Fusobacterium nucleatum induces oxaliplatin resistance by inhibiting ferroptosis through E-cadherin/ß-catenin/GPX4 axis in colorectal cancer.

Fusobacterium (F.) nucleatum is a carcinogenesis microbiota in colorectal cancer (CRC). Growing evidence shows that F. nucleatum contributes to chemoresistance. Ferroptosis is reported to restore the susceptibility of resistant cells to chemotherapy. However, the role of gut microbiota affecting ferroptosis in chemoresistance remains unclear. Here, we examined the CRC tissues of patients using 16S rRNA sequencing to investigate the possible connection between gut microbiota dysbiosis and the relapse of CRC. We found that a high abundance of F. nucleatum in CRC tissue is associated with relapse. We further demonstrated that F. nucleatum induced oxaliplatin resistance in vitro and in vivo. The transcriptome of an F. nucleatum-infected cell revealed ferroptosis was associated with F. nucleatum infection. We perform malondialdehyde, ferrous iron, and glutathione assays to verify the effect of F. nucleatum on ferroptosis under oxaliplatin treatment in vivo and in vitro. Mechanistically, F. nucleatum promoted oxaliplatin resistance by overexpressing GPX4 and then inhibiting ferroptosis. E-cadherin/ß-catenin/TCF4 pathway conducted the GPX4 overexpression effect of F. nucleatum. The chromatin immuno-precipitation quantitative PCR (CHIP-qPCR) and dual-luciferase reporter assay showed that F. nucleatum promoted TCF4 binding with GPX4. We also determined the E-cadherin/ß-catenin/TCF4/GPX4 axis related to tumor tissue F. nucleatum status and CRC relapse clinically. Here, we revealed the contribution of F. nucleatum to oxaliplatin resistance by inhibiting ferroptosis in CRC. Targeting F. nucleatum and ferroptosis will provide valuable insight into chemoresistance management and may improve outcomes for patients with CRC.

Evaluation of Fusobacterium nucleatum Enoyl-ACP Reductase (FabK) as a Narrow-Spectrum Drug Target.

Fusobacterium nucleatum, a pathobiont inhabiting the oral cavity, contributes to opportunistic diseases, such as periodontal diseases and gastrointestinal cancers, which involve microbiota imbalance. Broad-spectrum antimicrobial agents, while effective against F. nucleatum infections, can exacerbate dysbiosis. This necessitates the discovery of more targeted narrow-spectrum antimicrobial agents. We therefore investigated the potential for the fusobacterial enoyl-ACP reductase II (ENR II) isoenzyme FnFabK (C4N14_ 04250) as a narrow-spectrum drug target. ENRs catalyze the rate-limiting step in the bacterial fatty acid synthesis pathway. Bioinformatics revealed that of the four distinct bacterial ENR isoforms, F. nucleatum specifically encodes FnFabK. Genetic studies revealed that fabK was indispensable for F. nucleatum growth, as the gene could not be deleted, and silencing of its mRNA inhibited growth under the test conditions. Remarkably, exogenous fatty acids failed to rescue growth inhibition caused by the silencing of fabK. Screening of synthetic phenylimidazole analogues of a known FabK inhibitor identified an inhibitor (i.e., 681) of FnFabK enzymatic activity and F. nucleatum growth, with an IC50 of 2.1 µM (1.0 µg/mL) and a MIC of 0.4 µg/mL, respectively. Exogenous fatty acids did not attenuate the activity of 681 against F. nucleatum. Furthermore, FnFabK was confirmed as the intracellular target of 681 based on the overexpression of FnFabK shifting MICs and 681-resistant mutants having amino acid substitutions in FnFabK or mutations in other genetic loci affecting fatty acid biosynthesis. 681 had minimal activity against a range of commensal flora, and it was less active against streptococci in physiologic fatty acids. Taken together, FnFabK is an essential enzyme that is amenable to drug targeting for the discovery and development of narrow-spectrum antimicrobial agents.

Unveiling Therapeutic Potential: Targeting Fusobacterium nucleatum's Lipopolysaccharide Biosynthesis for Endodontic Infections-An In Silico Screening Study.

