Prostate Cancer Therapy And The Gut Microbiome
It may be that targeting the gut microbiome in the form of prebiotics, probiotics, or even fecal transplant may make ADT and other forms of treatment much more effective.
What does the microbiome in your gut have to do with the effectiveness of treatment for prostate cancer? Probably much more than we realize, says Brady scientist Karen Sfanos, Ph.D.
The gut microbiome can influence cancer therapy by its ability to chemically modify drugs. This relationship works both ways: Cancer-fighting drugs can also alter the composition of the bacterial species that live in the gut and this, in turn, may affect how well that treatment works.
In a recent study, Sfanos and colleagues were the first to examine the relationship between the gut microbiome and types of androgen deprivation therapy used to treat advanced prostate cancer. We found that there are measurable differences in the gut microbiome between men taking oral formulations of these medications and men who were not taking them, she says. The gut bacteria may not only influence clinical responses to ADT it also might modulate the anti-tumor effects of other drugs for advanced prostate cancer, including immunotherapy.
The Guts Many Connections To Health And Disease
While these nutrients and gut metabolites have been well studied in the context of heart disease and stroke, this is the first time that any gut microbiome metabolites have been studied clinically in relation to prostate cancer outcomes.
Dr. Hazen was the first to identify PAGlns association with increased cardiovascular disease risk. The findings were published in 2020 in Cell. Interestingly, we found that PAGln binds to the same receptors as beta blockers, which are drugs commonly prescribed to help lower blood pressure and subsequent risk of cardiac events. This suggests that part of beta blockers potent efficacy may be due to blocking the metabolites activity, said Dr. Hazen, director of the Cleveland Clinic Center for Microbiome & Human Health and chair of Lerner Research Institutes Department of Cardiovascular & Metabolic Sciences.
New insights are emerging from large-scale clinical datasets that show use of beta blockers is also associated with lower mortality due to prostate cancer, said Dr. Sharifi. We will continue to work together to investigate the possible mechanisms linking PAGln activity and prostate cancer disease processes in hopes of identifying new therapeutic targets for our patients.
The research team will continue to explore the reliability of using choline, betaine and PAGln as biomarkers of aggressive prostate cancer and how dietary interventions can be used to modulate their levels and reduce patients subsequent disease risk.
Microbial Immunotherapy For Prostate Cancer
Tumor microenvironment is typically beneficial to inflammation and immunosuppression, owing to the function of cancer-related fibroblasts in promoting tumor development and an increase in TGF- secreted by prostate tissue, which inhibits the function of NK cells and lymphocytes . Through the study of microbial metabolomics, most of the bodyâs microbes and their metabolites have the ability to stimulate the body to produce immunomodulatory effects. They may treat tumors through mechanisms that affect immune responses through their effects on host immune cells. In addition, it has been reported that prostate tissue-specific microorganisms may improve the immunogenicity of tumors and make drug-resistant cancer types sensitive to immunotherapy . In fact, the immunotherapy of microorganisms should not be underestimated.
Bacterial immunotherapy for prostate cancer: most of the current research is limited to gut bacteria, and there are few studies for prostate cancer bacteria . But prostate bacteria are indispensable in prostate cancer immunotherapy. In a recent animal experiment, it was discovered that the facultative anaerobe Escherichia coli could specifically produce TNF-α in mouse tumors . Although TNF-α can induce tumor cell apoptosis , it has been abandoned as a cancer treatment due to systemic side effects . Research on bacterial immunotherapy may now avoid this side effect and allow TNF-α to be reapplied to cancer therapy.
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How Some Gut Microbes Can Drive Resistance To Prostate Cancer Treatment
What is already known on this topicAndrogens promote the growth of prostate tumor cells, so androgen deprivation therapy is the most common treatment for people with advanced prostate cancer. However, some individuals develop resistance to ADT, which leads to tumor growth.
What this research addsResearchers found that ADT promotes the expansion of specific gut bacteria that can synthesize androgens, both in mice and people. In rodents, microbial-derived androgens that circulate in the body led to tumor growth, but using antibiotics to kill off the gut bacteria significantly slowed tumor progression. Fecal transplants from people and rodents who responded to ADT could control tumor growth in ADT-resistant mice.
