Non-tuberculous mycobacteria (NTM), such as Mycobacterium abscessus (Mab) are an increasing cause of human disease. While the majority of immunocompetent hosts control Mab infections, the robust survival of Mab within the environment has shaped survival in human cells to help drive persistence and cause inflammatory damage in susceptible individuals. With high intrinsic resistance to antibiotics, there is an important need to fully understand how Mab causes infection, define protective host pathways that control disease, and develop new strategies to treat those at high risk. This review will examine the existing literature related to host-Mab interactions with a focus on virulence, the host response, and therapy development. The goal is to highlight key gaps in our understanding and describe novel approaches to encourage new research avenues that better define the pathogenesis and host response against this increasingly important human pathogen.

Assessing causality is undoubtedly one of the key questions in microbiome studies for the upcoming years. Since randomized trials in human subjects are often unethical or difficult to pursue, analytical methods to derive causal effects from observational data deserve attention. As simple covariate adjustment is not likely to account for all potential confounders, the idea of instrumental variable (IV) analysis is worth exploiting. Here we propose a novel framework of antibiotic instrumental variable regression (AB-IVR) for estimating the causal relationships between microbiome and various diseases. We rely on the recent studies showing that antibiotic treatment has a cumulative long-term effect on the microbiome, resulting in individuals with higher antibiotic usage to have a more perturbed microbiome. We apply the AB-IVR method on the Estonian Biobank data and show that the microbiome has a causal role in numerous diseases including migraine, depression and irritable bowel syndrome. We show with a plethora of sensitivity analyses that the identified causal effects are robust and propose ways for further methodological developments.

Antibiotic use is known to contribute to the development of osteoporosis, although the exact mechanisms remain poorly understood. Metronidazole (MET), a commonly prescribed antibiotic for treating anaerobic infections, has been linked to alterations in the gut microbiota (GM), which in turn are associated with various adverse side effects in the host. Recent studies have shown that the GM plays a key role in regulating bone homeostasis, though the underlying mechanisms remain under investigation. In this study, we demonstrate for the first time that MET promotes inflammatory osteoporosis through gut dysbiosis, with Klebsiella variicola (K. variicola) identified as a major pathogen influencing bone metabolism. The pro-inflammatory extracellular vesicles (EVs) secreted by K. variicola induce enhanced inflammatory responses and osteoclastic differentiation in both bone macrophages and bone tissue. Notably, the use of antibiotics that target K. variicola effectively mitigates MET-induced bone loss in vivo. This study expands our understanding of the mechanisms underlying antibiotic-induced bone loss and underscores the significant role of the pathogenic bacterium K. variicola in the development of osteoporosis, providing new avenues for future research on the microbiota-gut-bone axis in bone-related diseases.

Autoimmune rheumatic diseases (ARDs) are a heterogeneous group of conditions characterized by excessive and misdirected immune responses against the body's own musculoskeletal tissues. Their exact aetiology remains unclear, with genetic, demographic, behavioural and environmental factors implicated in disease onset. One prominent hypothesis for the initial breach of immune tolerance (leading to autoimmunity) is molecular mimicry, which describes structural or sequence similarities between human and microbial proteins (mimotopes). This similarity can lead to cross-reactive antibodies and T-cell receptors, resulting in an immune response against autoantigens. Both commensal microbes in the human microbiome and pathogens can trigger molecular mimicry, thereby potentially contributing to the onset of ARDs. In this review, we focus on the role of molecular mimicry in the onset of rheumatoid arthritis and systemic lupus erythematosus. Moreover, implications of molecular mimicry are also briefly discussed for ankylosing spondylitis, systemic sclerosis and myositis.

The public health issue of bacterial multi-resistance to antibiotics has gained awareness among the public, researchers, and the pharmaceutical sector. Nevertheless, the spread of antimicrobial resistance has been considerably aggravated by human activities, climate change, and the subsequent increased release of antibiotics, drug-resistant bacteria, and antibiotic resistance genes in the environment. The extensive use of antibiotics for medical and veterinary purposes has not only induced increasing resistance but also other health problems, including negative effects on the patient's microbiome. Preventive strategies, new treatment modalities, and increased surveillance are progressively set up. A comprehensive approach is, however, lacking for urgently tackling this adverse situation. To address this challenge, we discussed here the main causes driving antimicrobial resistance and pollution of the environment by factors favorable to the emergence of drug resistance. We next propose some key priorities for research, prevention, surveillance, and education to supervise an effective clinical and sustainable response.

Shrimp farming, a highly profitable sector in global aquaculture, has seen remarkable growth in recent years. This increasing demand and the expansion of farming operations, including in Sarawak, Malaysia, highlight the sector's potential. However, the industry faces significant challenges, particularly the prevalence of vibriosis, a bacterial infection caused by Vibrio species. Contamination of food products has also increased the risk of vibriosis in humans. The widespread use of antibiotics to combat this disease has led to the rapid emergence of antimicrobial resistance (AMR) bacteria. This study specifically focuses on the isolation and characterization of phage EniLVP02, a novel bacteriophage with the potential to combat V. parahaemolyticus infections. EniLVP02 was successfully isolated from shrimp purchased at a retail market and exhibited strong lytic activity against V. parahaemolyticus strains. Structural analysis categorized EniLVP02 within the Straboviridae family, belonging to the class Caudoviricetes. The phage displayed a narrow host range and lytic nature only towards V. parahaemolyticus strains isolated from the Telaga Air shrimp farm. Phage EniLVP02 exhibited long latent period of 120 min and large burst size of 144 phages per infected cells. Stability studies revealed EniLVP02's resilience across various pH (pH 4.0-9.0) and temperature (28 °C-65 °C) conditions, particularly at physiological temperatures. Comparative genome analyses indicated its distinct evolutionary relationship and low homology with other Vibriophages, suggesting its novelty. EniLVP02 demonstrated significant potential in biofilm prevention and destruction, with absorbance (OD600 nm) reduction from 0.592 ± 0.055 to 0.204± 0.016 and from 0.843± 0.003 to 0.174± 0.026 respectively. Moreover, in the treatment of V. parahaemolyticus-contaminated shrimp meat, EniLVP02 effectively inhibit bacterial concentrations by 75.2 % at room temperature and 16.2 % at 4 °C after 24 h. Genomic sequencing revealed low similarity between EniLVP02 with other phages, suggesting its novelty. Importantly, the absence of lysogeny-related, antibiotic resistance, and virulence genes in its genome supports EniLVP02's safety for therapeutic use. This study underscores the importance of exploring phages from retail food products for therapeutic applications and highlights the promising attributes of phage EniLVP02 in combating V. parahaemolyticus infections in aquaculture. Further investigations on its compatibility with other phages and application in diverse food matrices are warranted to assess its full potential.

