logo
ResearchBunny Logo
The gut microbiome-prostate cancer crosstalk is modulated by dietary polyunsaturated long-chain fatty acids

Medicine and Health

The gut microbiome-prostate cancer crosstalk is modulated by dietary polyunsaturated long-chain fatty acids

G. Lachance, K. Robitaille, et al.

This groundbreaking study reveals the crucial role of the gut microbiome in prostate cancer progression and highlights how dietary omega-3 fatty acids can potentially mitigate this impact. Conducted by Gabriel Lachance and colleagues, the research uncovers the fascinating relationship between gut health and cancer growth, offering hope for new therapeutic approaches.

00:00
00:00
Playback language: English
Introduction
Prostate cancer (PCa) is a significant global health concern, and while its progression is often slow, the long-term effects of treatments like radical prostatectomy or radiotherapy can impact quality of life. Dietary factors are known to influence PCa progression, with high saturated fat diets linked to increased risk and omega-3 rich diets showing potential protective effects. The gut microbiota, a complex community of microorganisms residing in the gut, has emerged as a key player in various aspects of health and disease, including cancer. While prior research has highlighted the gut microbiome's influence on PCa response to hormonal treatments, its role in PCa development itself remains relatively unexplored. This study aimed to investigate the correlation between gut microbiota composition and PCa progression in patients without androgen deprivation therapy (ADT), utilizing both human and murine models, to determine whether and how dietary interventions with PUFAs might impact the gut-PCa axis.
Literature Review
A limited number of studies have explored the differences in gut microbiota between healthy individuals and PCa patients. Interestingly, several bacteria sequences found in PCa tissues are also present in stool samples, suggesting a potential link between gut microbes and tumor development. Furthermore, PCa treatments like ADT are known to disrupt the gut microbiome balance. Some studies indicated that ADT can stimulate commensal bacteria to synthesize androgens, potentially fueling castration-resistant prostate cancer (CRPC) development. Conversely, other research has shown that *Akkermansia muciniphila*, a gut bacterium, is enriched in patients treated with abiraterone acetate and may have beneficial effects. While these studies illustrate the role of the gut microbiome in response to PCa treatments, the impact of the gut microbiome on PCa development in patients without ADT remains under-investigated. This study adds to the existing literature by focusing on the relationship between gut microbiota and PCa progression in ADT-naïve patients, examining the potential for dietary intervention to modify this relationship.
Methodology
The study employed a multi-faceted approach involving human and murine models. For the human cohort, fecal samples were collected from two distinct groups of ADT-naïve PCa patients: one group before radical prostatectomy (RP) and another group years after RP, stratified based on PSA levels. 16S rRNA sequencing was used to profile the gut microbiota. In the pre-prostatectomy group, samples were categorized based on tumor volume. In the post-prostatectomy group, samples were categorized based on PSA levels, reflecting disease recurrence and aggressiveness. For the murine models, three syngeneic PCa models (TRAMP-C2, Pten;Rb1⁻⁻, and Pten;Rb1⁺⁺) were used. Fecal samples were collected at different time points to correlate microbiota changes with tumor growth and aggressiveness. Additionally, fecal microbiota transplantation (FMT) experiments were performed using human fecal samples from PCa patients with varying tumor volumes in antibiotic-treated mice, which were then injected with TRAMP-C2 cells to assess the impact of the human microbiota on tumor growth. PICRUSt analysis was utilized to predict microbial functions based on 16S rRNA sequencing data. To assess the impact of dietary intervention, mice were supplemented with different purified monoglyceride (MAG) PUFAs: omega-6 (MAG-AA), omega-3 (MAG-DHA, MAG-EPA), and omega-9 (HOSO) as a control. A human clinical trial sub-cohort that received either MAG-EPA or placebo (HOSO) before prostatectomy provided fecal samples for analysis of Ruminococcaceae levels and short-chain fatty acids (SCFAs). qPCR was performed to validate certain 16S rRNA sequencing results and to quantify the expression of several genes involved in the synthesis of SCFAs. Statistical analysis included various tests to compare groups and assess correlations (e.g., Welch's t-test, Permanova, paired-Wilcoxon test).
Key Findings
The study revealed a significant reduction in fecal microbiota alpha-diversity associated with increased PCa volume and aggressiveness in both human patient cohorts (pre- and post-prostatectomy) and in three distinct murine PCa models. FMT from patients with high PCa volume stimulated PCa growth in mice, demonstrating a microbiota-PCa crosstalk. Analysis of altered metabolic pathways in mouse models identified three enzymes involved in long-chain fatty acid (LCFA) degradation. Dietary supplementation with omega-3 LCFA (MAG-EPA) reduced tumor growth in mice and decreased cancer upgrading in patients before prostatectomy. This was associated with a decrease in fecal Ruminococcaceae levels in both mice and humans. Furthermore, MAG-EPA supplementation specifically reduced fecal butyrate levels in PCa patients. In contrast, increased fecal butyrate levels were observed in patients with early metastatic PCa post-prostatectomy, suggesting a potential link between butyrate and PCa aggressiveness. Overall, the findings highlight common gut microbiome alterations across multiple PCa models, indicating that specific microbes might drive diversity loss and participate in tumor development. Seven KEGG metabolic pathways were commonly altered in all the mouse models of aggressive PCa. This research uncovered a critical link between dietary omega-3 PUFAs, gut microbiota modulation, and PCa progression.
Discussion
This research substantially advances our understanding of the gut microbiome's role in PCa progression and the potential for dietary intervention. The consistent finding of reduced gut microbiota alpha-diversity across multiple models suggests a fundamental connection between microbiome dysbiosis and PCa aggressiveness. The successful FMT experiments highlight a causal link between the microbiota and PCa growth. The identification of three enzymes involved in LCFA metabolism and the effects of omega-3 supplementation underscore the importance of understanding the metabolic interactions between the gut microbiota and PCa. The observation of lower fecal butyrate levels in patients treated with omega-3s and higher levels in patients with aggressive PCa suggests a potential mechanism of action for omega-3s. The study's findings support the notion that dietary interventions, specifically targeting LCFA, may represent a promising approach to modulate the gut microbiome and thereby influence PCa development and progression.
Conclusion
This study demonstrates a significant association between gut microbiota dysbiosis, PCa aggressiveness, and LCFA metabolism. Dietary supplementation with omega-3 PUFAs shows promise in modulating this interaction, reducing tumor growth and cancer upgrading. Future research should focus on identifying specific microbial taxa and metabolites that mediate the omega-3 effects and exploring potential combinational therapies with omega-3 supplementation and other PCa treatments.
Limitations
The study's limitations include the relatively small sample sizes in some cohorts, the use of predominantly 16S rRNA sequencing (limiting detailed functional characterization of the microbiome), and the potential confounding effects of pre-existing factors in human patients. Additionally, the murine models, while useful, do not perfectly replicate the complexity of human PCa. The study focuses primarily on the impact of omega-3s; further research is needed to clarify the roles of other dietary components and their interaction with the gut microbiome in PCa.
Listen, Learn & Level Up
Over 10,000 hours of research content in 25+ fields, available in 12+ languages.
No more digging through PDFs, just hit play and absorb the world's latest research in your language, on your time.
listen to research audio papers with researchbunny