Complex microbial communities have been reported to be involved in endodontic infections. The microorganisms invade the dental pulp leading to pulpitis and initiating pulp inflammation. Fusobacterium nucleatum is a dominant bacterium implicated in both primary and secondary endodontic infections. Drugs targeting the molecular machinery of F. nucleatum will minimize pulp infection. LpxA and LpxD are early acyltransferases involved in the formation of lipid A, a major component of bacterial membranes. The identification of leads which exhibit preference towards successive enzymes in a single pathway can also prevent the development of bacterial resistance. A stringent screening strategy utilizing physicochemical and pharmacokinetic parameters along with a virtual screening approach identified two compounds, Lomefloxacin and Enoxacin, with good binding affinity towards the early acyltransferases LpxA and LpxD. Lomefloxacin and Enoxacin, members of the fluoroquinolone antibiotic class, exhibit wide-ranging activity against diverse bacterial strains. Nevertheless, their effectiveness in the context of endodontic treatment requires further investigation. This study explored the potential of Lomefloxacin and Enoxacin to manage endodontic infections via computational analysis. Moreover, the compounds identified herein serve as a foundation for devising novel combinatorial libraries with enhanced efficacy for endodontic therapeutic strategies.

Lemierre syndrome with pulmonary empyema caused by Prevotella intermedia.

Lemierre syndrome is a rare disease that is most often caused by Fusobacterium necrophorum We present a case caused by Prevotella intermedia in a young, healthy man, complicated by multiple cavitary lung lesions, loculated pleural effusions requiring chest tube placement and trapezius abscess. Our case highlights (a) P. intermedia as a rare cause of Lemierre syndrome and (b) clinical response to appropriate antimicrobial therapy may be protracted.

Epidemiology and Clinical Outcomes of Fusobacterium Infections: A Six-Year Retrospective Study.

Background and Objectives: Anaerobic bacteria like Fusobacterium can lead to severe and life-threatening infections. The inherent complexities in the isolation of these bacteria may result in diagnostic and therapeutic delays, thereby escalating both morbidity and mortality rates. We aimed to examine data from patients with infections due to Fusobacterium to gain insights into the epidemiology and clinical outcomes of patients with these infections. Methods and Results: We conducted a retrospective analysis of clinical data from a cohort of patients with cultures positive for Fusobacterium species at a tertiary care medical center in the United States. Between 2009 and 2015, we identified 96 patients with cultures positive for Fusobacterium. Patients could be categorized into three groups based on the site of primary infection. Patients with head and neck infections constituted 37% (n 36). Patients with infections of other soft tissue sites accounted for 38.5% (n 37). Patients with anaerobic bacteremia due to Fusobacterium formed 24% (n 23) of the cohort. Surgical intervention coupled with antibiotic therapy emerged as cornerstones of management for patients with head and neck or other soft tissue infections, who generally exhibited more favorable outcomes. Patients with bacteremia were older, more likely to have malignancy, and had a high mortality rate. When speciation was available, Fusobacterium necrophorum was the most frequently isolated species. Conclusions: Our retrospective analysis of epidemiology and clinical outcomes of Fusobacterium infections revealed three distinct cohorts. Patients with head, neck, or soft tissue infections had better outcomes than those with bacteremia. Our findings highlight the importance of employing management strategies based on infection site and underlying comorbidities in patients with Fusobacterium infections. Further research is needed to investigate the optimal therapeutic strategies and identify prognostic indicators to improve clinical outcomes for these complex infections.

Fusobacterium nucleatum bacteremia complicated with intracranial Porphyromonas gingivalis and HSV-1 infection: a case report and literature review.

BACKGROUND: Fusobacterium nucleatum (F. nucleatum) belongs to the genus Fusobacterium, which is a gram-negative obligate anaerobic bacterium. Bacteremia associated with F. nucleatum is a serious complication, which is not common in clinic, especially when it is combined with other intracranial pathogenic microorganism infection. We reported for the first time a case of F. nucleatum bacteremia combined with intracranial Porphyromonas gingivalis (P. gingivalis) and herpes simplex virus type 1(HSV-1) infection. CASE PRESENTATION: A 60-year-old woman was admitted to our hospital with a headache for a week that worsened for 2 days. Combined with history, physical signs and examination, it was characterized as ischemic cerebrovascular disease (ICVD). F. nucleatum was detected in blood by matrix-assisted laser desorption/ionization time-offight mass spectrometry (MALDI-TOF-MS). Meanwhile, P. gingivalis and HSV-1 in cerebrospinal fluid (CSF) were identified by metagenome next generation sequencing (mNGS). After a quick diagnosis and a combination of antibiotics and antiviral treatment, the patient recovered and was discharged. CONCLUSION: To our knowledge, this is the first report of intracranial P. gingivalis and HSV-1 infection combined with F. nucleatum bacteremia.