The development of new narrow-spectrum antibiotics is a promising approach to combat antibiotic resistance. Promysalin, a secondary metabolite isolated from Pseudomonas putida, exhibits potent species-specific inhibition of the pathogen P. aeruginosa (IC50 21 nM). Herein, the total synthesis and stereochemical assignment of promysalin, structure-activity relationship studies, and the identification of its molecular target, succinate dehydrogenase, are previously reported by the group. These findings enable computational studies of promysalin's interactions with succinate dehydrogenase, revealing a novel binding site region primed for π-π stacking interactions with a nearby tryptophan residue. It is hypothesized that new aromatic analogs of promysalin can target this beneficial interaction, potentially leading to more potent inhibitors of P. aeruginosa growth. Herein, the in silico design of these analogs, a scalable and general synthetic route to access them, and characterization of their activity against a panel of clinically relevant P. aeruginosa strains are reported.

The growing crisis of antibiotic resistance and the increasing incidence of cancer have prompted the exploration of innovative approaches, such as gene editing and antimicrobial peptides (AMPs). The human microbiome is integral to various aspects of health, disease, and therapeutic development, influencing metabolic pathways, immune function, and pathogen resistance. Recent advances in gene editing technologies, particularly CRISPR (clustered regularly interspaced short palindromic repeats), have opened new avenues for leveraging the microbiome to address complex medical challenges, including combating multidrug-resistant pathogens and cancer. The microbiome plays a crucial role in combating antibiotic resistance by modulating microbial communities, influencing pathogen survival and susceptibility to treatments. This review explores the microbiome's dynamic role in metabolic regulation, its contribution to cancer management, and how AMPs help maintain homeostasis and exhibit emerging anticancer properties, supported by both preclinical findings and clinical evidence. Additionally, CRISPR-based microbiome engineering offers potential to enhance host-microbiome interactions, optimizing therapeutic outcomes. The integration of microbiome metagenomics and proteomics has led to the discovery of novel AMPs with targeted anticancer effects. Innovative strategies, such as engineered probiotics and CRISPR-based microbiome engineering, present exciting prospects for next-generation therapies. Despite these advances, the translation of microbiome-based therapies into clinical settings remains challenging due to ethical, regulatory, and ecological hurdles. This review underscores the transformative potential of microbiome-based interventions, emphasizing the role of personalized medicine in maximizing therapeutic efficacy. Furthermore, we also address critical research gaps, limitations, and future directions, including optimizing AMP stability, delivery, and bioavailability, as well as overcoming the regulatory and ethical challenges in clinical translation.

The diameter, length, and shape of bacteria are maintained with such high fidelity that these parameters are classically used as metrics in the distinction of bacterial species. Increasing evidence indicates that bacteria transiently shift their shapes into distinctive morphologies in response to environmental changes. Elongation of bacterial length into a filamentous shape provides unique survival advantages for many bacterial species. Analysis of 42 clinical isolates of uropathogenic Escherichia coli (UPEC) revealed that filamentation to host-derived antimicrobials is a conserved phenotype. Therefore, we hypothesize that filamentation represents a conserved mechanism of pathogenic bacterial persistence that can be targeted for narrow-spectrum, anti-virulence therapies. We demonstrate that cranberries prevent SulA-mediated filamentation of UPEC. Furthermore, we identify multiple fractions of cranberries that retain anti-filamentation properties. These studies provide mechanistic insight into the clinical efficacy of cranberry for patients with recurrent urinary tract infections. Inhibition of filamentation represents a novel approach to promote bacterial pathogen susceptibility to immune and antibiotic-mediated clearance to attenuate disease.

Healthcare professionals face increasing challenges when managing older patients, a group characterized by significant interindividual variability in comorbidity patterns, homeostatic capacity, frailty status, cognitive function, and life expectancy. Complex therapeutic decisions may increase the risk of inappropriate polypharmacy, drug-drug, and drug-disease interactions in the context of age-associated pharmacokinetic and pharmacodynamic alterations, with consequent drug accumulation and toxicity.

This state-of-the-art narrative review article summarizes and critically appraises the results of original research studies and reviews published in PubMed, Scopus, and Web of Science, from inception to 9 April 2025, on age-associated changes in critical organs and systems and relevant pharmacokinetic and pharmacodynamic alterations. It also discusses the emerging role of frailty and the gut microbiota in influencing such alterations and the potential utility of machine learning techniques in identifying new signals of drug efficacy and toxicity in older patients.

The available knowledge regarding specific age-associated pharmacokinetic and pharmacodynamic alterations applies to a limited number of drugs, some of which are not frequently prescribed in contemporary practice. Future studies investigating a wider range of drugs and their patterns of use will likely enhance therapeutic efficacy and minimize toxicity in the older patient population.

The gut microbiome critically influences diverse aspects of physiology and surgical recovery. Conversely, surgery alters the microbiome, potentially predisposing to complications. We aimed to clarify the bidirectional interaction between surgery and gut dysbiosis.

On December 22nd, 2024, a systematic search of the Cochrane Library, PubMed, VHL, and WOS was completed. Relevant studies were assessed for risk of bias using STROBE and CONSORT guidelines.

Thirty studies, with 2500+ participants experiencing diverse procedures and complications, were incorporated. Although specifics varied, dysbiosis correlated with surgery and its complications. Patients with complications had more harmful bacteria and fewer beneficial bacteria. In some studies, probiotics reduced complications.

Gut dysbiosis is tied to postoperative complications in a complex, bidirectional relationship. Patients with surgical complications may have fewer beneficial and more pathogenic bacteria both before and after surgery. Early identification of dysbiosis and probiotic administration could predict or even reduce postoperative complications.

Broad-spectrum antimicrobials are commonly administered for community-acquired pneumonia (CAP); however, unnecessary administration may cause adverse events and poor outcomes. This study aimed to understand the impact of broad-spectrum anti-pseudomonal β-lactam use on clinical outcomes and healthcare resource utilization (HCRU) in inpatients with CAP and a low risk of drug-resistant pathogens (DRPs).

This historical cohort study reviewed Japan's hospital claims database (January to December of 2018) and included inpatients aged ≥ 20 years who received intravenous antimicrobial therapy for CAP. Those with high DRP risk were excluded. According to the initial antimicrobial regimen, patients were divided into broad-spectrum (anti-pseudomonal β-lactam therapy) and narrow-spectrum (non-anti-pseudomonal β-lactam therapy) groups. This study evaluated 30-day hospital mortality as a primary outcome using inverse probability of treatment weighting (IPTW) to adjust for differences between both groups and HCRU as an exploratory analysis.

A total of 15,617 patients were analyzed (2627 in the broad-spectrum group and 12,990 in the narrow-spectrum group). In the broad-spectrum group, the 30-day mortality rate was 10.6%, which was higher than that in the narrow-spectrum group (5.3%). Furthermore, it was associated with an increased 30-day mortality compared with the narrow-spectrum group after IPTW (adjusted odds ratio, 1.77; 95% confidence interval, 1.52-2.06; p < 0.001). The mean inpatient cost was USD 6139 and USD 5184 for the broad- and narrow-spectrum groups, respectively.

The initial use of anti-pseudomonal β-lactams for CAP with low DRP risk is associated with poor outcomes, including death and high HCRU. Thus, initial antimicrobials should be judiciously selected for CAP management.

