a spore suspension of such pathogen, stored at 25 °C for 6 d, and the severity index was recorded every 24 h. Film, bacteria and film + bacteria treatments significantly reduced the severity index with respect to control since day 2. The Bacteria treatment was the most effective to control R. stolonifer . However, it did not show the same efficacy to control weight loss or to prolong shelf life of strawberry. Results showed that the combination of candelilla wax edible films and the inoculation with B. subtilis HFC103 is an innovative strategy with the potential to prolong shelf life of strawberry. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus and Pseudomonas aeruginosa are part of the human microbiota and are also important bacterial pathogens, for which therapeutic options are lacking nowadays. The combined administration of corticosteroids and antimicrobials is commonly used in the treatment of infectious diseases to control inflammatory processes and to minimize potential toxicity of antimicrobials, avoiding sequelae. Although different pharmaceutical dosage forms of antimicrobials combined to corticosteroids are available, studies on the interference of corticosteroids on the pharmacological activity of antimicrobials are scarce and controversial. Here, we provide evidence of the interference of dexamethasone on the pharmacological activity of clinically important antimicrobial drugs against biofilms and planktonic cells of S. aureus and P. aeruginosa . Broth microdilution assays of minimal inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and minimum biofilm eradication concentration (MBEC) of gentamicin, chloramphenicol, oxacillin, ceftriaxone and meropenem were conducted with and without the addition of dexamethasone. The effect of all drugs was abrogated by dexamethasone in their MIC, MBC, and MBEC, except gentamicin and meropenem, for which the MBC was not affected in some strains. The present study opens doors for more investigations on in vitro and in vivo effects and safety of the combination of antimicrobials and glucocorticoids. [ABSTRACT FROM AUTHOR]

Bacterial therapies have been paid significant attentions by their ability to penetrate deep into the solid tumor tissue and its propensity to naturally accumulate in tumors of living animals. Understanding the actual mechanism for bacteria to target the tumor is therapeutically crucial but is poorly understood. We hypothesized that amino acids released from the specific tumors induced bacteria to those tumors and the experiments for chemotactic response of bacteria toward the cancer secreting amino acids was then performed by using the diffusion based multiple chemical gradient generator constructed by in situ self-assembly of microspheres. The quantitative analysis was carried out by comparison of intensity using green fluorescent protein (GFP) tagged Salmonella typhimurium ( S. typhimurium) in the gradient generator, which showed the clear preference to the released amino acids, especially from breast cancer patients. The understanding chemotaxis toward the cancer secreting amino acids is essential for controlling S. typhimurium targeting in tumors and will allow for the development of bacterial therapies. [ABSTRACT FROM AUTHOR]

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Bacteria navigate environments full of various chemicals to seek favorable places for survival by controlling the flagella’s rotation using a complicated signal transduction pathway. By influencing the pathway, bacteria can be engineered to search for specific molecules, which has great potential for application to biomedicine and bioremediation. In this study, genetic circuits were constructed to make bacteria search for a specific molecule at particular concentrations in their environment through a synthetic biology method. In addition, by replacing the “brake component” in the synthetic circuit with some specific sensitivities, the bacteria can be engineered to locate areas containing specific concentrations of the molecule. Measured by the swarm assay qualitatively and microfluidic techniques quantitatively, the characteristics of each “brake component” were identified and represented by a mathematical model. Furthermore, we established another mathematical model to anticipate the characteristics of the “brake component”. Based on this model, an abundant component library can be established to provide adequate component selection for different searching conditions without identifying all components individually. Finally, a systematic design procedure was proposed. Following this systematic procedure, one can design a genetic circuit for bacteria to rapidly search for and locate different concentrations of particular molecules by selecting the most adequate “brake component” in the library. Moreover, following simple procedures, one can also establish an exclusive component library suitable for other cultivated environments, promoter systems, or bacterial strains. [ABSTRACT FROM AUTHOR]

The rising incidence of cancer cases worldwide generates an urgent need of novel treatment options. Applying bacteria may represent a valuable therapeutic variant that is intensively investigated nowadays. Interestingly, the idea to apply bacteria wittingly or unwittingly dates back to ancient times and was revived in the 19th century mainly by the pioneer William Coley. This review summarizes and compares the results of the past 150 years in bacteria mediated tumor therapy from preclinical to clinical studies. Lessons we have learned from the past provide a solid foundation on which to base future efforts. In this regard, several perspectives are discussed by which bacteria in addition to their intrinsic antitumor effect can be used as vector systems that shuttle therapeutic compounds into the tumor. Strategic solutions like these provide a sound and more apt exploitation of bacteria that may overcome limitations of conventional therapies. [ABSTRACT FROM AUTHOR]

