Background
Prostate cancer (PCa) is the most prevalent malignant tumor in males, particularly in the United States [
1], significantly impacting public health. In 2022, PCa constituted approximately 27% of newly diagnosed male cancer cases, with its mortality rate ranking second among male cancers [
2]. The incidence of PCa is also rapidly increasing in many Asian countries [
3]. Research has indicated potential influences of various factors on PCa development, including genetics, race, age, local inflammation, and lifestyle habits [
4‐
7]. However, the definitive impact of these factors on PCa pathogenesis remains unconfirmed. Recent studies have highlighted an increasing association between human diseases and microbiota, notably the gut microbiota (GM). Consequently, microbial factors, such as urinary and gut microbiota, are attracting significant interest in their impact on health [
8,
9].
The term 'microbiota' denotes the collection of microorganisms residing in a specific biological environment, including bacteria, viruses, parasites, and fungi [
10]. The mammalian gastrointestinal tract hosts a complex community of trillions of symbiotic entities, such as bacteria, fungi, archaea, and viruses, collectively known as the GM [
11]. Research has linked the GM to various conditions, including diabetes, Alzheimer's disease, and ulcerative colitis [
12‐
15]. Advances in next-generation sequencing technologies have greatly improved our understanding of the GM's composition, for example, through the sequencing of the 16S rRNA gene or its amplicons, based on the variability of small subunit ribosomal RNA sequences [
16,
17]. This has enabled deeper exploration into the GM's relationship with diseases.
The prostate, being relatively distant from the gut, initially left the impact of gut microbiota (GM) on PCa unclear. However, recent studies have uncovered an association between GM and PCa. In 2018, Golombos et al. analyzed the GM of 20 male subjects, noting a higher prevalence of Bacteriodes massiliensis in PCa patients, although GM diversity appeared similar when comparing PCa patients with healthy controls [
18]. In 2022, Fernandes et al. observed differences in the relative abundance of phylum-level bacteria between PCa patients and healthy individuals [
19]. These studies suggest a significant link between GM and PCa, utilizing GM sequencing to analyze PCa patient samples.
Nevertheless, due to varying sample sizes and individual differences, the specific characteristics of GM in PCa patients remain ambiguous. To address this, our meta-analysis was conducted to examine changes in GM composition in PCa patients. This aims to discern GM's role in the etiology and progression of PCa and to explore new preventive and diagnostic methods.
Discussion
Our comprehensive review represents the first meta-analysis examining gut microbiota composition in prostate cancer (PCa) patients. We observed notable variations in the composition of GM between PCa patients and non-PCa individuals. Our results indicated a decline in alpha-diversity of GM in PCa patients compared to the control group. Additionally, significant differences in bacterial relative abundance were evident at the phylum, class, order, family, and genus levels. Specifically, at the phylum level, a higher proportion of Proteobacteria was observed in PCa patients, while the proportions of Actinobacteria, Bacteroidetes, and Firmicutes were comparatively lower. At the genus level, increased abundance of Prevotella, Escherichia-Shigella, Faecalibacterium, and Bacteroides was noted in PCa patients, with a decreased abundance of Veillonella and Megasphaera.
Dysbiosis in the gut is defined as any alteration (increase or decrease) in GM that adversely affects the health of the host organism. Several studies suggest that the diversity of GM is increasingly recognized as a crucial factor in host health. Concurrently, a decrease in microbial diversity has been associated with various gastrointestinal and systemic diseases [
31,
32]. Thus, GM is considered a regulatory factor in human health [
31]. This finding aligns with our research, where a declining trend in gut microbiota was observed in PCa patients. Our studies facilitate exploration into the correlation between PCa and GM, but do not establish a causal relationship. The following factors may contribute to the decrease in gut microbiota α-diversity.
Changes in estrogen levels in humans may contribute to the decline in gut microbial alpha-diversity in patients diagnosed with PCa. Barrett-Connor et al. suggested a potential link between increased estrogen levels in the body and an increased risk associated with the prostate [
33]. Thus, estrogen is considered a potential factor influencing the onset and progression of PCa [
34]. Estrogen can indirectly suppress androgens by inhibiting the hypothalamic luteinizing hormone-releasing hormone (LHRH), reducing the stimulation of the pituitary gland to secrete luteinizing hormone (LH) and thereby constraining PCa progression. Some gut bacteria can metabolize and produce estrogen, known as the estrobolome, affecting the body's estrogen levels [
35]. Normally, conjugated estrogen (glucuronide) produced in the liver cannot bind with estrogen receptors (ER). Gut microbiota can produce beta-glucuronidase to catalyze estrogen from a conjugated form to a dissociated form, which is closely related to human health. Dysbiosis of gut microbiota can impair this process, leading to decreased deconjugation and circulating estrogens, potentially linked with cancer emergence. Furthermore, estrogen might play a role in the progression of PCa, possibly via pathways such as genetic mutation, DNA damage, or chronic inflammation [
36].