The human body is habitat to a wide spectrum of microbial populations known as microbiota, which play an important role in overall health. The considerable research has mostly focused on the gut microbiota due to its potential to impact numerous physiological functions and its correlation with a variety of disorders, such as cardiovascular diseases (CVDs). Imbalances in the gut microbiota, known as dysbiosis, have been linked to the development and progression of CVDs through various processes, including the generation of metabolites like trimethylamine-N-oxide and short-chain fatty acids. Studies have also looked at the idea of using therapeutic interventions, like changing your diet, taking probiotics or prebiotics, or even fecal microbiota transplantation (FMT), to change the gut microbiota's make-up and how it works in order to prevent or treat CVDs. Exploring the cause-and-effect connection between the gut microbiota and CVDs offers a hopeful path for creating innovative microbiome-centered strategies to prevent and cure CVDs. This review presents an in-depth review of the correlation between the gut microbiota and CVDs, as well as potential therapeutic approaches for manipulating the gut microbiota to enhance cardiovascular health.

Paternal health and exposure to adverse environments in the period prior to conception have a profound impact on future generations. Adversities such as stress, diet, and toxicants influence offspring health. Emerging evidence indicates that epigenetic mechanisms including noncoding RNA, DNA methylation, and chromatin remodelling mediate these effects. Preclinical studies have contributed to advancing mechanistic understanding in the field; however, human research is limited and primarily observational. Here, we discuss the evidence linking paternal to offspring health and advocate for further research in this area, which may ultimately inform policy and healthcare guidelines to improve paternal preconception health and offspring outcomes.

Unlike the intravenous route, oral delivery systems face challenges due to an acidic gastric environment, which can degrade or inactivate therapeutic compounds before they reach the small intestine (SI). Therefore, developing oral delivery strategies that protect cargo from acidic environments and release the content in the SI is imperative. Herein, a novel approach utilizes the pH-sensitivity of alginate-based microcapsules that degrade and release the contents at pH ≥ 7.0. The microcapsules were used to encapsulate gold nanoparticles (AuNPs, a model nanozyme) of varying sizes (2, 15, and 70 nm) and horseradish peroxidase (HRP, a model enzyme). The AuNPs- and HRP-loaded microcapsules (AuNPs-MCap and HRP-PEG MCap) were unaffected at acidic pH (2.0-6.0), as the intrinsic structure and properties of encapsulated AuNPs and HRP were intact. The microcapsules rapidly released the encapsulated AuNPs and HRP at pH ≥ 7.0. In vivo, oral administration of AuNPs-MCap and HRP-PEG MCap to Wistar rats also showed significantly enhanced absorption of AuNPs and HRP in SI, leading to higher concentrations in blood than in their corresponding unencapsulated forms. Overall, the results underscore the potential of pH-responsive microcapsules for protecting pH-sensitive nanozymes, biological enzymes and other bioactive compounds from the acidic gastric environment and for effective and targeted delivery to the SI.

Healthcare-associated infections (HAIs), previously known as nosocomial infections, represent a significant threat to healthcare systems worldwide, prolonging patient hospital stays and the duration of antimicrobial therapy. One of the most serious consequences of HAIs is the increase in the rate of antibiotic resistance (AR) generated by the prolonged, frequent, and sometimes incorrect use of antibiotics, which leads to the selection of resistant bacteria, making treatment difficult and expensive, with direct consequences for the safety of patients and healthcare personnel. Therefore, timely and accurate diagnosis of HAIs is mandatory to develop appropriate infection prevention and control practices (IPC) and new therapeutic strategies. This review aimed to present the prevalence, risk factors, current diagnosis, including artificial intelligence (AI) and machine learning approaches, future perspectives in combating HAIs causative bacteria (phage therapy, microbiome-based interventions, and vaccination), and HAIs surveillance strategies. Also, we discussed the latest findings regarding the relationships of AR with climate change and environmental pollution in the context of the One Health approach. Phage therapy is an emerging option that can offer an alternative to ineffective antibiotic treatments for antibiotic-resistant bacteria causing HAIs. Clinical trials dealing with vaccine development for resistant bacteria have yielded conflicting results. Two promising strategies, fecal microbiota transplantation and probiotic therapy, proved highly effective against recurrent Clostridium difficile infections and have been shown to reduce HAI incidence in hospitalized patients undergoing antibiotic therapy. Artificial intelligence and machine learning systems offer promising predictive capabilities in processing large volumes of clinical, microbiological, and patient data but require robust data integration. Our paper argues that HAIs are still a global challenge, requiring stringent IPC policies, computer vision, and AI-powered tools. Despite promising avenues like integrated One Health approaches, optimized phage therapy, microbiome-based interventions, and targeted vaccine development, several knowledge gaps in clinical efficacy, standardization, and pathogen complexity remain to be answered.

Gastrointestinal tract of humans provides a niche to thousands of microbes, referred as gut microbiota (GM). GM establishes an intricate relationship with other organs via gut-organ axis, and modulates host health. The structure and functioning of these gut microbes can be influenced by the type of external exposome an individual experiences. Depending upon GM perturbations and host genotype, this can result in variable health implications. On the other hand, the huge arsenal of enzymes possessed by GM can chemically alter the xenobiotic structure. Its consequences can be numerous, including formation of harmful metabolites that cause organ damage, reversal of host detoxification pathways, or favourable health effects. Additionally, GM-mediated bio-transformation of pharmaceuticals can alter their pharmacokinetics and pharmacodynamics, potentially yielding variable drug responses, resulting into prolonged or ineffective treatments. To address this bi-facial relationship and the pivotal role of GM, this review incorporates recent in vitro, in vivo, and multiomics studies. It also suggests the need of machine learning approaches to decode the complex host-microbiota-xenobiotics interactions. These knowledge will aid in comprehending recent rise in chronic lifestyle-diseases which poses a huge burden on the health sector, and can also be a learning curve in making formulations and therapies for personalized treatment.

The human microbiota comprises a diverse microbial ecosystem that significantly impacts health and disease. Among its components, the gut microbiota plays a crucial role in regulating metabolic, immunologic, and inflammatory responses. Dysbiosis, an imbalance in microbial composition, has been linked to carcinogenesis through mechanisms such as chronic inflammation, metabolic disturbances, epigenetic modifications, and immune system dysregulation. Additionally, dysbiosis influences the efficacy and toxicity of cancer therapies. Given these associations, there is growing interest in leveraging the microbiota as a biomarker for cancer detection and outcome prediction. Notably, distinct microbial signatures have been identified across various cancer types, suggesting their potential as diagnostic markers. Furthermore, modulation of the microbiota presents a promising avenue for improving cancer treatment outcomes through strategies such as antibiotics, prebiotics, probiotics, fecal microbiota transplantation, dietary interventions, small-molecule inhibitors, and phage therapy. To explore these relationships, we conducted a comprehensive literature review using Web of Science, Scopus, PubMed, MEDLINE, Embase, and Google Scholar as our primary online databases, focusing on indexed peer-reviewed articles up to the present year. This review aims to elucidate the role of dysbiosis in cancer development, examine the molecular mechanisms involved, and assess the impact of microbiota on cancer therapies. Additionally, we highlight microbiota-based therapeutic strategies and discuss their potential applications in cancer management. A deeper understanding of the intricate interplay between the microbiota and cancer may pave the way for novel approaches to cancer prevention, early detection, and treatment optimization.

