DOI: 10.6084/m9.figshare.27290651
title: Microbiome and bladder cancer: the role of probiotics in treatment

description: Bladder cancer (BCa) remains a significant global health challenge, with increasing interest in the role of the bladder microbiome in its pathogenesis, progression and treatment outcomes. The complex relationship between bladder cancer and the microbiome, as well as the potential impact of probiotics on treatment effectiveness, is currently under investigation. Research suggests that the microbiota may influence BCa recurrence prevention and enhance the efficacy of the Bacillus Calmette–Guérin (BCG) vaccine. Recent studies reveal differences in the bladder microbiome between individuals without bladder cancer and those with the disease. In the healthy bladder, <i>Streptococcus</i> and <i>Lactobacillus</i> are consistently identified as the most prevalent genera. However, in men, the predominant bacterial genera are <i>Staphylococcus</i>, <i>Corynebacterium</i> and <i>Streptococcus</i>, while in women with bladder cancer, <i>Gardnerella</i> and <i>Lactobacillus</i> are dominant. Probiotics, particularly <i>Lactobacillus</i> spp., can exhibit anti-tumor properties by competing with pathogenic strains involved in carcinogenesis or by producing regulatory substances. They regulate cancer signaling, induce apoptosis, inhibit mutagenic activity, downregulate oncogene expression, induce autophagy, inhibit kinases, reactivate tumor suppressors and prevent metastasis. These mechanisms have shown promising results in both preclinical and some clinical studies. Bladder cancer is the tenth most common cancer globally. It is affected by factors such as age, gender, smoking habits, genetic predispositions, exposure to occupational chemicals, contaminated drinking water and a history of infectious diseases. The microbiome is the collection of all microbes that naturally live inside us. Probiotics are live microbes that stimulate the growth of a healthy microbiome and are widely used to address various health issues. We discuss their potential anti-tumor properties. Bladder cancer (BCa) is classified into two main types: muscle-invasive bladder cancer (MIBC) and superficial “non-muscle-invasive” bladder tumors (NMIBC), based on histological and biological characteristics. Risk factors for BCa include age, gender, smoking (one of the most significant risk factors), host genetics, exposure to occupational chemicals, contaminated drinking water, infections such as schistosomiasis, urinary tract infections and viral infections. Recent advances in high-throughput sequencing techniques have revealed differences in urinary microbiota between men and women. Research suggests that modifying the microbiota may reduce the risk of BCa or prevent disease recurrence. Probiotics enhance the function of dendritic cells (DCs), which play a crucial role in immune regulation by activating natural killer (NK) cells. With the advancement of molecular technologies such as high-throughput DNA sequencing and improved culture methods, the notion that the bladder is sterile has been disproven. <i>Lactobacillus</i> is the most prevalent species found in healthy female urine microbiomes. The male bladder microbiome is less diverse compared with the female bladder microbiome, with a higher prevalence of <i>Staphylococcus</i>, <i>Corynebacterium</i> and <i>Streptococcus</i>. Bacteria from the <i>Firmicutes</i> phylum are the primary microorganisms found in samples from both male and female BCa patients. Urine is the most suitable specimen for detecting the BCa microbiome due to its elevated salt levels, which help preserve the microbiome and nucleic acids. Fresh-frozen tissue (FFT) samples are considered the “gold standard” for high-throughput microbiome sequencing, as they effectively preserve DNA by enabling immediate freezing. Inflammation, bacterial toxins, biofilm formation, signaling pathways, epithelial damage, infection and microbial metabolites are mechanisms by which microorganisms affect BCa. Chronic bladder inflammation, long-term catheter use and superficial bladder inflammation are risk factors for BCa. Understanding the impact of microbiota on inflammatory cytokines and their interactions is crucial to comprehending the mechanisms contributing to cancer development. Bacterial biofilms contribute to chronic inflammation in the genitourinary system by interacting with epithelial cells and increasing the risk of bladder tumorigenesis. The development of BCa is driven by a combination of metabolic abnormalities, including inflammation, oxidative stress and angiogenesis. The virulence factors of pathogenic bacteria include bacterial toxins that disrupt cellular signaling, affecting processes such as cell proliferation, cell cycle progression, DNA repair and dysregulation, all of which are closely linked to oncogenesis. During chemotherapy treatment in BCa patients, no significant changes were observed in alpha and beta microbiome diversity metrics. Microbial metabolites can modulate signaling pathways, influence gene expression, alter cytokine levels within the tumor microenvironment and affect cell function. Bacillus Calmette–Guérin (BCG) is generally considered a safe therapeutic agent for NMIBC patients, though some adverse events have been observed in individuals treated with BCG. Human innate immunity, including antimicrobial peptides (AMPs), induces a low response rate to BCG, hindering its internalization. Probiotics can exert anti-tumor effects through various mechanisms, including modulating the gut microbiota, regulating the immune system, maintaining intestinal conditions, influencing metabolic activities, reducing inflammation, improving nutrient absorption and inhibiting carcinogenesis. Well-designed trials are needed to determine the most effective probiotic dosage, strain and delivery method.