The implementation of Androgen Deprivation Therapy (ADT) in patients diagnosed with PCa might be linked to a decrease in the alpha-diversity of GM. ADT, a standard treatment for PCa, aims to control disease progression by suppressing androgen production. Matsushita et al. identified a potential positive correlation between serum testosterone levels and the prevalence of
Firmicutes [
37]. A study involving PCa patients who underwent short-term, medium-term, and long-term ADT found that those receiving long-term ADT had significantly lower GM diversity compared to the other groups. At the phylum level, the abundance of Firmicutes and Bacteroidetes was higher in the long-term ADT group than in the other two subgroups [
38]. Additionally, Sfanos' research, which analyzed the feces of PCa patients undergoing androgen deprivation therapy (ADT), noted an enrichment of bacteria capable of steroid biosynthesis, such as
muciniphila,
Ruminococcaceae, or
Lachnospiraceae, in the GM of these patients. Gut bacteria can also produce androgens from corticosteroids. These studies suggest that GM undergoes changes due to androgen deprivation and serves as a source of androgenic steroids, potentially contributing to resistance against ADT. This aligns with our findings, where
Ruminococcaceae and
Lachnospiraceae are proportionally higher in PCa patients. However, as various bacteria can perform steroid synthesis, further research is needed to identify specific androgenic steroid biosynthetic pathways activated within bacteria [
39]. Therefore, the decline in GM diversity may be attributed to changes in testosterone levels [
40].
Long-term intake of a high-fat diet (HFD) may also contribute to a decrease in the alpha-diversity of GM in patients with PCa. The composition of GM is influenced by various factors, including lifestyle habits, diet, illness conditions, and drug usage, with dietary factors having a particularly significant impact [
41]. The consumption of HFD, dairy products, and processed meats has been confirmed as risk factors for prostate cancer [
42,
43]. A study using a prostate-specific Pten knockout mouse model suggests that a high-fat diet (HFD) promotes prostate cancer growth compared to a control diet, with the effects of the control diet being negated by administering broad-spectrum antibiotics [
44]. Short-chain fatty acids (SCFA) produced by GM can signal through IGF1 on prostate epithelial cells, activating MAPK and PI3K signaling pathways and stimulating prostate tumor growth. Additionally, SCFA produced by gut bacteria may mitigate inflammation by regulating cytokine production (such as IL-10) and promoting regulatory T cell expansion, though the specific mechanisms are not fully understood. Recent research indicates that HFD consumption increases the abundance of anaerobic bacteria and Bacteroides in the gut. HFD can alter GM, increasing the translocation of Gram-negative bacteria into the bloodstream and mesenteric fat tissue through the intestinal mucosa, leading to inflammation [
45]. HFD may also compromise the gut barrier, enhance intestinal permeability, and allow various intestinal metabolites or bacterial components to enter the host's circulation, triggering an inflammatory response. This inflammatory response is a crucial factor in HFD-induced prostate cancer growth, with HFD potentially leading to increased IL-6 expression in prostate tissue and triggering prostate cancer [
46].
Quantitatively analyzed at the phylum level, the GM of PCa and control populations exhibited differences, particularly in
Proteobacteria,
Actinobacteria,
Bacteroidetes, and
Firmicutes. The equilibrium of GM is primarily maintained by these phyla [
47], with
Bacteroidetes and
Firmicutes typically dominating the balance. A reduction in these bacteria often indicates gut dysbiosis, contributing to disease [
48], which aligns with our research findings. Additionally, an increased abundance of
Proteobacteria is considered indicative of GM dysbiosis. While a temporary rise in Proteobacteria in a healthy state may not cause clinical symptoms [
48,
49], a long-term overabundance might reflect microbiota dysbiosis or a diseased state [
48]. The specific relationship between
Proteobacteria and PCa, however, remains unclear and warrants further investigation to explore this connection.