The extensive use of antibiotics in animal husbandry, either for therapeutic purposes or as growth promoters, has raised significant concerns about their effects on poultry. However, when antibiotics are used as therapeutic agents, their impact on the gut microbiota of poultry remains unknown. This study aimed to address this gap by simulating therapeutic application of six frequently used antibiotics (lincomycin hydrochloride, gentamicin sulfate, florfenicol injection, benzylpenicillin potassium, ceftiofur sodium, and enrofloxacin infection) and investigated their effects on the composition and structure of poultry gut microbiota. Single-molecule real-time 16S rRNA sequencing was performed to analyze fecal samples collected from chickens treated with each antibiotic to assess the impact of antibiotic exposure on gut community diversity and dominant microbial species. Although the results demonstrated that antibiotic exposure reduced gut microbiota diversity and disrupted community stability, the impacts of different antibiotics differed considerably, specifically in the number of ASVs. Notably, the dominant bacterial phyla-Pseudomonadota and Bacillota-was largely consistent across different antibiotic exposures, except 11 days after gentamicin sulfate exposure. Moreover, six third-category pathogens were identified in fecal samples, namely, Shigella boydii, Escherichia coli, Shigella flexneri, Salmonella enterica, Corynebacterium bovis, Proteus mirabilis. Of these, three strains of Corynebacterium bovis were identified as potential novel pathogenic bacteria. These findings demonstrate the critical importance of rational antibiotics use in animal husbandry. This study provides a scientific basis for improving current antibiotics use in the treatment and prevention of poultry diseases, advancing the standardization and precision of antibiotic usage.

The gut mycobiome, the fungal component of the gut microbiota, plays a crucial role in health and disease. Although fungi represent a small fraction of the gut ecosystem, they influence immune responses, gut homeostasis, and disease progression. The mycobiome's composition varies with age, diet, and host factors, and its imbalance has been linked to conditions such as inflammatory bowel disease (IBD) and metabolic disorders. Advances in sequencing have expanded our understanding of gut fungi, but challenges remain due to methodological limitations and high variability between individuals. Emerging therapeutic strategies, including antifungals, probiotics, fecal microbiota transplantation, and dietary interventions, show promise but require further study. This review highlights recent discoveries on the gut mycobiome, its interactions with bacteria, its role in disease, and potential clinical applications. A deeper understanding of fungal contributions to gut health will help develop targeted microbiome-based therapies.

Antibiotic treatment contributes to gut microbiota dysbiosis. Previous studies have shown that fecal microbiota transplantation (FMT), fecal filtrate (FF), and activated charcoal (AC) treatments can prevent gut microbiota disturbances caused by antibiotics or Clostridioides difficile infection. However, these treatments have typically been limited to restoring gut microbiota after dysbiosis, and antibiotics must be discontinued beforehand. Here, we investigated the protective effects of these treatments on gut microbiota to prevent dysbiosis during concurrent systemic ceftriaxone administration.

C57BL/6 mice that received intraperitoneal ceftriaxone for seven consecutive days were concomitantly treated with AC, FMT, FMT + AC, FF, or FF + AC via oral gavage. Gut microbiomes were analyzed using 16 S rRNA gene sequencing, and intestinal mucosal pathology was evaluated through H&E staining.

Systemic ceftriaxone administration significantly altered gut microbiota diversity and composition but did not affect intestinal mucosal histology. Alpha and beta diversity analyses showed that microbiota diversity decreased in all ceftriaxone-treated groups, with the ceftriaxone + FF + AC group retaining the highest diversity. The ceftriaxone + AC group had higher Enterococcus but lower Muribaculaceae relative abundances than the control (no ceftriaxone), ceftriaxone only, and ceftriaxone + FF + AC groups.

These results show that fecal filtrate transplantation combined with activated charcoal treatment may help balance gut microbiota diversity and reduce the presence of resistant bacteria during ceftriaxone exposure.

Food allergies (FAs) in children have become increasingly prevalent. While early life factors such as gut microbiome disruptions have been implicated, the association between neonatal antibiotic exposure and subsequent FAs remains a topic of ongoing debate. This nationwide cohort study aimed to investigate the impact of neonatal antibiotic exposure on the development of childhood FA. This population-based retrospective cohort study analyzed data from Clalit-Healthcare-Services, Israel's largest state-mandated healthcare provider. The cohort included neonates (aged 0-60 days) admitted with fever between 2011 and 2018. Patients with confirmed infectious etiologies were excluded. The cohort was divided into two groups: those who received systemic antibiotics (Antibiotic ( +)) and those who did not (Antibiotic ( -)). FA cases were identified using ICD-9 codes up to age 6. Multivariate logistic regression and survival analysis models were utilized and adjusted for inflammatory markers, maternal atopy, and socioeconomic status. Among 2780 neonates, 1220 received antibiotics, while 1560 did not. The incidence of FAs was significantly higher in the Antibiotic ( +) group compared to the Antibiotic ( -) group (2.5% vs. 1.3%, P = 0.02). Adjusted analysis revealed that systemic antibiotic exposure during the neonatal period was associated with a threefold increased risk of FA up to age 6 (OR = 2.89, 95% CI = 1.34-6.92, P = 0.01). Conclusions: This study provides strong evidence linking neonatal antibiotic exposure to an increased risk of childhood FAs, particularly in the first 2 years of life. The findings highlight the importance of judicious antibiotic use in young infants.

Bacterial infections continue to pose a major threat to public health, contributing to high mortality rates worldwide. The growing ineffectiveness of conventional antibiotics has created an urgent need for alternative solutions. Nanomaterials (NMs) have emerged as a promising approach to combating bacterial infections due to their unique physicochemical properties, and extensive research has been conducted to address this crisis, yielding notable results. However, challenges such as limited light absorption and inherent cytotoxicity remain significant concerns. Furthermore, the clinical adoption of single-mode phototherapy is often restricted by the shallow tissue penetration of traditional light sources. The second biological window (NIR-II, 950-1450 nm) offers a groundbreaking opportunity for therapeutic and diagnostic applications by enabling deeper tissue penetration. As a result, growing research efforts are dedicated to developing NIR-II activated photosensitizers and nanomaterials to overcome challenges such as poor light absorption, limited tissue penetration, and suboptimal activation. Despite significant advancements, a comprehensive review of antibacterial nanomaterials specifically designed for the NIR-II window is still lacking in literature. This review aims to fill that gap by discussing the latest advancements, challenges, and potential of light-activated antibacterial nanomaterials within the BW-II region. The goal is to enhance understanding and guide the development of more efficient nanomaterials for future biomedical and clinical applications.