Bacterial natural products have proven to be invaluable starting points in the development of many currently used therapeutic agents. Unfortunately, traditional culture-based methods for natural product discovery have been deemphasized by pharmaceutical companies due in large part to high rediscovery rates. Culture-independent, or 'metagenomic,' methods, which rely on the heterologous expression of DNA extracted directly from environmental samples (eDNA), have the potential to provide access to metabolites encoded by a large fraction of the earth's microbial biosynthetic diversity. As soil is both ubiquitous and rich in bacterial diversity, it is an appealing starting point for culture-independent natural product discovery efforts. This review provides an overview of the history of soil metagenome-driven natural product discovery studies and elaborates on the recent development of new tools for sequence-based, high-throughput profiling of environmental samples used in discovering novel natural product biosynthetic gene clusters. We conclude with several examples of these new tools being employed to facilitate the recovery of novel secondary metabolite encoding gene clusters from soil metagenomes and the subsequent heterologous expression of these clusters to produce bioactive small molecules. [ABSTRACT FROM AUTHOR]

The term probiotic was derived from the Greek, meaning “for life”. They are basically the live microorganisms which, when administered in adequate amounts, confer a health benefit on the host. Most of the bacterial species are claimed to have probiotic properties usually belong to the genera Lactobacillus and Bifidobacterium. These good bacteria can easily reside in the human body causing no harm and plays a key role in milk fermentation. The widespread oral intake of probiotics as preventive and therapeutic products for gastrointestinal health makes a considerable interest amongst the researchers regarding the possible use of probiotics for the promotion of oral health. So, the oral cavity has only recently been suggested as a relevant target for probiotic application. Therefore, a detailed understanding of probiotics and its clinical application is necessary. [ABSTRACT FROM AUTHOR]

We present a novel but simple enteric coated sphere formulation containing probiotic bacteria ( Lactobacillus casei ). Oral delivery of live bacterial cells (LBC) requires live cells to survive firstly manufacturing processes and secondly GI microbicidal defenses including gastric acid. We incorporated live L. casei directly in the granulation liquid, followed by granulation, extrusion, spheronization, drying and spray coating to produce dried live probiotic spheres. A blend of MCC, calcium-crosslinked alginate, and lactose was developed that gave improved live cell survival during manufacturing, and gave excellent protection from gastric acid plus rapid release in intestinal conditions. No significant loss of viability was observed in all steps except drying, which resulted in approximately 1 log loss of viable cells. Eudragit coating was used to protect dried live cells from acid, and microcrystalline cellulose (MCC) was combined with sodium alginate to achieve efficient sphere disintegration leading to rapid and complete bacterial cell release in intestinal conditions. Viability and release of L. casei was evaluated in vitro in simulated GI conditions. Uncoated spheres gave partial acid protection, but enteric coated spheres effectively protected dried probiotic LBC from acid for 2 h, and subsequently released all viable cells within 1 h of transfer into simulated intestinal fluid. [ABSTRACT FROM AUTHOR]

There is an increasing need for new cancer therapies. The antitumour effect of bacterial infection has been well observed and practiced throughout history. Bacteria are well-suited to serve as anticancer agents due to their intrinsic mobility, cell toxicity, immunogenicity, and preferential accumulation within the anoxic tumour environment. Furthermore, advances in biotechnology and molecular techniques have made it easier than ever to engineer bacteria as both therapeutic agents themselves and as therapeutic vectors. Here, we review bacteriolytic therapy and immunotherapy strategies, and examine the development of bacteria as vehicles for cell- and tissue-targeted delivery of genetic cancer therapeutics. [ABSTRACT FROM AUTHOR]

Background: Nosocomial Methicillin-resistant Staphylococcus aureus (MRSA) enteritis is rare but can be fatal unless it is detected at an early stage and treated effectively. Dysbiosis of the gut is one of the leading reasons of MRSA enteritis. Fecal microbiota transplantation (FMT) is a burgeoning treatment to rectify this imbalance. But the impact of FMT on MRSA enterocoitis is still unknown yet. Methods: A total of 5 patients diagnosed as MRSA enteritis during the early postoperative period were given vancomycin 2 g/day for 3 days and FMT for three continuous days as a standard treatment. Result: There was a 100 % clinical response rate that all the symptoms resulting from MRSA enterocolitis disappeared and MRSA in the feces eliminated clearly. The microbiota profile in feces of the patients also regained balance. Conclusion: FMT can be a preferential measure to restore the dysbiosis caused by MSRA enterocolitis. [ABSTRACT FROM AUTHOR]

