Exploiting Human Microbiota-associated in Vivo Models for Mechanistic Studies to Understand the Benefits of Dietary Fibre Supplementation in Patients With Prostate Cancer
Exploiting Human Microbiota-associated in Vivo Models for Mechanistic Studies to Understand the Benefits of Dietary Fibre Supplementation in Patients With Prostate Cancer
The digestive tract (large intestine) contains microorganisms that digest complex carbohydrates in food to produce chemical substances which are beneficial to human health. The population of these microorganisms in faeces (stool samples) could be used to diagnose the health status of a person and this can be changed with the use of antibiotics, diet, radiotherapy or infection.
Dietary fibre supplements can help provide nutrients for the beneficial bacteria from the large intestine to produce useful chemicals that may delay growth or even shrink prostate cancer in patients.
The investigators will feed mice diets containing several dietary fibres (including inulin, pectin and hemp hull) and also faeces from healthy male human volunteers over 60 years old to see what effect this has on the makeup of the bacteria in their gut and the resulting beneficial metabolites (chemicals). For this work, the research team need to obtain four to six fresh faecal samples on the same day, so that these can be mixed fresh and stored for use as faecal microbiota transplant (FMT) in the mice.
The researchers will then test how altering the gut microorganisms with faeces and dietary fibre supplements can influence the growth of prostate cancer cell tumours in mice. The investigators expect to see an effect of the fibres in promoting beneficial bacteria and in shrinking the tumours.
This work will allow the investigators to identify dietary fibres that could be used in nutritional therapies for management of prostate cancer patients in future.
Prostate cancer is the commonest cancer in men and the fifth most common cause of cancer-related deaths globally. Increased prostate-specific antigen (PSA) screening and longer life expectancies in men have resulted in a substantial increase in the incidence and prevalence of prostate cancer in older men. Between 2021 and 2022, over 50,000 newly diagnosed cases of prostate cancer were reported in the UK, representing a 27% increase in incidence compared to 2019 and causing over 16,000 deaths.
Prostate cancer in its initial stages maybe asymptomatic and progresses slowly, meaning that some men do not need immediate active treatment but can be monitored on 'active surveillance'. Active surveillance was developed as an approach to addressing overtreatment; by delaying or preventing unnecessary definitive treatment, typically surgical removal of the prostate (radical prostatectomy, RP) or radical radiotherapy to the prostate (RT), and their related complications. It involves routine monitoring of PSA levels, medical imaging, digital rectal exams, and prostate biopsies and is recommended for prostate cancer patients with a low risk of developing aggressive tumours.
The process of active surveillance can be quite stressful for some patients and many of these patients are eager to do everything they can to slow the progression of their disease, including making lifestyle changes such as changing their diet and doing physical exercise.
Diet influences the diversity of the microbiota (archaea, bacteria, fungi and viruses) in the gastrointestinal tract. The gut microbiota play crucial functions in metabolic and regulatory processes that impact the body's immunity and disease development. One can increase the consumption of dietary fibre by providing supplements in powder or capsule form, where the dose administered can be controlled. When these dietary fibres are eaten, commensal colonic bacteria ferment them to produce metabolites, including short-chain fatty acids (SCFAs) which can have anti-tumour effects.
This study team and other researchers have reported the effect of the soluble dietary fibre inulin in delaying tumour growth in mice compared to low dietary fibre intake, in a range of tumour types (including bladder and colorectal cancers). Pectin has also been reported to have health benefits such as maintaining the intestinal barrier, improving physical bowel function and reducing glucose and cholesterol absorption. Apple pectin has also been shown to induce apoptosis in colorectal cancer cells.
UK fibre intake at a population level is well below the recommended levels of 30 g per day, with only 9% of adults meeting recommended intakes.
According to a US population-based study, higher fibre intake was inversely associated with prostate cancer aggressiveness and in an intervention study with modified citrus pectin, 78% of men with non-metastatic prostate cancer who had biochemically relapsed responded to therapy: 58% showed decreased PSA and 75% showed improvement in PSA doubling time (p=0.003).
Inulin and pectin are purified soluble fibres from chicory root, citrus, apple and other plants; in contrast, hemp hull is a rich source of whole fibre which also contains bioactive chemicals including flavonoids, proanthocyanidins and phenolic acids. It has been previously reported to have biological activities such as immune-modulating, anti-inflammatory and antineoplastic properties in different cancer cells. Furthermore, hemp hull is a rich source of phytic acid which releases myo-inositol in the human intestine by the activity of microbial phytases. Myoinositol supplementation significantly decreased triglycerides; men with elevated triglycerides might be at increased risk of developing prostate cancer or recurrence following surgery. Therefore, the consumption of whole fibres would bring additional benefits in the prevention of prostate cancer. Preliminary animal studies demonstrated that dietary phytic acid increased the production of microbial short-chain fatty acids (SCFA), including propionate and butyrate, with changes in microbial composition.
Hemp hull is a sustainable fibre source, from a carbon-neutral crop promoting agricultural biodiversity which can help meet dietary fibre intake recommendations. Hemp hulls (obtained after seed decortication) contain 74% fibre which can be milled into hemp hull flour.
Another method to improve tumour control by modifying the gut microbiota, which could be combined with dietary fibre supplementation, is via faecal microbiota transplantation (FMT). This method involves transferring faecal bacteria and other microorganisms from a healthy individual into another person to directly alter the recipient's microbial composition and provide a health benefit. There is increasing interest in the use of FMT for gastrointestinal infections and inflammatory diseases, as well as extraintestinal conditions including autoimmune and metabolic disorders such as cancer, diabetes and non-alcoholic fatty liver disease. In another study, FMT was administered with cancer immunotherapy drugs (nivolumab or pembrolizumab) to mice and enhanced the activity of these drugs in controlling the growth of MCA-205 sarcoma tumours. Also, in a phase I trial, 65% of all patients who received a faecal transplant successfully acquired similarity to the donor microbiomes and experienced an enrichment of immunogenic bacteria and a loss of deleterious bacteria following FMT.
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