The human gut microbiome represents an extended "second genome" harbouring about 1015 microbes containing >100 times the number of genes as the host. States of health and disease are largely mediated by host-microbial metabolic interplay, and the microbiome composition also underlies the differential responses to chemotherapeutic agents between people. Chemical information will be the key to tackle this complexity and discover specific gut microbiome metabolism for creating more personalised interventions. Additionally, rising antibiotic resistance and growing awareness of gut microbiome effects are creating a need for non-microbicidal therapeutic interventions. We classify chemical interventions for the gut microbiome into categories like molecular decoys, bacterial conjugation inhibitors, colonisation resistance-stimulating molecules, "prebiotics" to promote the growth of beneficial microbes, and inhibitors of specific gut microbial enzymes. Moreover, small molecule probes, including click chemistry probes, artificial substrates for assaying gut bacterial enzymes and receptor agonists/antagonists, which engage host receptors interacting with the microbiome, are some other promising developments in the expanding chemical toolkit for probing and modulating the gut microbiome. This review explicitly excludes "biologics" such as probiotics, bacteriophages, and CRISPR to concentrate on chemistry and chemical tools like chemoproteomics in the gut-microbiome context.

Over time, extensive research has underscored the pivotal role of gut microbiota in the onset and progression of various diseases, with a particular focus on fecal microbiota transplantation (FMT) as a potential therapeutic approach. The practice of transferring fecal matter from a healthy donor to a patient provides valuable insights into how alterations in gut microbiota can impact disease development and how rectifying dysbiosis may offer therapeutic benefits. Re-establishing a balanced symbiotic relationship in the gastrointestinal tract has shown positive results in managing both intestinal and systemic conditions. Currently, one of the most pressing global health issues is metabolic syndrome-a cluster of conditions that includes insulin resistance, lipid imbalances, central obesity and hypertension. In this context, FMT has emerged as a promising strategy for addressing key components of metabolic syndrome, such as improving insulin sensitivity, body weight and lipid profiles. However, further well-structured studies are needed to refine treatment protocols and establish the long-term safety and efficacy of this intervention.

Antibiotic resistance (AR) is an escalating worldwide health emergency, requiring inventive strategies for antibiotic treatment. This review examines the tactics used in designing smart antibiotics, with a specific emphasis on the mechanism of action of lolamicin, a newly developed microbiome-sparing antibiotic.

We review the recent advances in smart antibiotic development, particularly those aiming to preserve the gut microbiome while effectively targeting pathogens. The study focuses on lolamicin's selective targeting mechanism, its inhibition of the LolCDE complex in Gram-negative bacteria.

Lolamicin works by blocking the LolCDE complex, which is crucial for transporting lipoproteins in Gramnegative bacteria. It offers a significant improvement compared to conventional antibiotics and other microbiomesparing options by safeguarding the microbiome and reducing the development of resistance. However, its limited range of effectiveness - namely against certain harmful bacteria such as Pseudomonas aeruginosa - and the possibility of bacteria becoming resistant to it, remain areas of concern.

Lolamicin presents a hopeful resolution by selectively attacking Gram-negative bacteria while leaving the beneficial gut flora unharmed. Further investigation and rigorous clinical testing are essential to fully harness its promise and confirm its long-term utility in combating antibiotic resistance.

Antibacterials are among the most frequently prescribed medications. Antibacterial drugs have the unintended consequence of destroying healthy gut flora, which can lead to known adverse events such as Clostridium difficile infection. Given emerging research concerning the role of these microorganisms in the gut-brain axis and some limited epidemiological studies, the objective of this study was to determine if antimicrobial exposure is associated with increased risk for depression.

National Veterans Health Administration administrative data were used to identify 878,405 veteran patients prescribed an incident antimicrobial during calendar year 2018. Sequence symmetry analysis was used to compare the incidence of a depressive disorder in the 6 months before and after antibacterial exposure, with additional analyses conducted with other antimicrobial classes as negative controls including antifungals, antivirals, and nonsystemic antibacterials.

Antibacterial initiation was associated with a small but significant increase in the risk of incident depression (symmetry ratio [SR] = 1.04, 95% confidence interval [CI]: 1.03, 1.05), which was limited to the first 8 weeks following exposure. The strength of association varied with categories of antibacterial spectrum, from SR = 0.98 (95% CI: 0.95, 1.01) with the narrowest spectrum regimens, to SR = 1.12 (95% CI: 1.09, 1.15) with the broadest regimens. No significant association with incident depression was observed for antifungals, antivirals, and nonsystemic antibacterials.

Antibacterial exposure was associated with increased risk for a depressive disorder. These findings are consistent with emerging literature and support the need for further research investigating a causal relationship between antibacterial exposure and risk for adverse mental health outcomes.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss, affecting millions worldwide. Emerging evidence highlights the oral microbiome-a complex ecosystem of bacteria, fungi, viruses, and protozoa as a significant factor in cognitive health. Dysbiosis of the oral microbiome contributes to systemic inflammation, disrupts the blood-brain barrier, and promotes neuroinflammation, processes increasingly implicated in the pathogenesis of AD. This review examines the mechanisms linking oral microbiome dysbiosis to cognitive decline through the oral-brain and oral-gut-brain axis. These interconnected pathways enable bidirectional communication between the oral cavity, gut, and brain via neural, immune, and endocrine signaling. Oral pathogens, such as Porphyromonas gingivalis, along with virulence factors, including lipopolysaccharides (LPS) and gingipains, contribute to neuroinflammation, while metabolic byproducts, such as short-chain fatty acids (SCFAs) and peptidoglycans, further exacerbate systemic immune activation. Additionally, this review explores the influence of external factors, including diet, pH balance, medication use, smoking, alcohol consumption, and oral hygiene, on oral microbial diversity and stability, highlighting their role in shaping cognitive outcomes. The dynamic interplay between the oral and gut microbiomes reinforces the importance of microbial homeostasis in preserving systemic and neurological health. The interventions, including probiotics, prebiotics, and dietary modifications, offer promising strategies to support cognitive function and reduce the risk of neurodegenerative diseases, such as AD, by maintaining a diverse microbiome. Future longitudinal research is needed to identify the long-term impact of oral microbiome dysbiosis on cognition.

Neutrophils, as first-line immune cells, typically lose their edge within the diabetic wounds accompanied by methicillin-resistant Staphylococcus aureus (MRSA) infections (the D/M setting), playing the role of "more foe than friend" during the healing process. Specifically, reduced influx of calcium ions (Ca2+) and impaired calcium homeostasis yield the dysfunction of neutrophil sequential behaviors in pathogen killing and wound healing, manifesting as suppressed chemotaxis, decreased intracellular reactive oxygen species (ROS) generation, prolonged apoptosis, and retention of neutrophil extracellular traps (NETs). To address this challenge, this study fabricated potassium (K)-doped manganese dioxide nanoparticles (MnO2 NPs), which activated transmembrane Ca2+ channels by inducing neutrophil depolarization via electron transfer. Subsequently, this contributed to the initial Ca2+ influx and reprogrammed Ca2+-dependent behaviors of impaired neutrophils. Also, the potential antimicrobial capacity of K-MnO2 NPs created a favorable extracellular environment that restored calcium homeostasis, enabling apoptotic neutrophils to be removed timely. Therefore, the wounds treated with K-MnO2 NPs in the D/M setting exhibited potent resistance to MRSA and rapid healing, which could be attributed to the synergistic effects of K-MnO2 NPs in leveraging Ca2+ influx and maintaining calcium homeostasis. In brief, K-MnO2 NPs constitute an effective strategy to resist MRSA and rapid wound healing in the D/M setting.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic condition characterized by abnormal immune responses and intestinal inflammation. Emerging evidence highlights the vital role of gut microbiota in IBD's onset and progression. Recent advances have shaped diagnostic and therapeutic strategies, increasingly focusing on microbiome-based personalized care. Methodology: this review covers studies from 2004 to 2024, reflecting the surge in research on luminal microbial ecology in IBD. Human studies were prioritized, with select animal studies included for mechanistic insights. Only English-language, peer-reviewed articles - clinical trials, systematic reviews, and meta-analyses - were considered. Studies without clinical validation were excluded unless offering essential insights. Searches were conducted using PubMed, Scopus, and Web of Science.

we explore mechanisms for managing IBD-related microbiota, including microbial markers for diagnosis and novel therapies such as fecal microbiota transplantation, metabolite-based treatments, and precision microbiome modulation. Additionally, we review technologies and diagnostic tools used to analyze gut microbiota composition and function in clinical settings. Emerging data supporting personalized therapeutic strategies based on individual microbial profiles are discussed.