The first case report: diagnosis and management of necrotizing fusobacterium lung abscess via BALF next-generation sequencing.

BACKGROUND: Fusobacterium necrophorum (F. necrophorum)-induced necrotizing pneumonia is a rare but severe pulmonary infection. Insufficient microbiological detection methods can lead to diagnostic difficulties. METHODS: We report a case of F. necrophorum lung abscess diagnosed by next-generation sequencing (NGS) of bronchoalveolar lavage fluid (BALF). RESULTS: BALF-NGS detected F. necrophorum, guiding subsequent targeted antibiotic therapy. With active drainage and metronidazole treatment, the patient's condition was effectively treated. CONCLUSION: BALF-NGS is a valuable tool for the rapid diagnosis of infections caused by difficult-to-culture bacteria. It played a decisive role in the early identification of F. necrophorum, enabling timely and targeted antibiotic intervention. Early diagnosis and appropriate treatment are crucial for the management of F. necrophorum pneumonia.

Fusobacterium necrophorum intratonsillar abscess as a source of bacteremia in a patient with a history of substance abuse.

A 22-year-old male, with a history of recreational drug use, was admitted with a 24-hour history of sore throat, bilateral otalgia, fever, chills, sweats, and pain in the upper chest. The blood cultures were positive for Fusobacterium necrophorum. A thoracic and neck soft tissue computed tomography (CT) scan revealed an intratonsillar abscess and pulmonary septic emboli. Initial treatment with Piperacillin-tazobactam and Clindamycin was de-escalated after 5 days. The patient made a complete recovery after 22 days of antibiotic treatment.

Fusobacterium/Peptostreptococcus - A Case Report of Community- Acquired Empyema Resulting in Surgical Decortication with Prolonged Antibiotic Therapy: A Case Series and Review of the Literature.

Background: Infections caused by anaerobic bacteria occur frequently and can be serious and life-threatening. Anaerobes are a rare cause of community-acquired pneumonia with Streptococcus pneumonia and respiratory viruses being the most frequently detected pathogens. We, herein, report a case of Fusobacterium/Peptostreptococcus parapneumonic effusion with empyema in a patient without risk factors for aspiration pneumonia. This case presents an opportunity to discuss an unusual case of community-acquired empyema secondary to anaerobic infection in a patient without the common risk factors for aspiration.

Case Presentation: A 59-year-old male patient without significant past medical history apart from a twenty-five-year history of smoking presented due to left flank pain and shortness of breath. Findings of a complicated parapneumonic effusion were found on imaging, resulting in surgical decortication and prolonged antibiotic therapy.

Discussion: Parapneumonic effusions and empyema are relatively common complications of pneumonia. It is important to note that the incidence of anaerobic empyema has been on the rise due to more modern culturing techniques.

Conclusion: This case highlights an unusual presentation of community-acquired empyema secondary to anaerobes without any risk factors for aspiration pneumonia. Therefore, clinicians should consider the possibility of anaerobic coverage in the treatment of community-acquired empyema in the appropriate setting.

Peritonsillar abscess caused by Mycoplasma hominis and Fusobacterium necrophorum following oral sex.

Mycoplasma hominis is a bacterium that colonizes the genital tract of some females and males, as well as their respiratory tracts. Although only two cases of deep neck infection have been reported, the associations between the onset and sexual intercourse have not been reported. A healthy 19-year-old female was diagnosed with a left peritonsillar abscess. The patient had sexual intercourse with a new partner, including oral sex, two days prior to symptom onset. It was not known whether the male partner had urethritis symptoms. M. hominis and Fusobacterium necrophorum were isolated from the abscess culture. The patient's condition improved after drainage, and sulbactam ampicillin was switched to oral clindamycin.

Cryptogenic pyogenic liver abscess caused by Fusobacterium necrophorum in an immunocompetent patient.

Pyogenic liver abscesses are potentially fatal conditions that require prompt treatment with drainage and appropriate antimicrobial therapy. Fusobacterium necrophorum is a gram-negative rod that is found in the oral cavity, gastrointestinal tract and female genital tract. It is an extremely rare cause of liver abscess, particularly in the absence of risk factors or exposures. We describe an unusual case of a cryptogenic F. necrophorum hepatic abscess without a clear source despite extensive investigation in a young, immunocompetent patient without known risk factors or exposures for such an infection.

