Gut-bone axis research: unveiling the impact of gut microbiota on postmenopausal osteoporosis and osteoclasts through Mendelian randomization.

Background: Postmenopausal osteoporosis is a prevalent disease that affects the bone health of middle-aged and elderly women. The link between gut microbiota and bone health, known as the gut-bone axis, has garnered widespread attention. Methods: We employed a two-sample Mendelian randomization approach to assess the associations between gut microbiota with osteoclasts and postmenopausal osteoporosis, respectively. Single nucleotide polymorphisms associated with the composition of gut microbiota were used as instrumental variables. By analyzing large-scale multi-ethnic GWAS data from the international MiBioGen consortium, and combining data from the eQTLGen consortium and the GEFOS consortium, we identified microbiota related to osteoclasts and postmenopausal osteoporosis. Key genes were further identified through MAGMA analysis, and validation was performed using single-cell data GSE147287. Results: The outcomes of this study have uncovered significant associations within the gut microbiome community, particularly with the Burkholderiales order, which correlates with both an increase in osteoclasts and a reduced risk of postmenopausal osteoporosis. with an odds ratio (OR) of 0.400, and a P-value of 0.011. Further analysis using single-cell data allowed us to identify two key genes, FMNL2 and SRBD1, that are closely linked to both osteoclasts and osteoporosis. Conclusion: This study utilizing Mendelian randomization and single-cell data analysis, provides new evidence of a causal relationship between gut microbiota and osteoclasts, as well as postmenopausal osteoporosis. It was discovered that the specific microbial group, the Burkholderiales order, significantly impacts both osteoporosis and osteoclasts. Additionally, key genes FMNL2 and SRBD1 were identified, offering new therapeutic strategies for the treatment of postmenopausal osteoporosis.

Urgent Need for Regulatory Oversight of Human Cells, Tissues, and Cellular and Tissue-Based Products.

This Viewpoint discusses the death of a patient caused by unregulated biological products and efforts to encourage federal government oversight of such products.

Description of Corynebacterium hiratae sp. nov. isolated from a human tissue bone a novel member of Corynebacterium Genus.

BACKGROUND: Corynebacterium spp. are widely disseminated in the environment, and they are part of the skin and mucosal microbiota of animals and humans. Reports of human infections by Corynebacterium spp. have increased considerably in recent years and the appearance of multidrug resistant isolates around the world has drawn attention. OBJECTIVES: To describe a new species of Corynebacterium from human tissue bone is described after being misidentified using available methods. METHODS: For taxonomic analyses, phylogenetic analysis of 16S rRNA and rpoB genes, in silico DNA-DNA hybridization, average nucleotide and amino acid identity, multilocus sequence analysis, and phylogenetic analysis based on the complete genome were used. FINDINGS: Genomic taxonomic analyzes revealed values of in silico DNA-DNA hybridization, average nucleotide and amino acids identity below the values necessary for species characterization between the analyzed isolates and the closest phylogenetic relative Corynebacterium aurimucosum DSM 44532T. MAIN CONCLUSIONS: Genomic taxonomic analyzes indicate that the isolates analyzed comprise a new species of the Corynebacterium genus, which we propose to name Corynebacterium hiratae sp. nov. with isolate 332T (= CBAS 826T = CCBH 35,014T) as the type strain.

First Glimpse into the Genomic Characterization of People from the Imperial Roman Community of Casal Bertone (Rome, First-Third Centuries AD).