The findings could help explain why some people develop resistance to ADT, and may lead to the development of microbiota-based treatments to overcome this resistance.
Androgens promote the growth of prostate tumor cells, so androgen deprivation therapy is the most common treatment for people with advanced prostate cancer. However, some individuals develop resistance to ADT, which leads to tumor growth. Now, researchers have found that ADT promotes the expansion of specific gut bacteria that can synthesize androgens, thus promoting tumor progression.
The findings, published in Science, could help explain why some people develop resistance to ADT, and may lead to the development of microbiota-based treatments to overcome this resistance.
How Diet Affects Prostate Cancer
What does that mean for you? If youve been diagnosed with prostate cancer, cutting down on inflammatory foods and eating more foods that support healthy gut bacteria might help slow its progression. Certain foods may increase bodywide inflammation, which could fuel the growth of tumors, explains Pao-Hwa Lin, Ph.D., a member of the Duke Cancer Institute in Durham, NC. That’s where the following strategies comes into play. Take these dietary steps to help improve your gut health and possibly diminish prostate cancers influence on it.
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Reagents For Metabolomic Analysis
d9-choline , L-carnitine:HCL , d9-trimethylamine N-oxide , hippuric acid , and p-cresol sulfate potassium salt were purchased from Cambridge Isotope Laboratories. p-Cresol sulfate was purchased from Cayman Chemical. d9–betaine and N–L-glutamine were purchased from C/D/N Isotopes. d9–crotonobetaine were synthesized as previously described . All other reagents were purchased as HPLC grade from either Sigma-Aldrich or Fisher Scientific Chemicals.
Prospective Analysis Sheds New Light On Prostate Cancer Risk Factors
In this study, Dr. Sharifi and his collaboratorsincluding Stanley Hazen, MD, PhD, and Eric Klein, MD,analyzed data from patients previously enrolled in the National Cancer Institutes Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.
They studied baseline levels of certain dietary nutrients and metabolites found in patients blood serum prior to prostate cancer diagnosis. They compared serum levels between healthy patients and those who went on to receive a prostate cancer diagnosis and died from aggressive prostate cancer.
The researchers found that men with elevated levels of a metabolite called phenylacetylglutamine were approximately two or three times more likely to be diagnosed with lethal prostate cancer. Phenylacetylglutamine is produced when microbes in the gut break down an amino acid called phenylalanine, which is found in many plant- and animal-based protein sources like meat, beans and soy.
In addition to PAGln, the researchers also discovered that elevated levels of two nutrients abundant in animal products including red meat, egg yolks and high-fat dairy products, called choline and betaine, were also linked with increased risk for aggressive prostate cancer.
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Prostate Cancer And The Human Microbiome
Since 2015 there has been a steady rise in the number of publications looking at the association between the human microbiome and prostate cancer development, progression, and treatment outcome. While most research has focussed on the so called direct effect on PCa of the microbiome in the prostate tissue, others have also investigated associations between PCa and the core microbiota from different body sites, the so called indirect effects , as depicted in Fig. . These have mainly focussed on the effect of the gastrointestinal microbiota and the urinary microbiome on neoplastic transformation of prostatic epithelia , but also include studies evaluating associations between PCa and prostatic and seminal fluid microbiomes .
Fig. 2
Human microbiome from different body sites have been investigated for its association with prostate cancer . GI, gastrointestinal. Image created using Biorender.com
Prostatic And Seminal Fluid Microbiome And Pca
While it is interesting to profile the prostatic and seminal fluid microbiomes for associations with PCa due to their close proximity to the prostate gland, controlling for contamination from the urinary tract in these samples is often difficult. Few studies have evaluated the prostatic and seminal fluid microbiomes in PCa . Using PCR-DGGE, one study found a significantly increased abundance of Bacteroidetes, Alphaproteobacteria, Firmicutes, Lachnospiraceae, Propionicimonas, Sphingomonas, and Ochrobactrum, and a decreased abundance of Eubacterium and Defluviicoccus in the expressed prostatic secretions from Chinese PCa patients compared to Chinese men with BPH . In this study, qPCR detection of E.coli and Enterococcus revealed that E. coli was present in significantly higher number in the EPS and seminal fluid, whereas Enterococcus was present in significantly higher number in the seminal fluid of men with PCa compared to men with BPH .