Standardized microbiome research integration into clinical practice will enhance precision in IBD care, signaling a shift toward microbiota-based personalized medicine.

Social bees, with their specialized gut microbiota and societal transmission between individuals, provide an ideal model for studying host-gut microbiota interactions. While the functional disparities arising from strain-level diversity of gut symbionts and their effects on host health have been studied in Apis mellifera and bumblebees, studies focusing on host-specific investigations of individual strains across different honeybee hosts remain relatively unexplored. In this study, the complete genomic sequences of 17 strains of Gilliamella from A. mellifera, Apis cerana and Bombus terrestris were analyzed. The analysis revealed that the strains of A. mellifera display a more expansive genomic and functional content compared to the strains of A. cerana and B. terrestris. Phylogenetic analysis showed a deep divergence among the Gilliamella strains from different hosts. Additionally, biochemistry tests and antibiotic susceptibility tests revealed that gut strains from A. mellifera exhibited a more extensive pathway for carbohydrate metabolism and a greater resistance to antibiotics than gut strains from A. cerana and B. terrestris. Strains from A. mellifera and A. cerana showed higher colonization efficiency and competitive ability whithin their respective host species, indicating a higher degree of host-specific adaptation of local gut microbiota. In addition, colonization by A. mellifera-derived strain triggers a stronger transcriptional response in the host than A. cerana-derived strain. The variation in the number of differentially expressed genes and the involvement of distinct signaling pathways across these two host species suggest species-specific adaptations to Gilliamella strains. These findings suggest that despite occupying similar niches in the bee gut, strain-level variations can influence microbial functions, and their impact on host physiological functions may vary across different strains.

Oxidative stress (OS) and gut microbiota are crucial factors influencing human health, each playing a significant role in the development and progression of chronic diseases. This review provides a comprehensive analysis of the complex interplay between these two factors, focusing on how an imbalance between reactive oxygen species (ROS) and antioxidants leads to OS, disrupting cellular homeostasis and contributing to a range of conditions, including metabolic disorders, cardiovascular diseases, neurological diseases, and cancer. The gut microbiota, a diverse community of microorganisms residing in the gastrointestinal tract, is essential for regulating immune responses, metabolic pathways, and overall health. Dysbiosis, an imbalance in the gut microbiota composition, is closely associated with chronic inflammation, metabolic dysfunction, and various diseases. This review highlights how the gut microbiota influences and is influenced by OS, complicating the pathophysiology of many conditions. Furthermore, emerging evidence has identified extracellular vesicles (EVs) as critical facilitators of cellular crosstalk between the OS and gut microbiota. EVs also play a crucial role in signaling between the gut microbiota and host tissues, modulating immune responses, inflammation, and metabolic processes. The signaling function of EVs holds promise for the development of targeted therapies aimed at restoring microbial balance and mitigating OS. Personalized therapeutic approaches, including probiotics, antioxidants, and fecal microbiota transplantation-based strategies, can be used to address OS-related diseases and improve health outcomes. Nonetheless, further research is needed to study the molecular mechanisms underlying these interactions and the potential of innovative interventions to offer novel strategies for managing OS-related diseases and enhancing overall human health.

Colorectal cancer (CRC) is the third most diagnosed cancer and the second leading cause of morbidity worldwide. In Algeria, it ranks second in mortality-related deaths. Poor lifestyle, characterized by a low-fiber diet, insufficient physical activity, tobacco use, and alcohol consumption, is strongly associated with an increased risk of developing this disease. Probiotics have demonstrated anti-inflammatory and antitumor effects in preclinical and clinical studies. The World Health Organization (WHO) and European Food Safety Authority (EFSA) have recognized their safety and effectiveness, classifying them as Generally Recognized as Safe (GRAS) and Qualified Presumption of Safety (QPS), respectively. Probiotics exhibit immunomodulatory effects and maintain the equilibrium of the gut microbiota. However, the evidence for their clinical efficacy is inadequate, and additional research is requisite to establish them as therapeutic agents rather than simply as dietary supplements. Although probiotics are, in most cases, safe, high-risk patients should exercise caution due to the potential risk of infection. This review examines the current knowledge on probiotic strains, their therapeutic potential for colorectal cancer, limitations, and areas where further research is imperative to improve their efficacy.

Oncologists increasingly recognize the microbiome as an important facilitator of health as well as a contributor to disease, including, specifically, cancer. Our knowledge of the etiologies, mechanisms, and modulation of microbiome states that ameliorate or promote cancer continues to evolve. The progressive refinement and adoption of "omic" technologies (genomics, transcriptomics, proteomics, and metabolomics) and utilization of advanced computational methods accelerate this evolution. The academic cancer center network, with its immediate access to extensive, multidisciplinary expertise and scientific resources, has the potential to catalyze microbiome research. Here, we review our current understanding of the role of the gut microbiome in cancer prevention, predisposition, and response to therapy. We underscore the promise of operationalizing the academic cancer center network to uncover the structure and function of the gut microbiome; we highlight the unique microbiome-related expert resources available at the City of Hope of Comprehensive Cancer Center as an example of the potential of team science to achieve novel scientific and clinical discovery.

Antibiotics and antiparasitics are essential tools in controlling infectious disease outbreaks in commercial aquaculture. While the negative effects of antimicrobials on the gut microbiome of various farmed fish species are well documented, the influence of underlying host factors, such as age, on microbiome responses remains poorly understood. This is especially evident for peracetic acid, whose impact on the gut microbiome has not yet been studied. Understanding how microbiome dynamics vary by host age is critical to improving antibiotic stewardship in aquaculture. In this study, juvenile and sexually mature brown trout (Salmo trutta) were used as a model to investigate the age-dependent effects of florfenicol and peracetic acid on the gut microbiome using a 16S rRNA metabarcoding approach.

Fish age significantly shaped taxonomic composition and microbial co-occurrence network structure of the gut microbiome, regardless of treatment. Juvenile trout exhibited greater microbiome volatility and a stronger response to both florfenicol and peracetic acid compared to adult fish, with disruptions persisting up to 11 days post-treatment. Temporal dynamics were also evident, with microbial shifts characterized by a decline in beneficial commensals like Cetobacterium and Lactococcus. Although overall abundance recovered by 18 days post-treatment, network positions of key microbial community members remained altered, particularly in juvenile fish. Opportunistic pathogens, including Aeromonas and Streptococcus, were enriched and assumed more central roles within the microbial networks in treated fish.