This paper aims to provide a first glimpse into the genomic characterization of individuals buried in Casal Bertone (Rome, first-third centuries AD) to gain preliminary insight into the genetic makeup of people who lived near a tannery workshop, fullonica. Therefore, we explored the genetic characteristics of individuals who were putatively recruited as fuller workers outside the Roman population. Moreover, we identified the microbial communities associated with humans to detect microbes associated with the unhealthy environment supposed for such a workshop. We examined five individuals from Casal Bertone for ancient DNA analysis through whole-genome sequencing via a shotgun approach. We conducted multiple investigations to unveil the genetic components featured in the samples studied and their associated microbial communities. We generated reliable whole-genome data for three samples surviving the quality controls. The individuals were descendants of people from North African and the Near East, two of the main foci for tannery and dyeing activity in the past. Our evaluation of the microbes associated with the skeletal samples showed microbes growing in soils with waste products used in the tannery process, indicating that people lived, died, and were buried around places where they worked. In that perspective, the results represent the first genomic characterization of fullers from the past. This analysis broadens our knowledge about the presence of multiple ancestries in Imperial Rome, marking a starting point for future data integration as part of interdisciplinary research on human mobility and the bio-cultural characteristics of people employed in dedicated workshops.

Evaluating bacterial contamination of free bone fragments falling to the ground and the effectiveness of antiseptic solutions.

OBJECTIVES: This study aims to determine the contamination incidence rate of bone fragments that have been dropped on the floor of the operating theatre, as well as how effective antimicrobial solutions are at decontaminating them. METHODS: Bone fragments obtained after 30 total knee arthroplasties were used in the study. Inert pieces of bone emerging after the bone cuts during total knee arthroplasty were divided into 1 × 1 cm fragments. The bone fragments were first left in free fall on the floor of the operating theatre and then were kept in a number of antimicrobial solutions for 15 s. Subsequently, they were microbiologically and histopathologically examined. A swab culture was also taken from the floor of the operating theatre. RESULTS: It was determined that 63.3% of osteochondral fragments in the non-intervened group were contaminated. Growth was likewise detected in all swab cultures. Microorganisms growing in the swab culture and the non-intervened group were similar and mostly Staphylococcus epidermidis and Klebsiella pneumoniae. When the growth rates of the 10% povidone-iodine and 4% chlorhexidine gluconate groups were compared with the growth rate of the non-intervened group, a statistical difference was found. No difference was determined between the growth rates of the sodium hypochlorite and the non-intervened groups. The histopathological analysis revealed no statistical difference between the groups in terms of bone marrow, vascular structure, fat tissue, and osteoblastic activity results in the osteochondral fragments CONCLUSION: Bone tissues dropped from a sterile area on the floor of the operating theatre are highly contaminated. An effective decontamination without bone cell toxicity was achieved using povidone-iodine. Although chlorhexidine gluconate solution had an effective decontamination effect compared to the non-intervened group, it was not 100% effective. Sodium hypochlorite solution was not effective in the decontamination of grafts under our working conditions.

Native bone and joint infections caused by extended-spectrum ß-lactamase-producing Enterobacterales: experience of a reference centre in the Greater Paris area.

Antibiotic treatment of native osteomyelitis caused by extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-PE) is a challenge. Limited epidemiological and outcome data are available. This retrospective cohort study included osteomyelitis patients with ESBL-PE infections treated in a reference centre for bone and joint infections (BJIs) between 2011-2019. Twenty-nine patients with native BJI (mean age, 44.4 ± 15.7 years) were analysed. Fifteen cases were paraplegic patients with ischial pressure sores breaching the hip capsule. Other cases included eight other hip infections, four tibial infections and two foot infections. Infections were mostly polymicrobial (n = 23; 79.3%), including Staphylococcus aureus (n = 13; 8 methicillin-resistant). Klebsiella pneumoniae (n = 13) was the most frequent ESBL-producing species identified, followed by Escherichia coli (n = 10), including 3 E. coli/K. pneumoniae co-infections, and Enterobacter spp. (n = 9). ESBL-PE were rarely susceptible to fluoroquinolones (n = 4; 13.8%). Most therapies were based on carbapenems (n = 22) and combination therapies (n = 19). The median duration of treatment was 41 (5-60) days. Primary control of the infection was achieved in 62.1% (18/29) of cases and up to 86.2% after second look surgeries, after a median follow-up of 6 (1-36) months. Infection with ESBL-producing K. pneumoniae was associated with failure (P = 0.001), whereas age, infection location, prior colonisation and antimicrobial therapy were not found to be predictors of outcome. ESBL-PE native BJIs are often polymicrobial and fluoroquinolone-resistant infections caused by K. pneumoniae, highlighting the need for expert centres with pluridisciplinary meetings with experienced surgeons.