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Stay Away From Saturated Fat
If you want to destroy the beneficial bacteria living in your gut, eat saturated fat, according to a review published in Clinical Nutrition. Specifically it found high-fat and high saturated-fat diets causes negative changes to your microbiome composition. Also, excessive intake of saturated fat-rich foods like red meat, milk, and cheese is thought to contribute to the progression of prostate cancer, possibly by ramping up inflammation and the production of certain hormones, according to a review published in the International Journal of Molecular Sciences.
Gut Microbes May Be Linked To Prostate Cancer Risk
Men with prostate cancer have a distinct gut microbial profile to those with benign biopsies, which researchers say could partly explain the association between lifestyle factors and geographic differences in prostate cancer incidence.
The findings were presented at the European Association of Urology Annual Meeting in Amsterdam by Peter Boström, chief of the Department of Urology at Turku University Hospital in Finland.
Boström told Inside Precision Medicine that although it is well known that prostate cancer risk varies globally with incidence much higher in Western countries, and that lifestyle factors such as physical activity and diet affect an individuals prostate cancer risk. We know little about the mechanisms the increased/decreased risks associated with environmental and lifestyle factors.
As gut microbiota characteristics has recently been reported to be associated with many medical conditions, and gut microbiota characteristics is affected by environmental and lifestyle factors, we wanted to investigate if the microbiota composition could associate with prostate cancer risk, he said.
Boström and colleagues therefore carried out the prospective Multi-IMPROD Study, which included 181 men with suspected prostate who were undergoing ultrasound-guided biopsies and MRI scans for diagnosis.
Rectal swab samples, collected at the time of biopsy, were analyzed by RNA gene sequencing and the gut bacteria present were determined.
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Gut Bacteria May Fuel Prostate Cancer Growth
How does advanced prostate cancer continue to grow, despite hormone therapy? A new study implicates bacteria in the gut that make testosterone, fueling the tumor. This groundbreaking insight may also offer a new approach to treatment.
While the vast majority of prostate cancer is treatable, in 2021, nearly 34,000 patients are estimated to die of the disease most of an advanced form known as castration-resistant prostate cancer . These tumors continue to grow and spread, even as their fuel supplytestosteroneis lowered by androgen deprivation therapy . To date, the reasons behind progression to CRPC are not completely known, but a closer look into our gut microbiota, or bugs in the gut, may provide some answers.
According to a recent PCF-funded study by Pernigoni and colleagues published in the prestigious journal Science, when you start on ADT, bacteria in your gut can start making testosterone. This can provide prostate cancer cells with an alternative fuel supply, resulting in a cancer that can continue to grow.
Normally, trillions of bacteria and other micro-organisms live on and in our bodies, largely benefiting us through functions such as helping to digest our food and regulate our immune system. But certain bacteria may have dangerous consequences for some patients with prostate cancer.
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Effect Of Sexually Transmitted Pathogens On Prostate Cancer
Trichomoniasis caused by Trichomonas vaginalis infection is the most common sexually transmitted disease. Studies have shown that Trichomonas vaginalis increases the risk of prostate cancer. When Trichomonas vaginalis infection causes inflammation, a variety of cytokines are expressed, such as IL-6, IL-8, KF- κ B. These cytokines will interact with macrophage migration inhibitory factor, PIM-1, and prostate specific antigen to polarize macrophages into M2 and induce prostate cancer cell proliferation and migration . Another common vaginal microbe is Gardnerella vaginalis. When infected by Gardnerella vaginalis, LPCAT2, TLR3, and TGFB2 genes will be down-regulated or deleted, and the loss of the function of these genes will directly promote the progression of prostate cancer . Chlamydia trachomatis is an atypical bacterium that can be transmitted sexually. A recent in vitro study showed that Chlamydia trachomatis can proliferate in prostate cancer cells, resulting in enhanced transcription of IL-6 and FGF-2 genes, while FGF-2 can promote vascularization and metastasis of primary prostate cancer . In addition, after Chlamydia trachomatis infection, NF- kappa B was activated, TLR2 and TLR4 were significantly up-regulated, which promoted tumor progression . Therefore, early popularization of healthy sexual knowledge and safety measures may help to prevent the occurrence of prostate cancer.