Effects of metronidazole on colorectal cancer occurrence and colorectal cancer liver metastases by regulating Fusobacterium nucleatum in mice.

OBJECTIVE: Colorectal cancer (CRC) represents a leading cause of cancer-related deaths. Metronidazole (MNZ) is exceedingly implicated in CRC. This study explored the roles of MNZ in mouse CRC occurrence and liver metastasis (CRLM). METHODS: Male BALB/c nude mice were subjected to CRC and CRLM modeling, orally administration with MNZ (1 g/L) 1 week before modeling, and disease activity index (DAI) evaluation. Fresh stool and anal swab samples were collected on the morning of the 28th day after modeling. The relative expression of Fusobacterium nucleatum (F. nucleatum) DNA was assessed by quantitative polymerase chain reaction. After euthanasia, tumor tissues and liver tissues were separated and the tumor volume and weight change were measured. The liver tissues were stained with hematoxylin-eosin to quantitatively analyze the metastatic liver nodules. Malignant tumor biomarker Ki67 protein levels in liver tissues/DNA from stool samples were detected by immunohistochemistry/high-throughput 16S rRNA gene sequencing. Bioinformatics analysis was performed on the raw sequence data to analyze microbial community richness (Chao1 index, ACE index) and microbial community diversity (Shannon index). RESULTS: The DAI and F. nucleatum DNA relative expression in feces and anal swabs of the CRC and CRLM groups were raised and repressed after MNZ intervention. MNZ repressed tumor occurrence and growth in mice to a certain extent, alleviated CRLM malignant degree (reduced liver metastases and Ki67-positive cell density/number), and suppressed CRC liver metastasis by regulating intestinal flora structure, which affected the intestinal characteristic flora of CRC and CRLM mice. CONCLUSION: MNZ suppressed CRC occurrence and CRLM in mice by regulating intestinal F. nucleatum.

Fusobacterium Necrophorum bacteremia involving multi-organ systems.

A 62-year-old African American man with a history of avascular necrosis (AVN) of the right hip joint presented with severe right hip pain, dyspnea, fever, tachycardia, and hypertension. Computed tomography (CT) scan showed bilateral airspace opacities with a mild tree-in-bud nodularity in the left lower lobe. Ultrasonography of the lower extremities revealed a deep venous thrombus (DVT) in the right deep veins. Blood cultures grew Fusobacterium necrophorum. CT and magnetic resonance imaging showed right hip joint destruction and septic arthritis. The patient had a complicated hospital course leading to total hip arthroplasty with antibiotic-impregnated cementing.

Culture-Negative Fusobacterium nucleatum Brain Abscess and Pleural Empyema Cases Revealed by 16S rRNA Sequencing.

BACKGROUND: We reported two Fusobacterium nucleatum cases each of brain abscesses and pleural empyema, using 16S rRNA sequencing technology. METHODS: We reviewed clinical records and microbiological findings in four patients with F. nucleatum infection. RESULTS: All conventional culture results from peripheral blood, cerebrospinal fluid, and pleural fluid samples were found to be negative for this pathogen. Three patients were treated with antimicrobial agents for more than a week before specimen sampling. All patients recovered from their fusobacterial infections and were discharged. CONCLUSIONS: Molecular identification methods such as 16S rRNA sequencing should accompany conventional culture to detect obligate anaerobic bacteria in deep-seated sites and organs.

Complex Lemierre syndrome with multisystemic abscesses.

We present here the challenging case of severe Lemierre syndrome in a healthy woman in her late twenties, whose clinical presentation was characterised by lung abscesses and disseminated systemic abscesses in the brain, the abdomen and the soft-tissues, as a likely consequence of a patent foramen ovale. Blood cultures were positive for Fusobacterium necrophorum and a right lingual vein thrombosis was detected at a late stage when the patient developed a septic shock. Initial antimicrobial therapy with metronidazole and ceftriaxone was modified to meropenem due to progressive worsening. The patient underwent laparoscopy and neurosurgical drainage of a cerebral abscess. She spent many days in the intensive care unit and recovered fully after 6 weeks on meropenem therapy. Although considered rare, the incidence of Lemierre syndrome, a potentially life-threatening condition, is increasing. The clinician should promptly recognise and treat it while being aware of its potential atypical presentations.

Atypical involvement of the thyro-linguo-facial vein in Lemierre syndrome.