An injectable gellan gum-based hydrogel that inhibits Staphylococcus aureus for infected bone defect repair.

The treatment of infected bone defects in complex anatomical structures, such as oral and maxillofacial structures, remains an intractable clinical challenge. Therefore, advanced biomaterials that have excellent anti-infection activity and allow convenient delivery are needed. We fabricated an innovative injectable gellan gum (GG)-based hydrogel loaded with nanohydroxyapatite particles and chlorhexidine (nHA/CHX). The hydrogel has a porous morphology, suitable swelling ratio, and good biocompatibility. It exerts strong antibacterial activity against Staphylococcus aureus growth and biofilm formation in vitro. We successfully established an infected calvarial defect rat model. Bacterial colony numbers were significantly lower in tissues surrounding the bone in rats of the GG/nHA/CHX group after debride surgery and hydrogel implantation in the defect regions than in rats of the blank group. Rats in the GG/nHA/CHX group exhibited significantly increased new bone formation compared to those in the blank group at 4 and 8 weeks. These findings indicate that gellan gum-based hydrogel with nHA/CHX can accelerate the repair of infected bone defects.

The Use of Mushrooms and Spirulina Algae as Supplements to Prevent Growth Inhibition in a Pre-Clinical Model for an Unbalanced Diet.

Today's eating patterns are characterized by the consumption of unbalanced diets (UBDs) resulting in a variety of health consequences on the one hand, and the consumption of dietary supplements in order to achieve overall health and wellness on the other. Balanced nutrition is especially crucial during childhood and adolescence as these time periods are characterized by rapid growth and development of the skeleton. We show the harmful effect of UBD on longitudinal bone growth, trabecular and cortical bone micro-architecture and bone mineral density; which were analyzed by micro-CT scanning. Three point bending tests demonstrate the negative effect of the diet on the mechanical properties of the bone material as well. Addition of Spirulina algae or Pleurotus eryngii or Agaricus bisporus mushrooms, to the UBD, was able to improve growth and impaired properties of the bone. 16SrRNA Sequencing identified dysbiosis in the UBD rats' microbiota, with high levels of pro-inflammatory associated bacteria and low levels of bacteria associated with fermentation processes and bone related mechanisms. These results provide insight into the connection between diet, the skeletal system and the gut microbiota, and reveal the positive impact of three chosen dietary supplements on bone development and quality presumably through the microbiome composition.

A Case of In Situ Phage Therapy against Staphylococcus aureus in a Bone Allograft Polymicrobial Biofilm Infection: Outcomes and Phage-Antibiotic Interactions.

Phage therapy (PT) shows promising potential in managing biofilm infections, which include refractory orthopedic infections. We report the case of a 13-year-old girl who developed chronic polymicrobial biofilm infection of a pelvic bone allograft after Ewing's sarcoma resection surgery. Chronic infection by Clostridium hathewayi, Proteus mirabilis and Finegoldia magna was worsened by methicillin-susceptible Staphylococcus aureus exhibiting an inducible Macrolides-Lincosamides-Streptogramin B resistance phenotype (iMLSB). After failure of conventional conservative treatment, combination of in situ anti-S. aureus PT with surgical debridement and intravenous antibiotic therapy led to marked clinical and microbiological improvement, yet failed to prevent a recurrence of infection on the midterm. This eventually led to surgical graft replacement. Multiple factors can explain this midterm failure, among which incomplete coverage of the polymicrobial infection by PT. Indeed, no phage therapy against C. hathewayi, P. mirabilis or F. magna could be administered. Phage-antibiotic interactions were investigated using OmniLog® technology. Our results suggest that phage-antibiotic interactions should not be considered "unconditionally synergistic", and should be assessed on a case-by-case basis. Specific pharmacodynamics of phages and antibiotics might explain these differences. More than two years after final graft replacement, the patient remains cured of her sarcoma and no further infections occurred.