The gut microbiota has a significant role in human health and disease. Dysbiosis of the intestinal ecosystem contributes to the development of certain illnesses that can be reversed by favorable alterations by probiotics. The published literaturewas reviewed to identify scientific data showing a relationship between imbalance of gut bacteria and development of diseases that can be improved by biologic products. The medical conditions vary from infectious and antibiotic-associated diarrhea to obesity to chronic neurologic disorders. A number of controlled clinical trials have been performed to show important biologic effects in a number of these conditions through administration of prebiotics, probiotics, and synbiotics. Controlled clinical trials have identified a limited number of prebiotics, probiotic strains, and synbiotics that favorably prevent or improve the symptoms of various disorders including inflammatory bowel disease, irritable bowel syndrome, infectious and antibiotic-associated diarrhea, diabetes, nonalcoholic fatty liver disease, necrotizing enterocolitis in very low birth weight infants, and hepatic encephalopathy. Studies have shown that probiotics alter gut flora and lead to elaboration of flora metabolites that influence health through 1 of 3 general mechanisms: direct antimicrobial effects, enhancement of mucosal barrier integrity, and immune modulation. Restoring the balance of intestinal flora by introducing probiotics for disease prevention and treatment could be beneficial to human health. It is also clear that significant differences exist between different probiotic species.Metagenomics and metatranscriptomics together with bioinformatics have allowed us to study the cross-talk between the gut microbiota and the host, furthering insight into the next generation of biologic products. [ABSTRACT FROM AUTHOR]

Phage therapy is a promising option for fighting against staphylococcal infections. Two lytic phages, vB_SauM_phiIPLA-RODI (phiIPLA-RODI) and vB_SepM_phiIPLA-C1C (phiIPLA-C1C), belonging to the Myoviridae family and exhibiting wide host ranges, were characterized in this study. The complete genome sequences comprised 142,348 bp and 140,961 bp and contained 213 and 203 open reading frames, respectively. The gene organization was typical of Spounavirinae members, with long direct terminal repeats (LTRs), genes grouped into modules not clearly separated from each other, and several group I introns. In addition, four genes encoding tRNAs were identified in phiIPLA-RODI. Comparative DNA sequence analysis showed high similarities with two phages, GH15 and 676Z, belonging to the Twort-like virus genus (nucleotide identities of>84%); for phiIPLAC1C, a high similarity with phage phiIBB-SEP1 was observed (identity of 80%). Challenge assays of phages phiIPLA-RODI and phiIPLA-C1C against planktonic staphylococcal cells confirmed their lytic ability, as they were able to remove 5 log units in 8 h. Exposure of biofilms to phages phiIPLA-RODI and phiIPLA-C1C reduced the amount of adhered bacteria to about 2 log units in both monospecies and dual-species biofilms, but phiIPLA-RODI turned out to be as effective as the mixture of both phages. Moreover, the frequencies of bacteriophage-insensitive mutants (BIMs) of Staphylococcus aureus and S. epidermidis with resistance to phiIPLA-RODI and phiIPLA-C1C were low, at 4.05 × 10-7 ± 2.34 × 10-9 and 1.1 × 10-7 ± 2.08 × 10-9, respectively. Overall, a generally reduced fitness in the absence of phages was observed for BIMs, which showed a restored phage-sensitive phenotype in a few generations. These results confirm that lytic bacteriophages can be efficient biofilm-disrupting agents, supporting their potential as antimicrobials against staphylococcal infections. [ABSTRACT FROM AUTHOR]

Faecal microbiome transplantation (FMT) has generated huge recent interest as it presents a potential solution to a significant clinical problem--the increasing incidence of Clostridium difficile infection (CDI). In the short term, however, there remain many practical questions regarding its use, including the optimal selection of donors, material preparation and the mechanics of delivery. In the longer term, enhanced understanding of the mechanisms of action of FMT may potentiate novel therapies, such as targeted manipulation of the microbiome in CDI and beyond. [ABSTRACT FROM AUTHOR]

