Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy

Proceedings of the National Academy of Sciences, Journal Year: 2020, Volume and Issue: 117(13), P. 7374 - 7381

Published: March 13, 2020

Irinotecan treats a range of solid tumors, but its effectiveness is severely limited by gastrointestinal (GI) tract toxicity caused gut bacterial β-glucuronidase (GUS) enzymes. Targeted GUS inhibitors have been shown to partially alleviate irinotecan-induced GI damage and resultant diarrhea in mice. Here, we unravel the mechanistic basis for protection microbial using vivo models. We use vitro, fimo, models determine whether inhibition alters anticancer efficacy irinotecan. demonstrate that single dose irinotecan increases activity 1 d reduces intestinal epithelial cell proliferation 5 d, both blocked inhibitor. In tumor xenograft model, prevents maintains antitumor Remarkably, inhibitor also effectively blocks striking bloom Enterobacteriaceae immune-deficient genetically engineered mouse model cancer, alleviates damage, improves survival, does not alter composition; however, allowing intensification, it dramatically irinotecan's effectiveness, reducing tumors fraction achieved alone, while simultaneously promoting regeneration. These results indicate targeted enzyme can improve cancer chemotherapeutic outcomes protecting epithelium from dysbiosis proliferative crypt damage.

Language: Английский

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Role of the gut microbiota in anticancer therapy: from molecular mechanisms to clinical applications

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 13, 2023

Abstract In the past period, due to rapid development of next-generation sequencing technology, accumulating evidence has clarified complex role human microbiota in cancer and therapeutic response. More importantly, available seems indicate that modulating composition gut improve efficacy anti-cancer drugs may be feasible. However, intricate complexities exist, a deep comprehensive understanding how interacts with is critical realize its full potential treatment. The purpose this review summarize initial clues on molecular mechanisms regarding mutual effects between development, highlight relationship microbes immunotherapy, chemotherapy, radiation therapy surgery, which provide insights into formulation individualized strategies for management. addition, current emerging microbial interventions as well their clinical applications are summarized. Although many challenges remain now, great importance cannot overstated strategies, it necessary explore holistic approach incorporates modulation cancer.

Language: Английский

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A Procarcinogenic Colon Microbe Promotes Breast Tumorigenesis and Metastatic Progression and Concomitantly Activates Notch and β-Catenin Axes

Cancer Discovery, Journal Year: 2021, Volume and Issue: 11(5), P. 1138 - 1157

Published: Jan. 6, 2021

The existence of distinct breast microbiota has been recently established, but their biological impact in cancer remains elusive. Focusing on the shift microbial community composition diseased compared with normal breast, we identified presence Bacteroides fragilis cancerous breast. Mammary gland as well gut colonization enterotoxigenic (ETBF), which secretes B. toxin (BFT), rapidly induces epithelial hyperplasia mammary gland. Breast cells exposed to BFT exhibit "BFT memory" from initial exposure. Intriguingly, or duct ETBF strongly growth and metastatic progression tumor implanted ducts, contrast nontoxigenic fragilis. This work sheds light oncogenic a procarcinogenic colon bacterium progression, implicates β-catenin Notch1 axis its functional mediators, proposes concept that can have far-reaching implications after exposure ETBF. SIGNIFICANCE: is an inhabitant tissue, triggers augments metastasis. Short-term elicits long-term implications, functionally mediated by pathways.This article highlighted In Issue feature, p. 995.

Language: Английский

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The semen microbiome and its impact on sperm function and male fertility: A systematic review and meta‐analysis

Andrology, Journal Year: 2020, Volume and Issue: 9(1), P. 115 - 144

Published: Aug. 14, 2020

Male factor is attributable in up to 50% of cases infertility. In vitro studies demonstrate that bacteria can negatively impact sperm function. The use next-generation sequencing techniques has provided a better understanding the human microbiome, and dysbiosis been reported health. Evidence regarding semen microbiome on function fertility remains conflicting.A systematic search was conducted accordance with Preferred Reporting Items for Reviews Meta-analysis (PRISMA) statement. databases MEDLINE, OVID PubMed were searched identify English language related identification infertile fertile men, between 1992 2019. Fifty-five observational included, 51 299 subjects. We included identifying using sequencing, culture or polymerase chain reaction.The rich diverse both men. Three NGS clustering seminal predominant species. Lactobacillus Prevotella dominant respective clusters. associated improvements parameters. appeared exert negative effect quality. Bacteriospermia impacted concentration progressive motility, DNA fragmentation index (DFI; MD: 3.518, 95% CI: 0.907 6.129, P = .008). There an increased prevalence ureaplasma urealyticum men (OR: 2.25, 1.47-3.46). Ureaplasma morphology. no difference chlamydia trachomatis significant Enterococcus faecalis total Mycoplasma hominis concentration, PM morphology.Ureaplasma urealyticum, faecalis, parameters, whereas appears protect These findings may facilitate development novel therapies (eg probiotics), although evidence inconclusive further are needed investigate this association.

Language: Английский

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Periodontal pathogens are a risk factor of oral cavity squamous cell carcinoma, independent of tobacco and alcohol and human papillomavirus

International Journal of Cancer, Journal Year: 2019, Volume and Issue: 145(3), P. 775 - 784

Published: Jan. 24, 2019

Over the past decade, there has been a change in epidemiology of oral cavity squamous cell cancer (OC‐SCC). Many new cases OC‐SCC lack recognized risk factors smoking, alcohol and human papilloma virus. The aim this study was to determine if microbiome may be associated with nonsmoking HPV negative patients. We compared HPV‐negative nonsmoker OC‐SCC(n = 18), premalignant lesions(PML) (n 8) normal control patients 12). Their sampled by wash defined 16S rRNA gene sequencing. report that periodontal pathogens Fusobacterium, Prevotella, Alloprevotella were enriched while commensal Streptococcus depleted OC‐SCC. Based on four genera plus marker genus Veillonella for PML, we classified into two types. Gene/pathway analysis revealed progressive increase genes encoding HSP90 ligands TLRs 1, 2 4 along controls→PML → progression sequence. Our findings suggest an association between non smoking

Language: Английский

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