The Human Gut Microbiota: A Key Mediator of Osteoporosis and Osteogenesis.

An expanding body of research asserts that the gut microbiota has a role in bone metabolism and the pathogenesis of osteoporosis. This review considers the human gut microbiota composition and its role in osteoclastogenesis and the bone healing process, specifically in the case of osteoporosis. Although the natural physiologic processes of bone healing and the pathogenesis of osteoporosis and bone disease are now relatively well known, recent literature suggests that a healthy microbiome is tied to bone homeostasis. Nevertheless, the mechanism underlying this connection is still somewhat enigmatic. Based on the literature, a relationship between the microbiome, osteoblasts, osteoclasts, and receptor activator of nuclear factor-kappa-Β ligand (RANKL) is contemplated and explored in this review. Studies have proposed various mechanisms of gut microbiome interaction with osteoclastogenesis and bone health, including micro-RNA, insulin-like growth factor 1, and immune system mediation. However, alterations to the gut microbiome secondary to pharmaceutical and surgical interventions cannot be discounted and are discussed in the context of clinical therapeutic consideration. The literature on probiotics and their mechanisms of action is examined in the context of bone healing. The known and hypothesized interactions of common osteoporosis drugs and the human gut microbiome are examined. Since dysbiosis in the gut microbiota can function as a biomarker of bone metabolic activity, it may also be a pharmacological and nutraceutical (i.e., pre- and probiotics) therapeutic target to promote bone homeostasis.

A 3D printed Ga containing scaffold with both anti-infection and bone homeostasis-regulating properties for the treatment of infected bone defects.

Large bone defects face a high risk of infection, which can also lead to bone homeostasis disorders. This seriously hinders the bone healing process; therefore, the help of a dual-functional scaffold that has both anti-infection and bone-homeostasis-regulating capacities is needed in the treatment of infected bone defects. In this study, a 3D printed dual-functional scaffold composed of poly-ε-caprolactone (PCL), mesoporous bioactive glasses (MBG), and gallium (Ga) was produced. In vitro experiments demonstrated the excellent antibacterial ability of the PCL/MBG/Ga scaffold against methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli). The scaffold also significantly inhibited osteoclastic activity and promoted osteogenic differentiation. Furthermore, a rabbit model with an infected bone defect in the radius was used to evaluate the in vivo bone healing capability of PCL/MBG/Ga. The results demonstrate that the PCL/MBG/Ga scaffold can significantly accelerate bone healing and prevent bone resorption, suggesting its potential for application in repairing infected bone defects.

Histoplasmosis in the Republic of Congo dominated by African histoplasmosis, Histoplasma capsulatum var. duboisii.

The Republic of Congo (RoC) is one of the African countries with the most histoplasmosis cases reported. This review summarizes the current status regarding epidemiology, diagnostic tools, and treatment of histoplasmosis in the RoC. A computerized search was performed from online databases Medline, PubMed, HINARI, and Google Scholar to collect literature on histoplasmosis in the RoC. We found 57 cases of histoplasmosis diagnosed between 1954 and 2019, corresponding to an incidence rate of 1-3 cases each year without significant impact of the AIDS epidemic in the country. Of the 57 cases, 54 (94.7%) were cases of Histoplasma capsulatum var. duboisii (Hcd) infection, African histoplasmosis. Three cases (5.3%) of Histoplasma capsulatum var. capsulatum infection were recorded, but all were acquired outside in the RoC. The patients' ages ranged between 13 months to 60 years. An equal number of cases were observed in adults in the third or fourth decades (n = 14; 24.6%) and in children aged ≤15 years. Skin lesions (46.3%), lymph nodes (37%), and bone lesions (26%) were the most frequent clinical presentations. Most diagnoses were based on histopathology and distinctive large yeast forms seen in tissue. Amphotericin B (AmB) was first line therapy in 65% of the cases and itraconazole (25%) for maintenance therapy. The occurrence of African histoplasmosis in apparently normal children raises the possibility that African histoplasmosis is linked to environmental fungal exposure.