Does Your Gut Microbiome Affect Prostate Cancer Treatmentfebruary 22 2022
Medically reviewed by Steven N. Gange, MD,Susan Kerrigan, MD and on February 22, 2022
Do you remember learning to wash your hands? Your school may have shown you cartoon bacteria that resembled scary monsters. They may have had sharp teeth and hands that extended from their bodies to grab you . You may have been taught how to wash away the bad germs to be healthy and safe. Do you then remember years later how shocked you were to learn that not all germs are bad? That there are actually good germs that help strengthen the body?
Good germs have a great effect on gut health. This topic has become a popular research trend over the past few years. Scientists have dedicated more time to understand how probiotics, the healthy bacteria in our gut, can improve our overall wellness. Probiotics are a part of the microbiome, a complex system of bacteria, fungi, and viruses that live in our body and promote its growth. However, sometimes even our healthy bacteria can harm us.
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Alterations To Host Metabolism And Immunity Mediated By The Microbiota
While mechanistic studies investigating microbial regulation of host metabolism in men with PCa are limited, a recent study using PCa mouse models demonstrated that certain species of the intestinal microbiota can modulate the host hormone metabolism and in turn promote cancer growth. Conversely, the study also found that circulating host androgens can alter the composition of the gut microbiota . Notably, the same study showed that Ruminococcus gnavus and Bacteroides acidifaciens were enriched in the fecal microbiota of castrated male mice, and that these species can metabolise androgen precursors, pregnenolone and hydroxypregnenolone, into downstream metabolites of the androgen biosynthesis pathway, dehydroepiandrosterone and testosterone. As prostate tumors are reliant on androgens for continued growth, such an alternate source of androgen could lead to endocrine resistance in PCa patients undergoing castration treatment as shown in PCa mouse models .
Prostate Microbiota And Prostate Cancer: A New Trend In Treatment
- 1Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
- 2Department of Stomatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- 3Institute of Medical Science of Guizhou Medical University, Guiyang, China
Although the incidence and mortality of prostate cancer have gradually begun to decline in the past few years, it is still one of the leading causes of death from malignant tumors in the world. The occurrence and development of prostate cancer are affected by race, family history, microenvironment, and other factors. In recent decades, more and more studies have confirmed that prostate microflora in the tumor microenvironment may play an important role in the occurrence, development, and prognosis of prostate cancer. Microorganisms or their metabolites may affect the occurrence and metastasis of cancer cells or regulate anti-cancer immune surveillance. In addition, the use of tumor microenvironment bacteria in interventional targeting therapy of tumors also shows a unique advantage. In this review, we introduce the pathway of microbiota into prostate cancer, focusing on the mechanism of microorganisms in tumorigenesis and development, as well as the prospect and significance of microorganisms as tumor biomarkers and tumor prevention and treatment.
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More Evidence Gut Bacteria Differ In Men With Prostate Cancer
Scientists have found a big difference between the gut microbiota of men with benign biopsies and those with prostate cancer. Even though the finding is just an association, it could help explain why some places have higher rates of prostate cancer than others.
Gut microbiota is home to the microbes that live in the digestive tract. They affect how the body works and what it does. The health of the gut microbiota has been linked to various illnesses, including those in organs remote from the intestines, but their significance in prostate cancer is unknown.
In a prospective multi-center clinical investigation , Professor Peter Bostrom and colleagues at the University of Turku analyzed patient samples. The bacteria in the digestive tracts of 181 males undergoing diagnostic testing for prostate cancer were sequenced. After MRI scans, microbiota samples were taken at the time of prostate biopsies.
The gut microbiota profiles of the 60% of the men who had prostate cancer diagnoses were noticeably different from those of the men who had benign biopsies.
Prevotella 9, a member of the Erysipelotrichaceae family, and Escherichia-Shigella, a pathogen that causes diarrhea, were found in higher concentrations in the cancer-stricken men.
In comparison to those without, they also had reduced concentrations of Jonquetella, Moryella, Anaeroglobus, Corynebacterium, and CAG-352.
Image Credit: Getty