Some strains of Lactobacillus genus have antiproliferative activities against cancer cells. However, until now, the exact effector molecules of Lactobacillus strains with anticancer activity have not been identified. The aim of the present study was to explore which fraction of the Lactobacillus cells exerts the highest antiproliferative effect. For this purpose, the heat-killed bacterial cells, bacterial cell wall extract, and genomic DNA of 8 Lactobacillus strains were prepared to assess their antiproliferative activities against human myeloid leukemia cell lines K562. The heat-killed bacterial cells of the 8 lactobacilli strains exerted antiproliferative effect on K562 cells, and the inhibition rates exerted by the heat-killed bacterial cells of the strains G15AL, M5AL, SB31AL, SB5AL, and T3AL were significantly higher than those exerted by the cell walls and genomic DNA of the strains. The bacterial DNA of G15AL exerted higher antiproliferative effect on K562 cells. The exact effector molecules and the effect mechanism of the strains should be further explored for the application of these strains as probiotic strains or bioactive probiotic molecules. [ABSTRACT FROM AUTHOR]

In Nature, no individual can live in isolation; hence, living organisms are forced to interact with each other. This necessity has led many organisms to establish heterogeneous relations to enhance their ability to adapt to the environment, thus acquiring evolutionary advantages. These relationships are sometimes so intense, that on the long term the organisms may lose their individual identity. An example of these associations is the endosymbiotic ones, where eukaryote organisms generally harbor different prokaryote organisms. The endosymbiotic bacterium Wolbachia pipientis is a species described by Hertig and Wolbach in 1924. This microorganism can be isolated in a large variety of eukaryote organisms, with which it maintains different links. Until now, this species has only been described with 11 serogroups numbered from A to K within the Wolbachia genus. This work is intended to illustrate the relationship of Wolbachia pipientis with human pathogenic filaria and with arthropods, as well as to describe the implications of this bacterium in the treatment of filariasis. Finally, this work tries to describe recent studies that have targeted the use of artificially-created Wolbachia pipientis virulent strains that, once inoculated in infectious diseases-transmitting vectors, develop negative effects within them in order to, in this way, erradicate mosquitotransmitted infectious diseases for which no treatment is available at the moment or the prevention of its transmissibility has not been achieved. [ABSTRACT FROM AUTHOR]

This review gives an outline of the indications for faecal microbiota transplantation ( FMT) for diseases other than Clostridium difficile (C. difficile) infection. The remarkable efficacy of FMT against C. difficile infection has already been demonstrated. The use of FMT for other diseases, such as inflammatory bowel disease ( IBD), irritable bowel syndrome ( IBS), and metabolic syndrome, is now being evaluated. The currently available data suggest that FMT might be beneficial for IBD (including ulcerative colitis and, to some extent, Crohn's disease), IBS, and insulin resistance. Several randomized clinical trials are currently being performed, and data are eagerly awaited. A new field of research for the implementation of FMT is the eradication of pathogenic and multiresistant enteric microorganisms. A few animal studies have been performed within this field, but hardly any research data from human studies are available at present. [ABSTRACT FROM AUTHOR]

The intestinal microbiome is essential for maintaining human health and defending against intestinal pathogens. Alterations of the intestinal microbiota, also termed dysbiosis, play a pivotal role in the pathogenesis of various human diseases. Faecal microbiota transplantation ( FMT) is aimed at correcting these alterations by delivering faecal microorganisms from a healthy person to the intestines of a patient. At present, recurrent Clostridium difficile infection is the only indication supported by solid scientific evidence, but many ongoing studies are investigating FMT in other dysbiosis-related diseases, such as inflammatory bowel disease. As there are no systematic methodological investigations, several questions about techniques, donor screening and safety issues remain. This shortage of evidence, especially on long-term safety concerns, is leading to worldwide controversy regarding the use of FMT. Regulations by healthcare authorities vary among different countries. This review reflects the Austrian situation and its FMT guidelines concerning indications, techniques and donor screening, recently developed by local scientific societies. [ABSTRACT FROM AUTHOR]