The initial composition of the gut microbiome in brown trout is strongly influenced by fish age, which in turn affects the microbiome's response to antibiotic disruption. Juveniles displayed higher susceptibility to microbiome perturbation, and although recovery was observed at the community level, network properties remained altered. This study also provides the first evidence that external peracetic acid application can disrupt gut microbial communities. Since compositional shifts are often linked to functional alterations, even short-term disruptions may have important consequences for host health in developing fish. These findings emphasize the importance of considering gut microbial community structure in relation to fish age in aquaculture management practices.

Antibiotic consumption is considered an important risk factor for Clostridioides difficile infection (CDI). This ecological analysis investigates the influence of outpatient antibiotic prescriptions in statutory health insurance (SHI) on the admission prevalence of CDI in German hospitals participating in voluntary CDI surveillance through the hospital infection surveillance system (Krankenhaus-Infektions-Surveillance-System; KISS).

The annual CDI admission prevalence of a hospital at the federal state level was associated with the outpatient antibiotic consumption of the corresponding federal state. The quantification of outpatient antibiotic prescriptions was determined as the average DDD per 1000 insured persons per day. The risk factors for CDI on hospital admission included the annual consumption of the eight substance groups aminopenicillin combinations/staphylococcal penicillins, basic penicillins, cephalosporins, quinolones, lincosamides/macrolides, nitrofurantoin/fosfomycin/nitroxoline, sulphonamides/trimethoprim and tetracyclines, the type of care provided by the hospital, and the calendar year, and were examined using multivariable regression analyses (generalized estimating equations models).

Between 2011 and 2019, the number of outpatient antibiotic prescriptions decreased from 13.9 to 10.4 DDD per 1000 insured persons per day (-25%), and the CDI admission prevalence decreased from 0.22 to 0.12 per 100 patients (-45%). Basic penicillins and cephalosporins were identified as risk factors for increased CDI admission prevalence, while nitrofurantoin/fosfomycin/nitroxoline and sulphonamides/trimethoprim were associated with decreased CDI admission prevalence.

A decrease in outpatient antibiotic prescriptions with known risk of developing CDI was associated with a decrease in hospital CDI admission prevalence. Our ecological analysis indicates that rational and restrained antibiotic use in the outpatient setting may reduce the incidence of CDI in the population requiring inpatient treatment.

Huntington's disease (HD) is a currently incurable neurogenerative disorder and is typically characterized by progressive movement disorder (including chorea), cognitive deficits (culminating in dementia), psychiatric abnormalities (the most common of which is depression), and peripheral symptoms (including gastrointestinal dysfunction). There are currently no approved disease-modifying therapies available for HD, with death usually occurring approximately 10-25 years after onset, but some therapies hold promising potential. HD subjects are often burdened by chronic diarrhea, constipation, esophageal and gastric inflammation, and a susceptibility to diabetes. Our understanding of the microbiota-gut-brain axis in HD is in its infancy and growing evidence from preclinical and clinical studies suggests a role of gut microbial population imbalance (gut dysbiosis) in HD pathophysiology. The gut and the brain can communicate through the enteric nervous system, immune system, vagus nerve, and microbiota-derived-metabolites including short-chain fatty acids, bile acids, and branched-chain amino acids. This review summarizes supporting evidence demonstrating the alterations in bacterial and fungal composition that may be associated with HD. We focus on mechanisms through which gut dysbiosis may compromise brain and gut health, thus triggering neuroinflammatory responses, and further highlight outcomes of attempts to modulate the gut microbiota as promising therapeutic strategies for HD. Ultimately, we discuss the dearth of data and the need for more longitudinal and translational studies in this nascent field. We suggest future directions to improve our understanding of the association between gut microbes and the pathogenesis of HD, and other 'brain and body disorders'.

This review highlights several basic problems associated with bacterial drug resistance, including the decreasing efficacy of commercially available antimicrobials as well as the related problem of microbiome irregularity and dysbiosis. The article explains that this present situation is addressable through LAB species, such as Streptococcus salivarius and Ligilactobacillus salivarius, which are well established synthesizers of both broad- and narrow-spectrum antimicrobials. The sheer number of antimicrobials produced by LAB species and the breadth of their biological effects, both in terms of their bacteriostatic/bactericidal abilities and their immunomodulation, make them prime candidates for new probiotics and antibiotics. Given the ease with which several of the molecules can be biochemically engineered and the fact that many of these compounds target evolutionarily constrained target sites, it seems apparent that these compounds and their producing organisms ought to be looked at as the next generation of robust dual action symbiotic drugs.

The objective of the study was to analyse possible changes in antibiotic policy with ceftazidime-avibactam during the SARS-CoV-2 pandemic in an Intensive Care Unit (ICU) to determine patient mortality 28 days after initiation of antimicrobial therapy and to describe the microorganisms that most frequently colonise critically ill patients.

Observational, single-centre, cohort study that included patients on treatment with ceftazidime-avibactam in ICU between March 2020 and September 2021. Demographic (age, sex), microbiological (colonisation, microorganisms isolated in blood cultures), pharmacotherapeutic (duration of treatment with ceftazidime-avibactam, antimicrobials used in synergy with ceftazidime-avibactam) and clinical (mortality, length of hospital stay and comorbidities) variables were collected. As associated comorbidities, we identified how many of the patients included in the study had diabetes mellitus (DM), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD) or obesity.

Eighty-nine patients were included, 85.39% of whom were male. Forty-nine patients were infected with Sars-CoV-2. Median ICU stay was 46 days (RIQ = 58-27) in SARS-CoV-2 infected and 34 days (RIQ = 51-24) in non-infected patients. Patients were on ceftazidime-avibactam treatment for a median of 8 days (RIQ = 13-4), being 7 days (RIQ = 11-2) in COVID-19 positive patients and 11 days (RIQ = 14-6) in COVID-19 negative patients (p > 0.05). Empirical treatment with ceftazidime-avibactam was started empirically in 41.57% (n = 37) of the patients. The percentage of empiric initiations in SARS-CoV-2 infected patients was 43% and in non-infected patients 40%, with no statistically significant difference between empiric initiation according to SARS-CoV-2 diagnostic status (p > 0.05). A total of 43.8% (n = 39) of the patients were colonised by a multidrug-resistant (MDR) bacterium. Regarding on the microorganisms that colonised patients had, the most frequent was Klebsiella pneumoniae, present in 66.6% of patients (n = 26 patients). Overall mortality was 41.6%, with no statistically significant differences between SARS-CoV-2 infected and non-infected patients (42.9% and 40%, respectively; p > 0.05).

The SARS-CoV-2 pandemic did not lead to a change in the criteria for the use of ceftazidime-avibactam in the critically ill patient.