REVIEW OF PARASITES FOUND IN EXTINCT ANIMALS: WHAT CAN BE REVEALED.

Parasitism is inherent to life and observed in all species. Extinct animals have been studied to understand what they looked like, where and how they lived, what they fed on, and the reasons they became extinct. Paleoparasitology helps to clarify these questions based on the study of the parasites and microorganisms that infected those animals, using as a source material coprolites, fossils in rock, tissue, bone, mummy, and amber, analyses of ancient DNA, immunodiagnosis, and microscopy.

The microbiota-gut-bone axis and bone health.

The gastrointestinal tract is colonized by trillions of microorganisms, consisting of bacteria, fungi, and viruses, known as the "second gene pool" of the human body. In recent years, the microbiota-gut-bone axis has attracted increasing attention in the field of skeletal health/disorders. The involvement of gut microbial dysbiosis in multiple bone disorders has been recognized. The gut microbiota regulates skeletal homeostasis through its effects on host metabolism, immune function, and hormonal secretion. Owing to the essential role of the gut microbiota in skeletal homeostasis, novel gut microbiota-targeting therapeutics, such as probiotics and prebiotics, have been proven effective in preventing bone loss. However, more well-controlled clinical trials are still needed to evaluate the long-term efficacy and safety of these ecologic modulators in the treatment of bone disorders.

The spatial distribution of aerosols in high-speed bone burring with external irrigation.

It is well-known that the use of high-speed burring devices with irrigation used in bone surgery produces aerosols, and can toss tissue particles into space. The aim of this study was to assess the spatial vertical contamination in the sterile operation field while using a high-speed cutting device at various locations. A fresh porcine knee was resected for 10 min with a high-speed burring device. To determine the spatial contamination distribution bacteria were used as a tracer. In this novel method for detecting environmental contamination droplets of the contaminated irrigation solution were collected on vertically mounted Petri dishes and the number of colony-forming units was counted. Contamination of varying intensity was observed throughout the room. The highest contamination was found perpendicular to the bur rotation axis in a distance 0.5 m from the bur, at a height of 1.4 m. Around this spot, colony-forming units count isotropically drops to less than 100 CFUs at an area of 0.5 m in diameter. The contamination decreases with increasing distance to the bur head and a main direction of contamination was identified. Placing critical sterile objects in the highly contaminated space during and after bone resection procedures should be avoided whenever possible.

Programmed Multidrug Delivery Based on Bio-Inspired Capsule-Integrated Nanocoatings for Infected Bone Defect Treatment.

Infection and delayed wound healing are two major serious complications related to traumatic injuries and cause a significant burden to patients and society. Most currently available drug delivery materials typically carry a single drug, lack protection from drug loading, and face challenges in on-demand and precisely controlled drug release. Here, we report a flower (Cirsium arvense)-inspired capsule-integrated multilayer nanofilm (FICIF), synthesized using a layer-by-layer self-assembly, for programmed multiple drug co-delivery for trauma (open fracture as an example) treatments. Our approach allows polypeptide multilayer nanofilms and innovative impregnated capsules to assemble hierarchical reservoirs with specific drug binding sites, shielding protection capability, and ordered packing structures. The resultant FICIF nanocarriers enable sustained and on-demand co-delivery of a unique immune-tuning cytokine (interleukin 12p70) and a growth factor (bone morphogenetic protein 2) in clinical use, resulting in extraordinary anti-infection (3 orders of magnitude improved bacterial killing) and bone regeneration (5 times enhanced bone healing) in treating infected rat femur fractures. The successful synthesis of these biomimetic high-performance delivery nanocoatings is expected to serve as a source of inspiration for the development of biomaterials for various clinical applications.