Several trillions of bacteria, distributed among more than 1,000 species, are natural inhabitants of the human intestinal tract and constitute what is now known as the gut microbiota. Although its composition varies within and between individuals with age, diet, and health status, it is becoming increasingly recognized that imbalances in the bacterial microbiota (dysbiosis) are linked to a number of conditions such as antibiotic-associated diarrhea, inflammatory bowel disease, and obesity, among others. Fecal transplantation where a preparation of stool from a microbiologically screened donor is administered into the colon of an affected recipient has been shown to be highly effective for the treatment of recurrent Clostridium difficile infection. Several trials of this therapy are now underway for gut dysbiosis in a number of patient disease groups raising concerns on the risk of transmission of infectious agents from donor to recipient, possible long-term adverse consequences of treatment, and effective regulation of the stool material used for the procedure. A worrying aspect is the emergence of private stool banks providing samples to the general public for self-administration. [ABSTRACT FROM AUTHOR]

Metabolic disorders, including obesity, diabetes, and cardiovascular disease, are widespread in Westernized nations. Gut microbiota composition is a contributing factor to the susceptibility of an individual to the development of these disorders; therefore, altering a person's microbiota may ameliorate disease. One potential microbiome-altering strategy is the incorporation of modified bacteria that express therapeutic factors into the gut microbiota. For example, N-acylphosphatidylethanolamines (NAPEs) are precursors to the N-acylethanolamide (NAE) family of lipids, which are synthesized in the small intestine in response to feeding and reduce food intake and obesity. Here, we demonstrated that administration of engineered NAPE-expressing E. coli Nissle 1917 bacteria in drinking water for 8 weeks reduced the levels of obesity in mice fed a high-fat diet. Mice that received modified bacteria had dramatically lower food intake, adiposity, insulin resistance, and hepatosteatosis compared with mice receiving standard water or control bacteria. The protective effects conferred by NAPE-expressing bacteria persisted for at least 4 weeks after their removal from the drinking water. Moreover, administration of NAPE-expressing bacteria to TallyHo mice, a polygenic mouse model of obesity, inhibited weight gain. Our results demonstrate that incorporation of appropriately modified bacteria into the gut microbiota has potential as an effective strategy to inhibit the development of metabolic disorders. [ABSTRACT FROM AUTHOR]

Fecal microbiota transplantation (FMT) has been shown to be a superior therapeutic modality for the treatment of recurrent Clostridium difficile infection (RCDI). Recently the US Food and Drug Administration (FDA) determined that human stool should be classified as a biological agent and its use should be regulated to ensure patient safety. Consequently, the FDA determined that prescribers of FMT must possess an approved investigational new drug (IND) permit to administer FMT for the purpose of conducting research or treating any gastrointestinal condition other than RCDI. Although an IND is not required for use of FMT to treat RCDI, an IND is strongly encouraged and may ultimately be required. This article provides step-by-step guidance to infectious disease specialists on how to navigate the regulatory requirements and successfully obtain an IND before they can begin to use FMT as part of their clinical practice. [ABSTRACT FROM PUBLISHER]

Background: Recurrent Clostridium difficile infection (CDI) is a significant problem due to its increased incidence and severity. Failure rates for standard antibiotic therapies are high. In our hospital, faecal microbiota transplantation (FMT), or instillation of a culture mixture of known enteric bacteria in saline as rectal bacteriotherapy (RBT), has long been used as 'rescue therapy' in patients with recurrent disease, in whom repeated courses of standard antibiotic treatment have failed. We wanted to evaluate the effectiveness of FMT and RBT for recurrent CDI. Methods: The records of 31 patients treated with either FMT or RBT for recurrent CDI were reviewed retrospectively. FMT was based on faecal donation by a close relative and RBT on a defined saline mixture of 10 individually cultured enteric bacterial strains originally isolated from healthy persons. Both types of instillation were carried out through a rectal catheter. FMT (500 ml) was given as 1 installation. RBT (200 ml) was given as 2 or 3 installations with an interval of 2 days between courses. Treatment success was defined as a sustained loss of symptoms and discontinuation of diarrhoea within 3 days. Results: Of 31 patients, 23 (74%) responded successfully to the treatment: 16 of 23 (70%) receiving FMT and 7 of 8 (88%) receiving RBT. Conclusion: We found FMT to be effective in patients with recurrent CDI. RBT based on a predefined bacterial suspension was as effective as or better than FMT based on faecal donation; however, multiple installations may be needed. [ABSTRACT FROM AUTHOR]

The article presents insights on the potential of bacteriophages in the treatment of burn wounds. Topics discussed include the effectiveness of phage therapy in 80% of Enterococcus infections, the ability of the pathogen Acinetobacter baumannii to acquire resistance to many antibiotics and disinfectants, and the possible inflammatory properties of phage therapy.