Clostridioides difficile (C. difficile) is a leading cause of hospital-associated diarrhea, primarily due to gut dysbiosis following antibiotic use. Probiotics have been found to provide several benefits to hosts via modulation of the gut microbiota and their metabolites. However, till now, no conventional probiotics have been clearly proven to be an effective prophylactic option for CDI prevention. Therefore, more studies on developing specific probiotic candidates targeting CDI and improving diversity of probiotics administrated are needed. In this study, a human-origin highly diverse and highly targeted probiotic cocktail (Pro11) containing 11 various probiotic species was developed against C. difficile. Pro11 protected mice against CDI with lower clinical scores and higher survival rates, and inhibited C. difficile in vivo with less C. difficile burden and toxins production determined in colon. Histological analysis demonstrated that Pro11 strengthened gut barrier, reducing gut permeability (less secreted sCD14 in serum) and gut inflammation. In addition, gut microbiome analysis demonstrated that Pro11 increased gut microbiome diversity and beneficial species. Along with gut microbiome modulation, gut metabolites including butyrate, were significantly increased in the probiotics-fed group. Results from this study highlighted probiotics as a promising CDI therapy as gut microbiota modulators, which will lay the foundation for translating probiotics in mitigating CDI and other intestinal pathogens for clinical use.

Antibiotic therapy (ABT)-induced dysbiosis may affect the efficacy of immune checkpoint inhibitors (ICI) therapy. We investigated the association between ABT and real-world overall survival (rwOS) and progression-free survival (rwPFS) in patients with metastatic urothelial carcinoma (mUC) receiving ICI or cisplatin-based chemotherapy (CIS).

Three thousand, one hundred seventy-nine patients were included from a nationwide electronic health record-derived de-identified database. Three-month landmark Kaplan-Meier methods and log-rank tests were used to estimate rwOS/PFS between treatment modalities based on ABT groups (stratified by exposure, timing, excretion mode, and administration route). Cox proportional models with time-varying coefficients were used to investigate the associations between ABT, treatment modality, and rwOS/PFS.

A total of 402 (27.1%) ICI and 655 (38.6%) CIS patients received ABT (p < 0.001). ICI receipt (OR 0.65, p < 0.001) and advanced age (OR 0.98, p < 0.001) were associated with lower ABT use. ICI exclusive findings included a negative correlation with rwOS in patients who received post-treatment initiated (ICI median: pre-13.2 vs post-7.9 vs none-13.3 months; p = 0.009), oral (median oral-9.6 vs none-13.3 months, p = 0.03), and renally cleared (median renal-9.9 vs none-13.3 months, p = 0.04) ABT. ABT's effect was negatively associated with rwOS in ICI patients within first 6 months (HR 1.36, 95% CI 1.107-1.74, p = 0.01) but not thereafter (p = 0.7).

This study identified a potential ICI-specific negative correlation between ABT and rwOS in patients with mUC, specifically those exposed to ABT pills and receipt before treatment initiation. These results emphasize the importance of antibiotic stewardship and continued investigation of the role of gut microbiome in mUC treatment efficacy.

Background: A post-operative or late acute periprosthetic joint infection (PJI) after Total Knee Arthroplasty (TKA) requires a protocol of aggressive joint Debridement, modular implant Exchange, Component Retention, and post-operative Antimicrobial therapy (DECRA). Recently, the novel addition of intra-articular Antimicrobial Loaded Calcium Sulphate (AL-CaSO4) beads during DECRA has been utilized to improve microbial eradication. This study reviews a consecutive series of DECRA TKA procedures with AL-CaSO4 beads with a standardized antimicrobial regimen. We hypothesize AL-CaSO4 beads will not improve infection-free implant survival in compromised hosts and limbs. Methods: This consecutive series included DECRA procedures for acute post-operative or late hematogenous PJI-TKA (primary and revision) detected within 4 weeks. One gram of vancomycin powder and 240 mg of liquid tobramycin were added to 10 cc of CaSO4 powder to create 3.0 and 4.8 mm beads delivered into the joint at closure. All patients were risk stratified according to McPherson Staging and followed for a minimum of 1 year. Results: Forty-two patients were studied. The infection-free success rate of DECRA with AL-CaSO4 was 62% (26/42) at 1 year. Average bead volume per case was 18.6 cc (range = 10-40 cc). McPherson Host stage and Limb Score were found to be significantly correlated with the success of the DECRA (p < 0.05). The success rate was highest in A-hosts (87.5%), declining to 50% in B-hosts, and 25% in C-hosts. Similarly, the success rate was highest for patients with Limb score 1 (100%), declining to 58.6% with Limb score 2, and 20% with Limb score 3. Importantly, a previous episode of infection in the affected joint was associated with significantly increased failure (p = 0.000025). Conclusions: This study reports an overall higher infection-free success rate of DECRA using AL-CaSO4 beads compared to the current literature. Antibiotic beads provide an advantage in selected groups that include A or B hosts and Limb scores of 1 or 2. In C-hosts, where the immune system is weak, or Limb score 3, where the wound is compromised and leaks, antibiotic beads do not improve success. Importantly, DECRAs should not be considered curative with a prior history of joint infection. In these difficult circumstances, one should consider an exchange protocol.

Treatment with antibiotics is a major risk factor for Clostridioides difficile infection, likely due to depletion of the gastrointestinal microbiota. Two microbiota-mediated mechanisms thought to limit C. difficile colonization include the conversion of conjugated primary bile salts into secondary bile salts toxic to C. difficile growth and competition between the microbiota and C. difficile for limiting nutrients. Using a continuous flow model that simulates the nutrient conditions of the distal colon, we investigated how treatment with 6 clinically used antibiotics influenced susceptibility to C. difficile infection in 12 different microbial communities cultivated from healthy individuals. Antibiotic treatment reduced microbial richness; disruption varied by antibiotic class and microbiota composition, but did not correlate with C. difficile susceptibility. Antibiotic treatment also disrupted microbial bile salt metabolism, increasing levels of the primary bile salt, cholate. However, changes in bile salt did not correlate with increased C. difficile susceptibility. Furthermore, bile salts were not required to inhibit C. difficile colonization. We tested whether amino acid fermentation contributed to the persistence of C. difficile in antibiotic-treated communities. C. difficile mutants unable to use proline as an electron acceptor in Stickland fermentation due to disruption of proline reductase (prdB-) had significantly lower levels of colonization than wild-type strains in four of six antibiotic-treated communities tested. The inability to ferment glycine or leucine as electron acceptors, however, was not sufficient to limit colonization in any communities. The data provide further support for the importance of bile salt-independent mechanisms in regulating the colonization of C. difficile.IMPORTANCEClostridioides difficile is one of the leading causes of hospital-acquired infections and antibiotic-associated diarrhea. Several potential mechanisms through which the microbiota can limit C. difficile infection have been identified and are potential targets for new therapeutics. However, it is unclear which mechanisms of C. difficile inhibition represent the best targets for the development of new therapeutics. These studies demonstrate that in a complex in vitro model of C. difficile infection, colonization resistance is independent of microbial bile salt metabolism. Instead, the ability of C. difficile to colonize is dependent upon its ability to metabolize proline, although proline-dependent colonization is context dependent and is not observed in all disrupted communities. Altogether, these studies support the need for further work to understand how bile-independent mechanisms regulate C. difficile colonization.