Clinical features and outcome of Streptococcus agalactiae bone and joint infections over a 6-year period in a French university hospital.

BACKGROUND: Bone and joint infections (BJIs) due to Streptococcus agalactiae are rare but has been described to increase in the past few years. The objective of this study was to describe clinical features and outcomes of cases of S. BJIs. METHODS: We conducted a retrospective analysis of adult cases of S. agalactiae BJIs that occurred between January 2009 and June 2015 in a French university hospital. The treatment success was assessed until 24 months after the end of antibiotic treatment. RESULTS: Among the 26 patients included, 20 (77%) were male, mean age was 62 years ± 13 and mean Charlson comorbidity index score was 4.9 ± 3.2. Diabetes mellitus was the most common comorbidity (n = 14, 54%). Six had PJI (Prosthetic Joint Infections), five osteosynthesis-associated infections, 11 osteomyelitis and four native septic arthritis. Eleven patients had a delayed or late infection: six with a prosthetic joint infection and five with an internal fixation device infection. Sixteen patients (62%) had a polymicrobial BJI, most commonly with Gram-positive cocci (75%) notably Staphylococcus aureus (44%). Polymicrobial infections were more frequently found in foot infections (90% vs 44%, p = 0.0184). During the two-year follow-up, three patients died (3/25, 12%) and seven (7/25, 28%) had treatment failure. CONCLUSION: Diabetes mellitus was the most common comorbidity. We observed an heterogenous management and a high rate of relapse.

Human major infections: Tuberculosis, treponematoses, leprosy-A paleopathological perspective of their evolution.

The key to evolution is reproduction. Pathogens can either kill the human host or can invade the host without causing death, thus ensuring their own survival, reproduction and spread. Tuberculosis, treponematoses and leprosy are widespread chronic infectious diseases whereby the host is not immediately killed. These diseases are examples of the co-evolution of host and pathogen. They can be well studied as the paleopathological record is extensive, spanning over 200 human generations. The paleopathology of each disease has been well documented in the form of published synthetic analyses recording each known case and case frequencies in the samples they were derived from. Here the data from these synthetic analyses were re-analysed to show changes in the prevalence of each disease over time. A total of 69,379 skeletons are included in this study. There was ultimately a decline in the prevalence of each disease over time, this decline was statistically significant (Chi-squared, p<0.001). A trend may start with the increase in the disease's prevalence before the prevalence declines, in tuberculosis the decline is monotonic. Increase in skeletal changes resulting from the respective diseases appears in the initial period of host-disease contact, followed by a decline resulting from co-adaptation that is mutually beneficial for the disease (spread and maintenance of pathogen) and host (less pathological reactions to the infection). Eventually either the host may become immune or tolerant, or the pathogen tends to be commensalic rather than parasitic.

Disseminated cryptococcosis and anti-granulocyte-macrophage colony-stimulating factor autoantibodies: An underappreciated association.

The development of disseminated cryptococcosis has historically occurred in patients living with advanced human immunodeficiency virus or other immunosuppressive conditions affecting T-cell function. Recently, patients with anti-cytokine neutralising autoantibodies have been recognised to be at risk for disseminated infections by opportunistic intracellular pathogens, including Cryptococcus species. Herein, we present a previously healthy 26-year-old man who was evaluated with disseminated cryptococcosis involving the bone, lung, mediastinum and brain. The patient's serum cryptococcal antigen titres were >1:1,100,000, and evaluation for an underlying immunodeficiency revealed high titres for anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies. We also review the literature of all published cases of disseminated cryptococcosis associated with the presence of anti-GM-CSF autoantibodies. Clinicians should have a heightened awareness of anti-cytokine autoantibodies in patients without a known immunodeficiency and development disseminated infections by opportunistic intracellular pathogens.