Fusobacterium necrophorum is a Gram-negative anaerobic bacterium that can lead to severe infection in young patients even without immunodeficiency. Due to the length of time for isolation and speciation of this Gram-negative bacillus (typically 5-8 days), and its potential mortality, broad-spectrum antibiotic therapy should be started without delay. With a cervical thrombosis, even on an unusual site and with a standard condition such as tonsillitis, Lemierre syndrome should be considered. We report a case of Lemierre syndrome in a previously healthy young woman.

Myometritis with pelvic septic vein thrombophlebitis secondary to Fusobacterium necrophorum sepsis.

A young woman in her 20s presented with fever, abdominal pain and malodourous vaginal discharge. She was found to be in septic shock, in the setting of a recent medical abortion with subsequent intrauterine device placement. Her blood cultures grew Fusobacterium necrophorum Despite appropriate antibiotic therapy, the fever failed to defervesce. Subsequent evaluation revealed septic thrombophlebitis of the right gonadal vein and branches of the right iliac vein. She improved with a prolonged course of targeted antimicrobial therapy.

Atypical presentation of Lemierre syndrome in a young healthy man with acute jaundice.

This report presents a case of Lemierre syndrome caused by Fusobacterium necrophorum in a healthy young adult who presented atypically with shortness of breath and jaundice but no clinical or diagnostic evidence of thrombophlebitis. Due to this unusual presentation with jaundice, diagnosis was challenging and delayed. However, the patient was successfully initiated on a prolonged course of intravenous antibiotics; he required a period in the intensive care unit and was discharged without significant complications. This report aims to raise awareness of the diagnosis and treatment of this rare condition and to highlight both common and unusual presentations of the syndrome.

Diagnosis, treatment and prognosis of otomastoiditis induced by Fusobacterium necrophorum: A retrospective multicentre cohort study.

OBJECTIVES: Otomastoiditis caused by the anaerobic Fusobacterium necrophorum (F. necrophorum) often induces severe complications, such as meningitis and sinus thrombosis. Early diagnosis is difficult, partly because little is known about specific early signs. Comprehensive research about clinically chosen antimicrobial therapy has not been done yet and prognostic information about otomastoiditis caused by F. necrophorum is scarce. More knowledge about this subject is required. METHODS: In this retrospective cohort study, we included all cases of otomastoiditis caused by F. necrophorum treated in two university medical centres in the Netherlands during the past 10 years. Data was gathered from patient records and analysed using independent sample T-tests and Chi2-tests. RESULTS: This study reveals that otomastoiditis caused by F. necrophorum potentially induces neurological sequelae. Thereby, 80% of all included patients (n = 16) needed readmission within six months due to recurrence or complications of otomastoiditis caused by F. necrophorum. Mean (range) of age, CRP and temperature were 4.5 years (0.9-29.3), 243 mg/L (113-423) and 40 °C (37-41). All patients were hospitalized and treated with antibiotics, mostly metronidazole (n = 13/16) and a ß -lactam (n = 15/16). Additional treatment contained low molecular weight heparin (83%, n = 10/12), dexamethasone (78%, n = 7/9) and/or surgery (80%, n = 12/16, whereof 9/12 mastoidectomy). CONCLUSIONS: Patients and/or their parents need to be informed about this potential unfortunate prognosis when otomastoiditis caused by F. necrophorum is diagnosed. To improve early diagnosis, otomastoiditis caused by F. necrophorum should be suspected and therefore immediately cultured when a) young children present with otomastoiditis, with b) high CRP values, and/or c) vomiting and decreased consciousness.

A case report of severe Fusobacterium nucleatum sepsis secondary to nephrectomy.

BACKGROUND: Fusobacterium nucleatum (F. nucleatum) is a resident anaerobic bacterium, which in rare cases may invade blood from the head and neck or the digestive tract to cause bacteremia and induce venous thrombosis. F. nucleatum is closely related to abdominal tumors, but it has not been reported in relation to renal tumors. We report herein a possible case. CASE PRESENTATION: This patient had kidney cancer with thrombosis in the right renal vein but had no sign of infection. After radical nephrectomy, thrombi formed in his left renal vein, and when removed, severe sepsis occurred. He did not respond to treatment with antibiotics and died, but the blood culture done confirmed that he had F. nucleatum bacteremia. CONCLUSION: F. nucleatum may also be associated with kidney cancer, and could cause post-operative renal vein thrombosis, and sepsis or septic shock after thrombectomy.