Quantitatively analyzed at the genus level, the gut microbiota (GM) of PCa and control populations show differences, particularly in
Prevotella,
Escherichia-Shigella,
Faecalibacterium,
Bacteroides,
Veillonella, and
Megasphaera. Among these,
Faecalibacterium is a core genus in the human gut. Research indicates that
Faecalibacterium can stimulate the NF-KB pathway and elevate the expression of multiple pro-inflammatory cytokine genes, potentially driving the progression of colorectal cancer [
50]. While a direct link between
Faecalibacterium and PCa has not been established, considering the gut inflammation response as a risk factor for PCa [
46], a connection is plausible. Studies have shown that the abundance of
Prevotella is high in the GM of patients with colorectal cancer [
51]. Interestingly, Prevotella is also abundant in the gut of PCa patients, suggesting a possible connection. However, the specifics of this relationship and its underlying mechanisms remain to be explored, necessitating further research. Although we have conducted a thorough analysis at the phylum and genus levels, the role of GM at the order, class, and family levels in relation to PCa remains unclear. Future studies are required to explore these aspects and deepen our understanding of GM's role in PCa.
Additionally, dietary habits, medical procedures, race, geographic location, and other factors may contribute to the observed differences in diversity and abundance of GM between the PCa population and the control group. In terms of diet, Western-style diets are often associated with an increased risk of PCa compared to Chinese cuisine. However, current research yields inconsistent findings regarding whether the Western-style diet affects PCa risk through the mediation of GM, or through other factors such as metabolism or inflammation in prostate tissue [
52,
53]. Dietary nutrients, including fats, proteins, carbohydrates, vitamins (such as A, D, and E), and polyphenols, may also play a role in preventing PCa by influencing GM, though their specific mechanisms are not yet clear. Geographic variations also influence GM composition; for example, the gut microbiota in Japan exhibits a more abundant
Actinobacteria phylum [
54]. In terms of race, the participants in Alanee's studies were Caucasians [
24], while those in Zhong's studies were Asians [
25]. The diversity of subjects may impact the results, underscoring the need for more research to examine the influence of various factors on GM composition.
Given the presence of treatment-resistant cases in current PCa therapies, the GM offers a potential avenue for the prevention and treatment of prostate cancer. Understanding the intricate relationship between GM and PCa could lead to novel approaches in managing this disease.
Regarding screening potential, the use of serum PSA screening remains controversial due to modest risk reduction, a high rate of false positives, and questions about cost-efficacy at the population level [
55]. Hence, detecting "unfavorable" characteristics in gut microbiota may be incorporated into prostate cancer risk screening. Our research results offer a reference for clinical physicians in this regard.
In terms of therapeutic potential, strategies aimed at transforming the gut microbiota of prostate cancer patients from unfavorable to favorable characteristics may aid in delaying or treating the disease. Various methods, such as fecal microbiota transplantation (FMT), prebiotics, probiotics, or synbiotics, can be used to treat the gut microbiota in prostate cancer. For instance, probiotics have seen wide application in patients with obesity and alcoholic liver disease [
56‐
58]. Our research findings indicate potential bacterial differences between the cancer and control groups, which could guide future researchers in identifying "favorable" or "unfavorable" microbiota. This offers a reference for the development of future microbiota therapies in prostate cancer management.
Strengths and limitations
Our study exhibited several advantages. We maintained strict inclusion criteria, systematically retrieved all relevant studies that meet our predetermined conditions, and adhered to the PRISMA guidelines for reporting systematic reviews and meta-analyses. Additionally, our research included recent matching cohorts, providing an in-depth examination of the diversity and richness of gut microbiota in patients with PCa.
Despite these strengths, our study faced several limitations. 1. The number of articles included was limited, with only seven studies being available for quantitative analysis. 2. High heterogeneity among the included studies could have influenced the results, a common challenge in observational studies [
59], as opposed to randomized controlled trials. 3. The included studies showed significant clinical and methodological heterogeneity, with factors like participant sample size, race, diet, residence, treatment methods, and age impacting GM composition. 4. Variations in DNA extraction methods, sequencing platforms, and sequencing depths used for sequencing the 16S rRNA gene region might have led to inconsistent results. 5. The methods of feces collection, such as stool samples and rectal swabs, also varied, potentially affecting the outcomes. The composition of the control group was not always consistent, and the inclusion of both healthy samples and benign prostatic hyperplasia (BPH) samples might have introduced biases.
Furthermore, our study could not encompass all bacterial strains associated with PCa. While we established a correlation between GM and PCa, this did not definitively imply a causal relationship. Future high-quality studies are required to validate these findings.